METHIONINE A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES
J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS
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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1
Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Methionine: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-00723-1 1. Methionine-Popular works. I. Title.
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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.
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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on methionine. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.
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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.
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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health
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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON METHIONINE ............................................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Methionine .................................................................................... 5 E-Journals: PubMed Central ....................................................................................................... 66 The National Library of Medicine: PubMed ................................................................................ 75 CHAPTER 2. NUTRITION AND METHIONINE................................................................................. 123 Overview.................................................................................................................................... 123 Finding Nutrition Studies on Methionine................................................................................. 123 Federal Resources on Nutrition ................................................................................................. 126 Additional Web Resources ......................................................................................................... 127 CHAPTER 3. ALTERNATIVE MEDICINE AND METHIONINE .......................................................... 129 Overview.................................................................................................................................... 129 The Combined Health Information Database............................................................................. 129 National Center for Complementary and Alternative Medicine................................................ 130 Additional Web Resources ......................................................................................................... 144 General References ..................................................................................................................... 150 CHAPTER 4. DISSERTATIONS ON METHIONINE ............................................................................ 151 Overview.................................................................................................................................... 151 Dissertations on Methionine...................................................................................................... 151 Keeping Current ........................................................................................................................ 152 CHAPTER 5. PATENTS ON METHIONINE ....................................................................................... 153 Overview.................................................................................................................................... 153 Patents on Methionine............................................................................................................... 153 Patent Applications on Methionine ........................................................................................... 171 Keeping Current ........................................................................................................................ 191 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 195 Overview.................................................................................................................................... 195 NIH Guidelines.......................................................................................................................... 195 NIH Databases........................................................................................................................... 197 Other Commercial Databases..................................................................................................... 199 The Genome Project and Methionine......................................................................................... 199 APPENDIX B. PATIENT RESOURCES ............................................................................................... 205 Overview.................................................................................................................................... 205 Patient Guideline Sources.......................................................................................................... 205 Finding Associations.................................................................................................................. 207 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 209 Overview.................................................................................................................................... 209 Preparation................................................................................................................................. 209 Finding a Local Medical Library................................................................................................ 209 Medical Libraries in the U.S. and Canada ................................................................................. 209 ONLINE GLOSSARIES................................................................................................................ 215 Online Dictionary Directories ................................................................................................... 215 METHIONINE DICTIONARY.................................................................................................... 217 INDEX .............................................................................................................................................. 305
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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with methionine is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about methionine, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to methionine, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on methionine. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to methionine, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on methionine. The Editors
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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.
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CHAPTER 1. STUDIES ON METHIONINE Overview In this chapter, we will show you how to locate peer-reviewed references and studies on methionine.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and methionine, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “methionine” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •
Importance of Amino Acid Supplements for Dialysis Patients Source: For Patients Only. 14(2): 13-14. March-April 2001. Contact: Available from For Patients Only. 18 East 41st Street, New York, NY 10017. (818) 704-5555. Fax (818) 704-6500. Summary: Amino acids are required by everyone, not just people on dialysis, to maintain body tissues and to promote a normal rate of growth. However, amino acids are removed from the blood during dialysis. This article reviews the importance of amino acid supplements for dialysis patients. Amino acids are the building blocks of protein, and amino acid supplements can be thought of as predigested protein. Eggs, milk, cheese, meat, poultry, and fish are considered good quality protein because they provide essential amino acids. Essential amino acids are those that cannot be made in
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sufficient amounts by the body and must be present in the diet. They include L histidine, L isoleucine, L leucine, L lysine, L methionine, L phenylalanine, L threonine, L tryptophan, L tyrosine, and L valine. The author explains why serum albumin levels are measured and why low serum albumin (SA) levels are a concern; dialysis patients with a low SA level have more frequent and longer hospitalizations, and increased incidence of infection as well as a greater risk of dying. Low SA levels have also been independently associated with decreased physical and social functioning or a poor quality of life. The author concludes by describing how amino acid supplements can help patients improve serum albumin levels without increasing the quantity of food eaten or the amounts of liquids ingested each day. Amino acid supplements are available to kidney patients in two forms: Aminess N tablets and Nutramine T powder. 6 references. •
Emerging Cardiac Risk Factors Source: Patient Care. 35(10): 38-40, 43-44,46, 49-50. May 30, 2001. Contact: Available from Medical Economics. 5 Paragon Drive, Montvale, NJ 07645. (800) 432-4570. Fax (201) 573-4956. Summary: Recent findings support the existence of additional cardiac risk factors, traits that might allow better identification of patients who are at risk for a heart attack. This article summarizes the findings regarding four of those risk factors: C reactive protein (CRP), homocysteine, lipoprotein a, and fibrinogen. The research in CRP supports the intriguing theory that, like rheumatoid arthritis, atherosclerosis is an inflammatory disease. A number of prospective studies indicate that as levels of CRP rise, so does the risk of a future myocardial infarction (MI, heart attack) or stroke. The CRP test described in the article is not the same assay used to assess inflammation due to other causes, such as rheumatic disease or acute infection. Homocysteine is generated during metabolism of methionine, an essential amino acid. Research has shown that rises in fasting homocysteine levels increased the likelihood of coronary heart disease (CHD). Ingestion of folate reduces homocysteine levels, regardless of the process responsible for elevations. Although lipoprotein A levels do not fluctuate in response to low density lipoprotein (LDL) and high density lipoprotein (HDL) concentrations, their atherogenic (creating heart disease) effect is blunted with LDL concentrations are reduced. Fibrinogen, a plasma protein, has been implicated in other processes that fuel vascular disease. As with other emerging risk factors, fibrinogen can be brought under control when the traditional risk factors (smoking, weight problems, lack of exercise) are addressed. 2 tables. 21 references.
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Functional Vitamin B12 Deficiency and Alzheimer Disease Source: Neurology. 58: 1395-1399. May 2002. Summary: This article explores the association between Alzheimer's disease (AD) and vitamin B12 deficiency. Moderately elevated total serum homocysteine is associated with an increased risk of atherothrombotic vascular events. Accordingly, serum homocysteine is increased in patients with vascular dementia but is also increased in clinically diagnosed and histologically confirmed AD. It is generally considered that homocysteine accumulation increases the potential for endothelial and neuronal oxidative damage in these diseases. A complementary model of oxidative stress-induced hyperhomocystinemia is proposed by the authors. The hypothesis accounts for several unusual features relating to single-carbon metabolism and AD, including the absence of macrocytic anemia in these patients. It is suggested that cerebral oxidative stress
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augments the oxidation of an intermediate form of vitamin B12 (cob[I]alamin) generated in the methionine synthase reaction, thereby impairing the metabolism of homocysteine. Oxidative stress also compromises the intraneuronal reduction of the vitamin to its metabolically active state. Currently available pharmaceutic forms of vitamin B12 are unlikely to be utilized by neurons under these conditions. Glutathionylcobalamin might be preferable for the treatment of such patients. 3 figures, 32 references. (AA). •
Methotrexate for Inflammatory Bowel Disease: Pharmacology and Preliminary Results Source: Mayo Clinic Proceedings. 71(1): 69-80. January 1996. Summary: This article reviews the limited published experience with methotrexate treatment for inflammatory bowel disease (IBD). The authors examine the proposed anti-inflammatory and immune-modifying mechanism of action and pharmacologic properties of methotrexate, and detail its limiting toxicities. Long-term low-dose methotrexate therapy (25 mg or less once a week) inhibits production of thymidylate, purines, and methionine, and leads to accumulation of adenosine, a potent antiinflammatory substance. These actions inhibit cellular proliferation, decrease formation of antibodies, and decrease production of mediators of inflammation such as interleukins and eicosanoids. Three uncontrolled trials and two controlled trials have demonstrated efficacy of low-dose methotrexate therapy for inducing remission in Crohn's disease and possibly in ulcerative colitis. Methotrexate may also help maintain remission for both diseases. Although methotrexate is generally well tolerated for longterm use at low dose, several serious toxicities potentially limit its use.
Federally Funded Research on Methionine The U.S. Government supports a variety of research studies relating to methionine. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to methionine. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore methionine. The following is typical of the type of information found when searching the CRISP database for methionine:
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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).
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Project Title: A BACTERIAL FACTORY FOR PRODUCTION OF MEMBRANE PROTEINS Principal Investigator & Institution: Laible, Philip D.; None; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2005 Summary: (verbatim from the applicant's abstract) Membranes and the proteins embedded within them compartmentalize specialized machinery that provides the means by which cells and organelles communicate, generate energy, take up nutrients, excrete wastes, transduce signals by transporting metabolites between internal compartments, and build gradients of ions (and other small molecules) which are used to fuel all normal cellular activities in healthy organisms. Structural information for membrane proteins is exceedingly scarce - it is notoriously difficult to purify quantities of native material that are sufficient for crystallization attempts. Today's methods for the overproduction of protein cannot deal with membrane proteins, thus this important class is virtually ignored. In order for significant advances to be made, innovative strategies are needed rather than incremental advances in existing technology. We have exploited the unique physiology of the Rhodobacter species of photosynthetic bacteria to overexpress heterologous proteins, and have recently shown that a human outer membrane protein is expressed and incorporated into induced membranes of this organism. We now propose to develop this system to be a general one for the expression of functional membrane proteins - from any organism - in quantities that are sufficient for biochemical studies and crystallization trials for structure determination. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: A RANDOMIZED, CONTROLLED TRIAL FOR HOMOCYSTEINE Principal Investigator & Institution: Bostom, Andrew G.; Associate Professor of Medicine; Rhode Island Hospital (Providence, Ri) Providence, Ri 029034923 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JAN-2006 Summary: (Adapted from the application) This multicenter, randomized, double-blind controlled clinical trial has been designed to determine whether total homocysteine (tHcy)-lowering treatment with a standard multivitamin augmented by a high dose combination of folic acid, vitamin B12, and vitamin B6, versus treatment with a standard multivitamin devoid of these three B-vitamins, reduces the pooled rate of recurrent and de novo cardiovascular disease outcomes (i.e., pooled occurrence of non-fatal and fatal arteriosclerotic outcomes, including coronary heart, cerebrovascular, and peripheral vascular disease events= primary outcome), among clinically stable renal transplant recipients who have mild to moderately elevated tHcy levels. The basic eligibility criteria are age 35 to 75 years old, functioning renal allograft for greater than six-months with serum creatinine based creatinine clearance greater than 30 mL/min, and a screening random tHcy level greater than12 uM/L. Patients will be stratified based on the presence/absence of clinical CVD, and randomly assigned to treatment with a standard multivitamin containing a high dose combination of folic acid, vitamin B6, and vitamin B12, or an identical multivitamin devoid of these three micronutrients. Randomized patients will also undergo a methionine loading test. All patients will receive standard clinical management for traditional CVD risk factor reduction. The study is designed to recruit 4000 patients (2000 in each group) over a two-year period for 83% power to detect a 25% treatment effect. Follow-up continues until occurrence of de novo or recurrent non-fatal CVD, or death, or a maximum of four-years. Data analysis will be performed on the basis of original randomization (intention to treat)
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using the log-rank test of difference in survival-without-endpoint curves. In the current era of cereal grain flour fortified with physiologic amounts of folic acid, RTRs comprise a patient population particularly well-suited to test the tenable hypothesis that tHcylowering treatment will reduce CVD outcomes, given: a) their persistent excess prevalence of mild hyperhomocysteinemia post-fortification, in contrast, for example, to coronary heart disease patients with normal renal function; b) the demonstrated capability of B-vitamin treatment regimens featuring supraphysiologic amounts of folic acid to successfully "normalize" tHcy levels in RTRs. Furthermore, overall "conditions" in the RTR population (i.e., renal impairment, mild to moderate hyperhomocysteinemia which can be normalized by supraphysiologic dose B-vitamin supplements, and high CVD event rates) are representative of the larger population of patients with chronic renal insufficiency, who are not yet dialysis-dependent. Accordingly, findings from the proposed trial are very likely to be generalizable to the much more sizable population of patients with renal insufficiency progressing to end-stage renal disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ACCESSORY CELLS FOR IMMATURE T LYMPHOCYTES Principal Investigator & Institution: Staerz, Uwe D.; Chairman and Chief Scientific Officer; Institute for Therapeutic Biology 1899 Gaylord St Denver, Co 80206 Timing: Fiscal Year 2004; Project Start 01-FEB-1991; Project End 31-MAR-2009 Summary: (provided by applicant): The focus of this research grant has been the study of cellular interactions that guide T lymphocyte development in the thymus. In our last competitive renewal application (1997), we had argued that to understand positive selection, a natural, i.e. physiological, ligand of positive selection had to be identified. We had hypothesized that this goal could be best achieved, if by design the number of peptide candidates was severely limited. We had therefore proposed to produce a T cell antigen receptor transgenic (TCRtrans+) mouse using a CD8 + cytotoxic T lymphocyte (CTL) cell line that recognized peptides presented on the non-classical MHC class Ib molecule H2-M3 wt. This experimental design was based on the rational that H2-M3 wt MHC molecules preferentially bound peptides carrying a formylated Methionine (fM) in the N-terminal position. We had predicted further that in the thymus an H2-M3 with restricted CTL was selected on endogenous fM-peptides, whose only source were the thirteen genes of the mitochondrial genome. As originally proposed, we established an H2-M3 wt-restricted CTL line (C10.4), identified its cognate fM peptide (AttM), produced a C10.4 TCR transgenic mouse (C10+) and defined its physiological ligand of positive selection as the ND1 fM-peptide (ND1). Having identified the positively selecting and the cognate ligand during the previous funding period, we now present experiments aiming further to analyze how recognition of these ligands is used to guide thymic selection. To be able to control thymocyte recognition events, we have now reduced the complexity of C10+ thymic selection model to a two-cell in vitro thymic selection system, in which cloned lines of thymic epithelial cells (TECs) supported the selection and maturation of double positive (DP) into single positive (SP) thymocytes. We will provide evidence that this C10+ in vitro thymic selection model offers unique opportunities to define how thymic recognition events are translated into the development of T cells. More specifically, we are proposing to investigate how antigen recognition, accessory cell functions, signal delivery and thymocyte maturation states are integrated to guide the selection, maturation and lineage commitment of alpha/betaT lymphocytes in the thymus. Since it has not been established that thymic selection of MHC class II-restricted T lymphocytes fully mimicked that of MHC class I-restricted T
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lymphocytes, we will adapt our in vitro thymic selection model to be used with H-2Ekrestricted AND TCRtrans+ (AND+) T cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ADOHCY HYDROLASE INHIBITORS AS ANTIPARASITIC AGENTS Principal Investigator & Institution: Borchardt, Ronald T.; Solon E. Summerfield Distinguished Profe; Pharmaceutical Chemistry; University of Kansas Lawrence Youngberg Hall Lawrence, Ks 660457563 Timing: Fiscal Year 2003; Project Start 01-DEC-1980; Project End 31-JAN-2007 Summary: (provided by applicant): S-Adenosyl-L-homocysteine (AdoHcy) hydrolase (EC 3 3 1 1) in mammalian cells and certain parasites [e.g., Leishmania, Plasmodium, Trypansoma] plays a key role in controlling the intracellular levels of AdoHcy by catalyzing its metabolism to homocysteine (Hcy) and adenosine (Ado). By controlling intracellular levels of AdoHcy, this enzyme plays a pivotal role in regulating Sadenosyl-L-methionine (AdoMet)-dependent methyltransferases which are crucial for the viability of mammalian cells and parasites (e.g., AdoMet-dependent methyltransferases in parasites are involved in mRNA capping and in trans-splicing). When these biochemical processes are inhibited by elevating intracellular levels of AdoHcy using known inhibitors of human AdoHcy hydrolase, antiparasitic effects were observed in vitro and in vivo. These results suggest that, if specific inhibitors of parasite AdoHcy hydrolases could be designed, they would have clinical potential as antiparasitic agents. Crucial for the clinical success of these compounds would be their lack of inhibitory effects on human AdoHcy hydrolase, thus, minimizing toxic effects to mammalian cells. Recently, our laboratory has cloned and overexpressed AdoHcy hydrolases from Leishmania (L) donovani and Trypansoma (T) cruzi and differences in their binding of NAD + compared to the human enzyme (i.e., the Kd for binding of NAD+ to human AdoHcy hydrolase is 120 nM compared to Kd values of approx 1-2 uM for the parasite enzymes) were observed. These differences in NAD+ affinity explain why 3'-deoxyadenosine (3'- deoxy-Ado) is a potent inhibitor of the L donovani and T cruzi enzymes but it has no effect on the human AdoHcy hydrolase. Based on these important new discoveries, we plan during the next grant period to (i) optimize the structural features of 3'-deoxy-Ado for binding to the NAD+ binding site of L donovani, T cruzi, as well as Plasmodium (P) falciparium, AdoHcy hydrolases, (ii) to elucidate the structural basis for the differences in the binding of NAD + to the human and parasite enzymes, and (iii) to elucidate the relationships of structure, catalytic activity and susceptibility to inhibition and their differences between the human and parasite enzymes. The outcome of this research program should be the identification of specific inhibitors of parasite AdoHcy hydiolases that have clinical potential as antiparasitic agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ALTERED METHIONINE METABOLISM IN ALCOHOLIC LIVER INJURY Principal Investigator & Institution: Lu, Shelly Chi-Loo.; Professor of Medicine; Medicine; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: (Adapted from the Applicant's Abstract): Altered hepatic methionine metabolism and hyperhomocysteinemia are well recognized in alcoholic liver disease
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but the exact mechanisms and pathogenetic consequences are not well defined. The protective mechanisms of SAM in alcoholic liver injury also remain ill defined. We hypothesize that abnormal hepatic methionine metabolism has important pathogenetic consequences in the development of alcoholic liver injury. This hypothesis is based on several novel key findings. First, using the Tsukamoto-French intragastric ethanolfeeding model, we observed a switch in the expression of methionine adenosyltransferase (MAT), the key enzyme that catabolizes methionine to form Sadenosyl-methionine (SAM) in both whole liver and Kupffer cells. In the liver, this was associated with decreased SAM level and global DNA hypomethylation. Second, homocysteine in pathologically relevant concentrations induced the expression of tissue inhibitor of metalloproteinases-4 (TIMP- 1) and a 1(I) procollagen in a hepatic stellate cell line and collagen production in primary cultures of hepatic stellate cells. The current proposal will extend these findings, test several hypotheses and examine the protective mechanisms of SAM. The aims are: 1) examine changes in hepatic methionine metabolism during the development of ethanol-induced liver injury and the effect of SAM treatment - using the intragastric ethanol and high fat feeding, define stagespecific changes in methionine metabolism, examine key enzymes that affect the steady state SAM and homocysteine levels, investigate consequence of these changes and the effect of SAM treatment; 2) define the role of homocysteine in ethanol-induced liver fibrosis -evaluate the effect of homocysteine on markers of fibrogenesis in primary cultures of stellate cells and examine biological markers such as collagen production and proliferation, test the hypothesis that there is increased homocysteine release from hepatocytes of ethanol-fed animals due to abnormalities in methionine metabolism, which can exert paracrine effects on stellate cells to induce fibrogenesis; 3) examine changes in MAT expression and SAM homeostasis in Kupffer cells during the course of ethanol-induced liver injury and the effect of SAM treatment - test the hypothesis that the switch in MAT expression in Kupffer cells may result in lower SAM level and induce TNF expression, examine the effect of SAM treatment on TNF expression in vitro in LPS-stimulated normal Kupffer cells, ex-vivo in Kupffer cells obtained from ethanol-fed animals, and in vivo, investigate the mechanisms of SAM's suppressive effect on TNF expression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AMINO ACID THERAPY FOR HOT FLASHES/POSTMENOPAUSAL WOMEN Principal Investigator & Institution: Guttuso, Thomas J.; Neurology; State University of New York at Buffalo Suite 211 Ub Commons Buffalo, Ny 14228 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Hot flashes affect approximately 75% of postmenopausal women. Although hormone replacement therapy (HRT) is highly effective in reducing hot flashes, long-term HRT is associated with increased rates of breast cancer and heart disease. Safe, effective, and well-tolerated hot flash alternative therapies are needed. We have shown the anticonvulsant gabapentin to be effective in the treatment of hot flashes in postmenopausal women; however, 50% of patients receiving gabapentin reported side effects of sleepiness or dizziness. Gabapentin is known to bind to the alpha2delta subunit of voltage-gated calcium channels (VGCCs) in the central nervous system (CNS). The amino acids L-methionine and L-norleucine also bind to the alpha2delta subunit with high affinity. Recently, we have noted a 75-100% reduction in hot flash frequency among 5 women after initiating either open-label oral L-methionine or L-norleucine therapy. Long-term L-methionine therapy may carry
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increased cardiovascular risks by increasing serum homocysteine levels while Lnorleucine therapy will not increase homocysteine levels. Over the 5-year career development award, the applicant will principally pursue clinical research examining the safety, tolerability, and efficacy of L-norleucine therapy in hot flash treatment. The clinical research will be performed in the University's General Clinical Research Center under the mentorship of Drs. Kieburtz and Guzick. In addition to this clinical work, the applicant will concurrently pursue basic science training in the laboratory of co mentor Dr. Richfield on better elucidating the mechanism of action of L-norleucine therapy in the treatment of hot flashes and on optimizing future hot flash therapies. Direct mentored training will occur throughout the 5-year award. The applicant will participate in one clinical research meeting and one basic science journal club meeting every week. In addition, formal didactic training in epidemiology and neuroscience will occur at the University. The applicant will also attend two didactic training seminars in complementary & alternative medicine at The Osher Institute at Harvard Medical School and at the Duke Center for Integrative Medicine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BIODYNAMICS: SPECTROSCOPY
VIBRATIONAL
ECHO
CORRELATION
Principal Investigator & Institution: Fayer, Michael D.; Chemistry; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2004; Project Start 01-APR-2000; Project End 31-MAR-2008 Summary: Research is proposed to study dynamics and structure of biologically important systems including heme proteins, proteins with multiple metal centers, water in nanoscopic environments, and water-protein interactions in nanoscopic environments. Building on our current work and recent experimental and theoretical advances make possible the application of Vibrational Echo Correlation Spectroscopy, a powerful new approach to the study of these problems. Vibrational echo correlation spectroscopy with full phase information will be used to directly examine the structural degrees of freedom and dynamical interactions of biologically important systems in a manner that is akin to multidimensional NMR. The new research expands our currently successful application of multidimensional vibrational echo methods. Extending work on myoglobin-CO, mutants will be used to unravel structural dynamics throughout the protein. Experiments on hemoglobin-CO will relate the allosteric affect to protein dynamics at the active site and examine the temperature dependence of structural evolution. Cytochrome c mutant M80A, where the axial methionine residue is replaced with an alanine binds both CO and CN-, in the Fe+2 and Fe+3 oxidation states, respectively. This mutant will be studied to address fundamental dynamical differences that occur in the protein when the oxidation state of the heme group is changed. Proteins with multiple Cu centers will be studied. First, hemocyanin will be studied with CO bound at the active site, and insights into the active site protein dynamics gained from studies of hemocyanin will be applied to other binuclear copper proteins such as tyrosinase. The hemocyanin experiments are a precursor to the study of trinuclear Cu proteins such as laccase, ascorbic oxidase, and ceruloplasmin. Multiple azide anions will be bound to these electronically coupled Cu centers to study the dynamics and vibrational mode coupling between the azide ligands. Vibrational echo correlation spectroscopy provides a new type of analytical tool for the study of coupled metal centers that will also be applied to the several multiple metal centers in carbon monoxide dehydrogenasetacetyI-CoA synthase (CODH/ACS). Building on recent fundamentally new studies of water dynamics, the biologically important issue of the
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dynamics of water in nanoscopic environments will be studied. In addition, waterprotein dynamical interactions and water-protein hydrogen bond dynamics in nanoscopic water environments will be examined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BIOINORGANIC COPPER COORDINATION CHEMISTRY Principal Investigator & Institution: Karlin, Kenneth D.; Professor; Chemistry; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 01-APR-1991; Project End 31-MAR-2007 Summary: (provided by applicant): The goal of the proposed research is to further develop fundamental aspects of copper coordination chemistry relevant to its essential role in the biochemical processing of dioxygen (O2) and nitrogen oxides (NOx). Many questions remain concerning copper(I)/O2 interactions, formation of adducts, derived structures and their associated spectrocopy, O-O bond cleavage, and substrate oxidation chemistries. These may also be relevant to situations of oxidative stress, e.g., in neurological disorders such as Alzheimer's or prion diseases. Copper-NOx investigations are relevant to the active site chemistry in nitrous oxide reductase, and the possibly crucial role of copper ion in nitric oxide (.NO) biochemistry, including (cysteine) thiol nitrosylation chemistry, or mediation of nitroxyl (NO-) chemistry and peroxynitrite oxidative stress. The research methods break down into sub-projects, directed along various themes, questions or chemical systems. These include, (1) amplification of basic Cu/O2 chemistry: study sub-millisecond CuI/O2 interactions by Cu(I)/carbon monoxide photochemical triggering, and ligand electronic effects on Cu/O2 binding and hydroxylation, (2) study of Cu-superoxides, (3) mechanistic investigation of Cun/O2 mediated substrate oxidations, including probing dicopper side-on peroxo vs. bis-mu-oxo interconversion, and protonation-reduction of Cu(III)2(O)2 moieties, (4) generation of relevant chemistry with methionine (thioether) type ligands, and O-O cleavage chemistry with Cu(n)-OOR species, (5) modeling of amino-acid modified Cu-protein active-site cofactors, their biogenesis and chemistry, (6) elucidation of copper ion chemistry with.NO, NO-, peroxynitrite, their relationship to Cu/O2 derived species, and study of Cu mediated dentirosylation, i.e., Cu(I) + RSNO, (7) development of O2-chemistry with tricopper Cu3-cluster complexes relevant to copper oxidases, and (8) elaboration of new Cu-sulfide chemistry and N2O reactivity relevant to nitrous oxide reductase. The proposed studies contribute to a broader understanding of copper biochemistry, to protein activation/reduction of O2 and/or NOx, as applied to other metals (i.e., heme or non-heme iron) and disease states. Potential applications include development of enzyme inhibitors and relevant disease therapeutic strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CASPASE ACTIVATION IN APOPTOSIS Principal Investigator & Institution: Joshua-Tor, Leemor; Associate Professor; Cold Spring Harbor Laboratory 1 Bungtown Road Cold Spring Harbor, Ny 11724 Timing: Fiscal Year 2002; Project Start 15-FEB-2002; Project End 31-JAN-2007 Summary: (provided by applicant) Programmed cell death, or apoptosis, plays a crucial role throughout the life of all multicellular organisms. This mechanism allows for the controlled removal of cells during development in sculpturing the body, maintaining body structure and tissue size, and is also used for eliminating damaged or infected cells. Apoptosis has to be a tightly regulated process or else various abnormalities and
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diseases may arise from either too much or too little cell death. These include various developmental defects, neurodegenerative diseases, autoimmune diseases and cancer. Central to this process are a family of cysteine proteases called caspases. Their activation leads to the typical morphological changes that occur during apoptosis and thus their regulation is key for proper control of apoptosis. The objectives of this proposal is to provide the structural framework which will enable us to understand the mechanism by which caspases are activated from their inactive, zymogen form to a fully active enzyme, and how these relate to enzymatic activity and ultimately to cellular function. We will focus specifically on caspase-9 activation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CATALYTIC MECHANISM OF BIOTIN SYNTHASE Principal Investigator & Institution: Jarrett, Joseph T.; Associate Professor; Biochemistry and Biophysics; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2004; Project Start 01-APR-1999; Project End 31-MAR-2008 Summary: (provided by applicant): Biotin is an essential vitamin used as a cofactor in carboxylation reactions central to human metabolism, particularly in enzymes involved in fatty acid biosynthesis, gluconeogenesis, and branched-chain amino acid catabolism. Biotin is biosynthesized in microbes and plants through a four-step pathway that terminates with addition of sulfur and formation of the thiophane ring. This sulfur insertion is an impressive feat of enzyme catalysis that requires removal of two unactivated hydrogen atoms from the substrate dethiobiotin. In E. coli, sulfur insertion is catalyzed by the homodimeric iron-sulfur protein biotin synthase (BS), requires flavodoxin and S-adenosylmethionine (AdoMet), and produces methionine and 5'deoxyadenosine. Collectively these traits indicate that biotin synthase is an AdoMetdependent radical enzyme that catalyzes reductive cleavage of the AdoMet sulfonium to produce 5'-deoxyadenosyl radicals. We have proposed and provided evidence for a mechanism in which AdoMet coordinates a [4Fe-4S] 2+ cluster and subsequent electron transfer into the AdoMet/[4Fe-4S] 2+ cluster complex results in production of a 5'deoxyadenosyl radical. This radical abstracts a hydrogen atom from the substrate, dethiobiotin, generating a substrate carbon radical. The substrate radical is quenched by a sulfur atom from the [2Fe-2S] 2+ cluster, generating 9-mercaptodethiobiotin as a discrete intermediate. A second AdoMet cleavage triggers a similar reaction sequence, leading to formation of the second C-S bond in the product biotin. We have solved the crystal structure of E. coil biotin synthase with substrates bound and the relative positions of the respective reactants strongly supports this mechanistic proposal. Armed with knowledge derived from the structure, along with the expertise we have developed in anaerobic biochemistry, we are poised to test several key aspects of this mechanism. First, we will use the structure as a guide and test the roles of several conserved protein residues in catalysis. Second, we have developed a half-turnover reaction that will allow us to study the formation of 9-mercaptodethiobiotin and the associated iron-sulfur cluster states using stopped-flow and quench-flow kinetic methods. Finally, since the mechanism we propose describes a single turnover that results in destruction of the [2Fe-2S] 2+ cluster, we are examining possible mechanisms for cluster reassembly that facilitate multiple enzyme turnovers in vivo. A detailed knowledge of the chemical requirements for production of 5'-deoxyadenosyl radicals and for controlled utilization of these radicals for substrate activation and biotin formation will contribute to our expanding understanding of the general features common to all radical enzymes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CONTROL OF ARG-2 GENE EXPRESSION IN NEUROSPORA Principal Investigator & Institution: Sachs, Matthew S.; Associate Professor; Environmental and Biomolecular Systems; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 01-MAY-1992; Project End 31-MAY-2006 Summary: (provided by applicant): The goal of this work is to understand how a peptide encoded by an upstream open reading frame (uORF) controls the movement of ribosomes on mRNA and regulates gene expression. The arginine attenuator peptide (AAP) is encoded by a uORF in mRNAs specifying a fungal arginine (Arg) biosynthetic enzyme and reduces gene expression when Arg is high. AAP-mediated regulation is observed in vitro using extracts from fungi and wheat germ. The nascent AAP causes the ribosome to stall in response to Arg. Stalled ribosomes block access to the downstream start coclon that initiates enzyme synthesis. The AAP is a unique eukaryotic peptide because its synthesis can arrest ribosomes involved in both termination and elongation. Its study provides exceptional opportunities to examine central translational processes that are still not understood. It will provide valuable information on events within the ribosome for evaluating the functions of antibiotics that interfere with translation. Since uORFs that control gene expression are found in animals, plants, fungi, viruses and bacteria, the proposed work is directly relevant to understanding these important regulatory elements.In a working model for regulation, the nascent AAP stalls the ribosome by adopting a conformation that, with Arg, interferes with decoding at the ribosomal A site, or with other steps crucial for translation. The proposed studies will test and refine models for AAP-mediated regulation. Specific aims are: 1. Directly examine the regulatory mechanism by (a) establishing whether stalled ribosomes contain the nascent AAP covalently linked to tRNA to determine whether peptidyl transferase activity is blocked, (b) using photocross-linking of the nascent chain to the ribosome to examine conformational changes in the interaction between the nascent AAP and the ribosome in response to Arg, (c) using photocros s-linking of Arg analogs to determine whether Arg interacts with the AAP or with the translational machinery, and (d) determining whether regulation requires only translational components conserved between prokaryotes and eukaryotes. 2. Examine mutations in nonsense-mediated mRNA decay (NMD) for their effects on mRNA stability and AAP-termination codon recognition. NMD mutations eliminate regulation by the uORF-encoded AAP in vivo. 3. Identify additional transacting genes important for translational control by examining mutations in fungi that affect Arg-specific regulation or translation in vivo for their effects on AAP-mediated ribosome stalling in vitro. Cloning and identification of the genes and analysis of their functions should provide a rational explanation of the mutations. 4. Obtain an in-depth understanding of regulatory function by mutational analysis of stalling sites in combination with the use of antibiotics affecting translation and trans-acting mutants affecting regulation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DEVELOPMENT OF NOVEL FLUORINATED AMINO ACIDS Principal Investigator & Institution: Goodman, Mark M.; Professor of Radiology; Radiology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2003; Project Start 05-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): The objective of this research project is to develop [18F]radiotracers that can be used to image brain and systemic tumors in vivo based
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upon amino acid transport with the imaging technique Positron Emission Tomography (PET). Our approach will focus on the development of [18F]cyclobutyl and [18F]branched nonmetabolized amino acids that move across tumor capillaries by carrier-mediated facilitated transport involving either the "L" large-neutral amino acid or "A" alanine amino acid transport systems. Preliminary evaluation of amino acids labeled with positron emitters and which are substrates for the "L" and "A" transport systems have shown excellent potential in clinical oncology for tumor imaging in patients with brain and systemic tumors. The development of this class of radiotracers with optimal imaging properties remains an active area of investigation. Our choice of cyclobutyl and branched nonmetabolized amino acids as suitable radiopharmaceuticals for imaging tumors stems from our preliminary in vitro studies in rat 9L gliosarcoma cells demonstrating that fluorine containing cyclobutyl analogs show high and selective uptake by the type "L" transport system while the fluorine containing (R,S) alpha-amino isobutyric acid (AIB) analogs show high and selective uptake by the type "A" transport system. Secondly, our preliminary in vivo studies in rats with intracranial 9L rat tumor implants displayed high 6:1 tumor to brain ratios for [18F]cyclobutyl nonmetabolized amino acids and even higher 37-100:1 tumor to brain ratios for the [18F]AIB nonmetabolized amino acids. Finally, low uptake of the cyclobutyl analogs in the kidney, lungs and muscle in rats and low uptake of the AIB analogs in lungs and muscle strongly support our proposed studies to evaluate [18F]cyclobutyl/AIB analogs in tumor bearing mice implanted with human derived tumors in order to determine their potential as imaging agents for systemic solid tumors. The Specific Aims of this proposal are: 1) to synthesize nonmetabolized amino acids that have high uptake in human derived tumors and high selectivity for either the "L" large-neutral amino acid or "A" alanine amino acid transport systems; 2) to synthesize the precursors for 18F-labeling and to prepare the corresponding [18F]amino acids for the in vitro and in vivo evaluation studies; 3) to determine the uptake and transport mechanism of the [18F]amino acids in different tumor cell lines with different malignant phenotypes; 4) to determine the biodistribution and metabolic stability of the most promising "L"-type and "A"-type selective amino acids in tumor-bearing mice with human (DU145) prostate tumors, (SKOV3) ovarian tumors, (A549) lung tumors, (EB) colon tumors, (HTB-46) renal tumors, and (MDA MB468) breast tumors. Our hypotheses include: 1) [18F]cyclobutyl and [18F]AIB analogs will demonstrate high selectivity for the "L" and "A" transport systems, respectively in a number of common human tumors and high tumor to normal tissue ratios in vivo; 2) [18F]cyclobutyl and [18F]AIB analogs will provide clinically useful and important information, especially in brain, kidney, and prostate tumors, which cannot be obtained using other currently available imaging modalities including PET imaging with 2-[18F]FDG) or [11C]-methyl]- methionine or by contrast enhanced computed tomography (CT) and magnetic resonance imaging (MRI); 3) [18F]cyclobutyl and [18F]AIB analogs will provide substantial logistical and economic benefits for tumor imaging in a nuclear medicine clinic as compared to [11C]amino acids, due to the [18F] half-life (t1/2=110 min), a large number of doses can be prepared from a single batch production ,the alternative [11C] (t1/2=20 min,) can only provide relatively few doses from each batch production of [11C]amino acid. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DIETARY & GENETIC CONTRIBUTIONS TO INTESTINAL TUMORIGENE Principal Investigator & Institution: Edelmann, Winfried; Associate Professor; Montefiore Medical Center (Bronx, Ny) Bronx, Ny 104672490 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2008
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Summary: (provided by applicant): Project 1 is fundamental to the overall program. In this project, we will develop a matrix of data that defines how the major nutritional and genetic factors responsible for colonic cancer interact to alter intestinal homeostasis and probability of tumor formation. We will use three mouse genetic models: two already established and well characterized by us - the Apc1638 and the Muc2 mouse - and a third under construction, the Msh2G674S mutant mouse. Each of these will be compared to wild-type mice. Each model will be maintained on control AIN76A diet as well as a new western style high risk diet (nwdiet#1) that is sufficient to induce premalignant changes and tumor formation in wild-type mice - a diet high in fat and phosphate, low in calcium, vitamin D, choline, methionine and folate. Additional groups will consist of wild-type mice and each of the genetic models maintained on the nwdiet#1 with calcium and vitamin D reconstituted back to control levels, and for the Apc1638 mice and wild type mice, groups in which each of the other constituents of the nwdiet#1 will be reconstituted individually. The primary endpoint is tumor formation, with detailed, standardized analysis also carried out by the Histopathology Core to evaluate alterations in cell proliferation, apoptosis, lineage specific differentiation, and cell migration. The Genomics Core will perform microarray analysis utilizing RNA from each of four mice in each dietary/genetic group. Microarray analysis of the wild-type mice maintained on the control and nwdiet#1, as well as the nwdiet#1 with each component added back, has already been completed. The arrays are 27,000 member mouse cDNA arrays fabricated by the Albert Einstein Core Microarray facility, and the methodology for generation and analysis of the data has been well-established in our group. These data will be analyzed by the Genomics and the Biostatistics Cores in collaboration, and altered expression of important sequences confirmed through a combination of Real-Time PCR, laser capture microdissection and related methodologies in the Histopathology Core. The data will be fundamental in identifying genes and pathways that are modified by genetic and/or dietary factors in establishing relative risk for tumor formation, and the analysis will be instructed by microarray data bases we have already developed (published and unpublished) that dissect intestinal cell maturation pathways. These data will be highly interactive in interpreting similar data to be generated from biopsies of patients in Project 3. The data will also be integrated with data to be generated by the Genomics Core on genome wide alterations in methylation, to determine the extent to which altered gene expression is dependent upon altered locus methylation, and to identify subsets of genes regulated in this manner. Sequences identified in this Project will be prioritized for application of unique technological resources in the Genomics Core for functional studies, utilizing methods of Imaging of Transcription Sites in situ, and high-throughput Structural Proteomics. Finally, the tissue from the mice in this Project will be banked by the Histopathology Core. The tissues will be distributed to Project 2 for studies on the role of the ?-cateninTcf -- c-myc/cyclin D1/cdk4 -- p21/p27 pathway, and its intersections with machinery of the cell cycle, and investigation of a novel method of regulation of c-myc transcription by nutritional factors. The tissue is also used by the Histopathology Core for the generation of Tissue Arrays. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DIETARY PROTEIN INTAKE AND HUMAN AA METABOLISM Principal Investigator & Institution: Young, Vernon R.; Professor of Nutritional Biochemistry; None; Massachusetts Institute of Technology Room E19-750 Cambridge, Ma 02139 Timing: Fiscal Year 2002; Project Start 01-SEP-1983; Project End 31-MAR-2006
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Summary: This application concerns the dynamic aspects of whole-body acid metabolism in adult humans, with reference to the dietary importance of the nutritionally "dispensable" (non-essential) or "conditionally indispensable" amino acids. Our hypothesis is that, despite a constitutive capacity for de novo synthesis, their cellular availability for tissue/organ protein synthesis and other functions in vivo is determined by the nitrogen and amino acid composition of the diet. We also hypothesize that there is a strict dietary need for a preformed source of alpha-amino nitrogen, additional to that from the indispensable amino acids. A major focus here is on sulfur amino acid (SAA) interrelationships. We hypothesize that dietary cystine is a more efficient source as a glutathione (GSH) precursor than methionine. The SAA aims are: (i) to further explore the interrelationships between methionine and cysteine (or procysteine) intakes on methionine/cyst(e)ine and GSH metabolism in healthy adults, including measurement of isotopic enrichments of plasma homocysteine (hcy)and cystathionine; (ii) to measure rates of GSH synthesis using L-2 5-13C oxothiazolidine-4carboxylic acid (OTZ) as labeled precursor and to use L- 2-13C OTZ as a marker of GSH metabolism; (iii) to study the metabolism of homocysteine, using labeled metaprobes, in relation to SAA intake; (iv) to further refine and improve upon our tracer model of GSH metabolism using measurements of isotopic labeling in glutamyl-cysteine and cysteinyl glycine; (v) to begin to accumulate the data necessary for the eventual construction of a compartmental model of GSH metabolism. With respect to dietary alpha-amino acid nitrogen intake we will (i) use the 24h indicator (13C-leucine) amino acid oxidation technique to evaluate the requirement for a source of alpha-amino N, including an assessment of its role in GSH homeostasis and (ii) use of 15N-homoarginine as a metaprobe for assessing of arginine metabolism. The proposed studies will further establish the quantitative and metabolic role played by the non-specific nitrogen component of the "protein" intake in whole-body protein (nitrogen) and specific amino acid homeostasis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DOCTORAL TRAINING/BIOCHEMISTRY/TRANSSULFURATION ENZYMES Principal Investigator & Institution: Hudson, Andre O.; Biotech Ctr/Agric & Environ; Rutgers the St Univ of Nj New Brunswick Asb Iii New Brunswick, Nj 08901 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): The broad, long-term objective of the project is to understand the structure and function relationship of enzymes that catalyze reactions around cystathione, a central intermediate in the trans-sulfuration pathways that interconvert cysteine and homocysteine. The trans-sulfuration enzymes play important roles in supplying cysteine and methionine for growth and in regulating the homeostasis of these amino acids. Certain genetic diseases in humans, such as homocysteinemia, are caused by mutations in the genes for these enzymes.The specific aim of project is to characterize the enzymatic function and physiological role of a gene encoded by locus At1g33320 of the genetic model plant Arabidopsis thaliana. Based on sequence homology this gene was proposed to encode cystathionine gamma-synthase, a carbonoxygen lyase. However, preliminary evidence suggests that it functions as cystathionine beta-lyase, a carbon-sulfur tyase. This hypothesis will be examined by carrying out in vitro enzyme kinetic experiments, and by examining the function of the enzyme under in vivo conditions using a genetic complementation test. The physiological role of the gene product will also be explored by studying its expression, its subcellular
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localization, and by examining the phenotype resulting from knock-out mutation of the gene. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DOUBLE-BLIND STUDY OF SAME VS ESCITALOPRAM IN MDD Principal Investigator & Institution: Price, Lawrence H.; Professor of Psychiatry; Butler Hospital (Providence, Ri) 345 Blackstone Blvd Providence, Ri 02906 Timing: Fiscal Year 2004; Project Start 15-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Major depressive disorder (MDD) is a common, typically recurrent and disabling disorder, costing the U.S. over $44 billion/year in direct and indirect costs, and with point prevalence rates estimated at 5%-9% for women, and 2%-3% for men. More than one third of patients suffering from MDD appear to use alternative therapies in the U.S. Routinely prescribed in Europe for nearly 30 years and released four years ago in the U.S. as an over-the-counter dietary supplement, s-adenosyl-l-methionine (SAMe) has gained significant popularity as an agent marketed for improving mood and emotional well being. A number of relatively small double-blind studies have shown that parenteral or oral preparations of SAMe, compared with a number of standard tricyclic antidepressants, were generally equally effective, and tended to produce fewer side effects A relatively smaller number of studies have also examined the efficacy of SAMe compared to placebo, with the majority of these studies showing a significant advantage of SAMe over placebo. The recent report of the Southern California Evidence-Based Practice Center for the U.S. Department of Health and Human Services [Agency for Healthcare Research and Quality (AHRQ Publication 2002; http://www.ahrq.gov) ] states that "The results of these studies justify additional randomized clinical trials to evaluate the efficacy and tolerability of SAMe for treatment of depression." No adequately powered placebocontrolled study of SAMe in depression has ever been conducted in the U.S. We therefore propose a five-year, placebo-controlled, two-site study to assess the efficacy and safety of SAMe and of a standard selective serotonin reuptake inhibitor (SSRI), escitalopram in outpatients with MDD. This proposal is a parallel comparison of the efficacy and safety of SAMe, escitalopram, and placebo, with a crossover phase during which non-responders to any of these three treatments receive open-label treatment with the combination of escitalopram and SAMe. It is important to assess the efficacy of this combination therapy because patients frequently self-medicate with SAMe during standard antidepressant treatment. The primary aim of the proposed study is to test the acute antidepressant efficacy and tolerability of both SAMe and escitalopram, each compared to placebo, for the treatment of MDD. Secondary aims are to assess the acute effects of SAMe or escitalopram vs. placebo on remission rates, quality of life, and psychosocial functioning. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DRUG DISCOVERY AGAINST CRYPTOSPORIDIUM PARVUM Principal Investigator & Institution: Keithly, Janet S.; Director of Parasitology Laboratory; Wadsworth Center Empire State Plaza Albany, Ny 12237 Timing: Fiscal Year 2002; Project Start 10-MAR-2001; Project End 31-JAN-2004 Summary: Cryptosporidium parvum causes one of the opportunistic infections (0I) in AIDS patients for which no treatment is yet known. Although many drugs have been tested against this 0I. knowledge about the presence of target enzymes, biosynthetic pathways, and expression or regulation are virtually unknown. Our preliminary
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biochemical, molecular and ultrastructural data indicate that C. parvum has a mitochondrion for generating energy, and that an unusual fusion gene pyruvate: ferredoxin oxidoreductase/cytochrome P450 (PFO/P450) is important for its function. Unexpectedly. this apicomplexan PFO/P450 fusion most closely resembles that of Euglena gracilis. and in both, the C-terminus appears to function in methionine biosynthesis. C. parvum encodes S-adenosyl-methionine synthetase (SAMS) and Sadenosylhomocysteine hydrolase (SAHH). both of which are essential for its plant-like polyamine biosynthetic pathway. These genes appear to be functional since transcripts were detected by RT-PCR both in sporozoites and intracellular stages. Together this discovery suggests energy metabolism and polyamine biosynthesis in C. parvum are interrelated, thus different from that of humans. The long-term goal of this proposal is to determine whether these pathways in C. parvum can serve as a rational target for drug development. The specific aims of this application are: 1. Characterize the C. parvum SAHH, SAMS & PFO/P450 gene structure, transcription and subcellular localization during the life cycle of the parasite. 2. Elucidate the function of SAHH, SAMS, & PFO in vitro using recombinant proteins. 3. Determine whether CpSAHH and CpPFO/P450 can serve as rational targets for drug development by screening specific analogs against C. parvum in vitro and in vivo. Completion of these specific aims will either support or refute our hypothesis that energy metabolism and polyamine biosynthesis in C. parvum are interrelated and sufficiently different from humans to be exploited for chemotherapy. If the pathway is verified as a parasite-specific target, then a major obstacle in the treatment of this OI in AIDS patients will have been overcome. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LEISHMANIA
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Principal Investigator & Institution: Beverley, Stephen M.; Professor; Molecular Microbiology; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2003; Project Start 01-DEC-1984; Project End 31-DEC-2007 Summary: (provided by the applicant): Leishmania are important tropical parasites, causing disease in more than 10 million people worldwide; more than 400 million people are at risk for infection in endemic regions. Currently, there are no vaccines available against leishmaniasis, and the only approved chemotherapies are marginally effective, difficult to administer, and have significant toxicity. An underlying tenet of our work is that improved understanding of key pathways required for parasite virulence and viability may provide opportunities for the development of improved therapies; several of the pathways identified in this project offer good opportunities. Leishmania are pteridine auxotrophs and our studies have revealed a fascinating and unique complexity of pteridine salvage and utilization, involving specific transporters (BT1 and FT1) and reductases (PTR1 and DHFR-TS), and now we plan to study the enzymes that utilize pteridines for the synthesis of key metabolites, determine their role in metabolism, and assess their effect on parasite virulence and survival. Our previous studies revealed for the first time a role for biopterin specifically in parasite differentiation to the infective metacyclic stage, and possibly other pathways relevant to parasite infectivity and virulence. Our aims include: 1) Studies of the Leishmania requirement for tetrahydrobiopterin (H4B) throughout the infectious cycle, and how loss of the broad spectrum pteridine reductase PTR1 leads to elevated virulence in both fly and mammalian hosts. 2) Identification of enzymes that utilize H4B as cofactors and functional dissection of their role in parasite survival and virulence, including studies of a novel aromatic amino acid hydroxylase (AAAH). Significantly, WT Leishmania
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synthesizes catecholamines while aaahknockouts do not, and the role of parasitesynthesized catecholamines in virulence will be sought. 3) Studies of folate metabolic enzymes such as methylene tetrahydrofolate reductase and two isoforms of methionine synthase, which play key roles in intermediary metabolism and additionally may be targets of a new class of antifolates whose action is primarily outside of their ability to inhibit DHFR and PTR1. Powerful genetic and bioinformatic screens will be used to identify new biopterin and folate utilizing enzymes and drug targets in aims 2 and 3. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ENZYMES IN THE CRYSTALLINE STATE Principal Investigator & Institution: Ludwig, Martha L.; Professor; Biophysics Research Division; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2004; Project Start 01-SEP-1977; Project End 31-AUG-2008 Summary: (provided by applicant): The long-term goal is to relate molecular structure to specificity and reactivity in selected enzymes, with an emphasis on enzymes that require vitamin-based cofactors or essential metals. Three of the enzymes to be studied, B12dependent methionine synthase (MetH), methylenetetrahydrofolate reductase (MTHFR), and betaine-homocysteine methyltransferase (BHMT), are key catalysts in the metabolism of one-carbon units and control the cellular and plasma levels of homocysteine and methionine. These metabolites are believed to be important indicators of risk for cardiovascular disease and neural tube defects. High-resolution xray analysis will be the primary tool to examine local and global conformation changes that are fundamental features of catalysis and control in these enzymes. Mutagenesis and biophysical techniques will also be employed to determine how these enzymes exploit conformation changes and how mutation leads to dysfunction. Descriptions of domain rearrangements will be obtained for B12-dependent methionine synthase (MetH), a prototype for complex proteins that undergo large domain movements. In MetH from E. coli, a large enzyme with four ligand binding modules, the B12-binding domain is required to move long distances to interact in turn with homocysteine, methyltetrahydrofolate, and S-adenosylmethionine. Structures of each module were determined earlier; the current goal is to understand how the modules interact and what drives their movements. Impairment of human methionine synthase, an ortholog of the E. coli enzyme, is responsible for many of the manifestations of B12 deficiency. Comparisons will be made with B12-independent methionine synthase, which catalyzes methylation of homocysteine without requiring an intermediate methyl carrier. Structure-function studies of human BHMT, an important enzyme in homocysteine homeostasis in liver, are aimed at understanding the conformation changes that produce ordered binding of substrates. The structure of methylenetetrahydrofolate reductase (MTHFR) from E. coli has been determined as a model for the catalytic module of human MTHFR, an enzyme that lies at a critical branch point in one-carbon metabolism and is allosterically controlled by S-adenosylmethionine. The bacterial model has been used to show how folates protect the activity of MTHFR, thereby lowering homocysteine levels. The larger human enzyme, containing both catalytic and regulatory modules, has now been expressed by our collaborators; structural studies are aimed at understanding the regulatory mechanisms. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ENZYMOLOGY OF HOMOSERINE ACYLATION IN METHIONINE BIOSYNT Principal Investigator & Institution: Born, Timothy L.; Chemistry and Biochemistry; George Mason University Fairfax, Va 220304444 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2006 Summary: (provided by applicant): The methionine biosynthetic pathway, absent in mammals, produces two compounds required for bacterial survival, methionine and Sadenosylmethionine. Disruption of this pathway prevents bacterial growth unless sufficient methionine is obtained from the environment. Therefore, enzymes in this pathway may potentially be targets for novel antibacterial compounds. The first unique step in methionine biosynthesis, acylation of the g-hydroxyl of homoserine, controls flux of homoserine into the pathway. This acylation is catalyzed by one of two enzymes, homoserine transacetylase (HTA) or homoserine transsuccinylase (HTS). The long-term goals of this project are to ascertain whether these enzymes are potential targets for antibacterial agents and to design inhibitors that will function as lead compounds. Initial kinetic characterizations of both enzymes have been reported. In this proposal three specific aims will be pursued. First, the amino acids comprising the Ser-Asp-His catalytic triad of HTA will be identified. This will be accomplished through the combination of sequence alignments, site-directed mutagenesis and steady-state kinetic characterization. Second, the active site residues of HTS, which are different from those of HTA, will be identified. This will be accomplished through a combination of sequence alignment, site-directed mutagenesis, chemical modification, and steady-state kinetic characterization. Third, structural analysis of HTA, HTS, and select mutants will be pursued in an effort to correlate function with structure. All three of these aims directly support the long-term goals of this project. The proposed experiments will be used to train both undergraduate and Master's level students in the area of biochemistry Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: FOLATE, 1-CARBON NUTRIENTS, GENE VARIANTS & COLON CANCER Principal Investigator & Institution: Hunter, David J.; Director; Epidemiology; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 18-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Most of the over twenty epidemiologic studies that have examined the relationship between dietary folate intake and the risk of developing colorectal neoplasms, have reported that higher folate intakes are associated with lower risk. Animal studies, using either carcinogen-induced or genetically engineered rodent models of colorectal cancer, have indicated an inverse relationship between dietary folate and the risk of colorectal cancer. The folate metabolic pathway influences genomic methylation and the supply of nucleotides for DNA synthesis; these can also be influenced by adequacy of supply of vitamins B12, B6, and B2, all co-factors for critical enzymatic reactions in the pathway. The overall long-term objective of our Team is to establish the role of folate and other nutritional contributors to one-carbon metabolism in colorectal cancer by combining animal, mechanistic, human observational studies and clinical trials. We will accomplish this by establishing a Cooperative Specialized Center for the study of Folate, One carbon nutrients, Gene variants and Colorectal cancer. This Center will be a Collaborative Program between Harvard and Tufts Universities in Boston, Dartmouth University in New Hampshire, the International Agency for Research in Cancer and the University of Bergen in Europe, Variagenics Inc. in Boston,
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and the Division of Cancer Prevention and the Center for Cancer Research at the NCI. We are organized into three projects, developmental projects, and two cores. Project 1 will pool data from three large prospective cohort studies with 2,700 expected colorectal cancer cases to establish whether higher intake of folic acid reduces risk of colorectal cancer and examine whether this reduced risk is greater among persons with low methionine intake, low plasma folate, vitamins B12, B6, and B2 levels, consumers of more than one alcoholic beverage per day, and homozygotes for the methylenetetrahydrofolatereductase (MTHFR) C677T polymorphism, and compound heterozygotes for the MTHFR A1298C polymorphism. Project 2 will validate mouse models of colon carcinogenesis as systems to examine modification of risk by folate and other contributors to one-carbon metabolism. Project 3 will assess whether the degree of uracil misincorporation and genomic methylation in peripheral blood lymphocytes and distal colon biopsies represent biomarkers of one-carbon nutrient adequacy and colorectal adenoma risk, using data and samples from two randomized clinical trials of folate supplementation. The projects will be supported by innovative Developmental Projects. In initial Developmental Project 1 transgenic mice with the null allele of MTHFR, and the homologous C677T polymorphism; these mice will be available for incorporation into feeding studies in Project 2. In Developmental Project 2 we will explore five folate-metabolism genes for polymorphisms that influence plasma folate and homocysteine levels. All Projects will be supported by the Administrative and Statistical Core (based at the Harvard School of Public Health), and the Measurement Core (based at the Human Nutrition Research Center at Tufts University). These highly interrelated studies will help integrate epidemiologic and mechanistic observations and help provide a basis for public health recommendations on optimal levels of folate and B vitamin intake. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FOLIC ACID REQUIREMENTS AND ONE CARBON METABOLISM Principal Investigator & Institution: Shane, Barry; Professor and Chair; Nutritional Scis & Toxicology; University of California Berkeley Berkeley, Ca 947205940 Timing: Fiscal Year 2002; Project Start 01-JAN-1990; Project End 31-DEC-2004 Summary: Folylpolyglutamates are coenzymes in, and potential regulators of, a large number of reactions known collectively as one carbon (1-C) metabolism. These reactions which include the metabolic cycles for the synthesis of thymidylate, purines and the amino acids, methionine, serine and glycine, are compartmentalized in the mitochondria and cytosol of cells. This application is for the continuation of a series of studies aimed at investigating the control of the 1-C metabolism in cells and animals, and the role that mitochondrial folate metabolism plays in this process. The new application has five specific aims that are designed to test four hypotheses. The specific aims are: (1) to investigate the interrelationship between mitochondrial and cytosolic 1C metabolism; (2) to study the regulation of 1-C entry and loss from the folate pool via the two compartmental forms of serine hydroxymethyltransferase; (3) to study the heterozygous disruption of the mouse methionine synthase gene and other genes for folate-dependent enzymes on the flux of 1-C units through the various metabolic cycles; (4) to investigate the use of the mouse methionine synthase heterozygous knockout as a model for the pathological and metabolic effects of vitamin B12 deficiency; and (5) to examine the regulation of expression of methionine synthase, methylenetetrahydrofolate reductase and serine hydroxymethyltransferase and to clone and characterize additional other genes of folate-dependent 1-C metabolism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GENE-ENVIRONMENT CARCINOGENESIS
INTERACTION
AND
COLON
Principal Investigator & Institution: Chen, Jia; Community and Preventive Med; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 21-SEP-1998; Project End 31-DEC-2003 Summary: Jia Chen received her Sc.D. in 1994 in the fields of Toxicology and Environmental Engineering from Massachusetts Institute of Technology. Since 1995 she has been working as a Research Associate in Medicine at Harvard Medical School and a Research Fellow at Harvard School of Public Health. She is interested in an academic research career in molecular epidemiology studying genetic susceptibility to cancer. David J. Hunter, MBBS, MPH, ScD, has extensive experience in chronic disease and molecular epidemiology. He has mentored numerous graduate students and postdoctoral fellows; two graduate students he co- supervised are now postdoctoral fellows in the NCI Genetic Epidemiology Program. He is a co-investigator of the Nurses' Health Study I and Health Professionals Follow-Up Study based at Harvard. Dr. Hunter is familiar with the research methods proposed in this project and he will oversee Dr. Chen's research activities and education. Dr. Chen proposes to use the resources of three large well-characterized cohort studies (the Nurses' Health Study I, the Health Professionals Follow-Up Study, and the Physicians Health Study) to prospectively assess gene-nutrient and other gene-environment interactions in the etiology of colorectal adenoma and carcinoma. Specifically, she will assess whether polymorphisms in the alcohol dehydrogenase type 3 (ADH3), cytochrome P450IIE1 (CYP2E1), and methylenetetrahydrofolate reductase (MTHFR) genes are associated with these cancers and whether they modify associations with intake of folate, methionine and alcohol, as well as other potentially carcinogenic or anticarcinogenic nutrients on risk of colon cancer and polyps. In addition, she will modify the existing PCR- RFLP based genotyping methods and adapt more flexible and efficient technologies while maintaining high accuracy. The proposed study would be valuable as positive associations would clearly implicate the substrates of the gene product as environmental carcinogenic exposures, clarifying colon cancer etiology and pointing to preventive dietary and other lifestyle modifications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: METABOLISM
GENETIC
EFFECTS-FOLATE-DEPENDENT
ONE-CARBON
Principal Investigator & Institution: Gregory, Jesse F.; Professor; Food Science & Human Nutrition; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-DEC-2004 Summary: One-carbon (Cl) metabolism consists of the generation of carbon units for use in cellular processes including DNA synthesis, regeneration of methionine (Met) from homocysteine (Hcy), and methylation of many biological compounds. Conditions that impair one-carbon metabolism (e.g. folate deficiency) are associated with elevation in plasma Hcy and increased risk of vascular disease, certain cancers, and neural tube defects. A common mutation of methylene-tetrahydrofolate reductase (MTHFR), known as the "thermolabile" or C677T mutant, has been associated with elevations in plasma IIcy (especially in low folate status), lower plasma folate, altered distribution of erythrocyte folate, potentially increased risk of vascular disease, and decreased risk of colon cancer. The in vivo metabolic effects of the C677T mutation have not been determined directly. Our overall hypothesis is that the rate of acquisition and generation
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of methyl groups from serine (primary source of C1 units) is reduced in individuals homozygous for the C677T mutation, and that the genotypic effect is greatest when folate nutriture is inadequate. We also hypothesize that the rate of folate-dependent synthesis of nucleotides (purines and thymidylate) will be reduced in folate deficiency but may be enhanced by the C677T mutation. The proposed studies will determine nutritional and genetic dependence of the flow of Cl units from serine (Ser) to Met and from Ser to nucleotides. This protocol also will allow measurement of the transsulfuration pathway of Hcy catabolism important in disposal of excess Hcy. Specific aims. To determine: (a) The kinetics by which Ser serves as a donor of Cl units for methyl group synthesis and nucleotide synthesis and the possible degree of impairment caused by the C677T mutation and/or low folate status. (b) The influence of the C677T mutation and folate status on cellular Cl status as reflected by the distribution of folate species in erythrocytes. (C) The influence of the C677T mutation and folate status on homocysteine catabolism. (d) The relative contributions of cytosolic and mitochondrial metabolism in the generation of Cl units for synthesis of methyl groups and nucleotides. (e) The significance of mitochondrial glycine cleavage in generation of Cl units. Protocol: In the main protocol, healthy adequately nourished human subjects (20-30 yr) will be classified by MTHFR genotype, (homozygous control and homozygous mutant). Subjects will be given infusions with 13C-serine as primary precursor initially and following 8-wk dietary depletion of 120 ugld folate to evaluate the effect of nutritional and genotypic effects on Cl kinetics. Two variations of this study will be conducted to determine the relative roles of mitochondrial and cytosolic routes of Cl generation from serine and the role of the mitochondrial glycine cleavage pathway. In total, these studies will yield new functional data regarding the effects of folate deficiency, and the influence of common polymorphism of MTHFR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETICS OF PROSTATE CANCER RISK & AGRESSIVENESS Principal Investigator & Institution: Casey, Graham; Associate; Molecular Medicine; Cleveland Clinic Lerner Col/Med-Cwru Cleveland, Oh 44195 Timing: Fiscal Year 2003; Project Start 12-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): We hypothesize that multiple genes are involved in risk of prostate cancer and tumor aggressiveness and that many of these genetic risk factors will be represented by low penetrance gene mutations, each accounting for a small effect on risk. We propose to build upon two promising areas of our research program concerned with the influence of genes on prostate cancer risk and tumor aggressiveness. We have localized prostate tumor aggressiveness genes to 7q32-q33 and 19q13.1 through whole genome linkage analysis of sib pairs and loss of heterozygosity studies. We have identified a strong candidate, podocalyxin (PODXL), on 7q32-q33 in which in-frame deletions and SNPs independently are associated with markers of tumor aggressiveness. We will also build upon our studies investigating the impact of single nucleotide polymorphisms (SNPs) in candidate genes involved in metabolic pathways involved in prostate growth on prostate cancer risk and tumor aggressiveness. Thus our Specific Aims are: Specific Aim 1: To further characterize candidate prostate tumor aggressiveness loci identified through whole genome linkage analysis. We will determine whether PODXL functions as a prostate tumor aggressiveness gene by developing stable transfectants expressing wild-type or variant-containing PODXL and assessing their effect on in vitro and in vivo growth of prostate cancer cells. We will also determine PODXL expression in prostate tumors by in situ hybridization and immunohistochemical staining using tissue microarrays. We will further pursue the
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identification of the 19q13.1 aggressiveness gene using complementary approaches, including positional cloning methods and use of the public Human Genome Project (HGP) and Celera databases. The relationship between the 19q13.1 candidate gene(s) and prostate tumor aggressiveness will be evaluated by mutation analyses followed by association studies. Candidates will be further evaluated by in situ hybridization and immunohistochemical staining. Specific Aim 2: To determine the impact of single nucleotide polymorphisms (SNPs) in candidate genes on prostate cancer risk and tumor aggressiveness. We will study SNPs in candidate genes involved in 1) vitamin D metabolism (vitamin D receptor, 1-alpha-hydroxylase (CYP27B1) and 24-hydroxylase (CYP24)), 2) insulin-like growth factor signaling (IGFBP-3), 3) folate metabolism (5,10Methylene-tetrahydrofolate reductase (MTHFR) and Methionine Synthase (MTR)), and 4) steroid hormone metabolism (CYP3A7). For SNP association studies, we will employ a fully recruited population consisting of 943 men in 431 families with at least one brother affected with prostate cancer. Epidemiologic and clinical data have been collected, as well as biospecimens and banked DNA. The relationship between these genetic factors and prostate cancer risk and aggressiveness will be statistically evaluated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GONOCOCCAL INFECTION AND GENE EXPRESSION IN FEMALE MICE Principal Investigator & Institution: Jerse, Ann E.; Associate Professor; Henry M. Jackson Fdn for the Adv Mil/Med Rockville, Md 20852 Timing: Fiscal Year 2004; Project Start 01-FEB-1999; Project End 31-MAY-2009 Summary: (provided by applicant): The capacity of N. gonorrhoeae to evade innate defenses in the female genital tract is hypothesized to be multifactorial and complex. Antioxidant factors may protect gonococci from killing by reactive oxygen species produced by phagocytes. Sialyltranferase (Lst) and other factors promote evasion of complement-mediated defenses. Evidence that these factors protect gonococci against evasion of innate host defenses is based primarily on in vitro assays. With the support of the first award, we developed the first reproducible small animal model of gonococcal genital tract infection. This model provides us with a valuable and unique research tool to test gonococcal interactions with host innate defenses. To satisfy the need for in vivo studies on factors hypothesized to contribute to evasion of PMN and complementmediated killing, here we will i.) measure the relative contribution of the known antioxidant defenses of N. gonorrhoeae (catalase, cytochrome C peroxidase, manganese uptake, methionine sulfoxide reductase) in protection from killing by human PMNs and in survival during experimental murine genital tract infection. We will construct single and double mutants in genes hypothesized to directly defend against oxidative stress (kat, ccp, mntC, msrA), and test their capacity to survive opsonophagocytic killing by human and murine PMNs, and to infect normal mice and NADPH oxidase-deficient mice; ii.) define the role of gonococcal sialyltransferase in conferring resistance to opsonophagocytic killing by murine PMNs and in enhancing survival of N. gonorrhoeae in the murine lower genital tract We will determine if Lst-deficient gonococci are more senstive to PMN killing due to increased uptake or the induction of a stronger respiratory burst. We will utilize C3 and C4-deficient mice and NADPHdeficient mice to test predictions made from PMN killing assays, iii.) Determine the basis for the observed increased infectivity of anaerobically grown N. gonorrhoeae for estradiol-treated mice and for increased resistance to the bactericidal activity of normal human serum. We will test mutants in genes that may confer increased survival in vivo
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as identified by DNA microarray technology to see if they are responsible for anaerobically-induced increased infectivity. We will assess the role of anaerobically induced nitrite reductase (AniA) in conferring an advantage in vivo and increased resistance to serum by testing the infectivity of an aniA mutant in mice, and by utilizing AniA-specific antiserum to block interactions between anaerobically grown gonococci and complement. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: H2-M3 RESTRICTED T CELL RESPONSES Principal Investigator & Institution: Pamer, Eric G.; Professor/ Chief, Infectious Diseases; Sloan-Kettering Institute for Cancer Res New York, Ny 100216007 Timing: Fiscal Year 2002; Project Start 15-AUG-2000; Project End 31-MAY-2005 Summary: (Adapted from the Investigator's abstract): MHC class Ib molecules are members of a diverse family of non-polymorphic proteins that present bacterial peptides to cytolytic T lymphocytes (CTL). The murine H2-M3 molecule is an MHC class Ib molecule that binds short, hydrophobic peptides that contain N-formyl methionine at the amino terminus. Murine infection with Listeria monocytogenes, an intracellular bacterium, elicits CTL that recognize bacterial N-formylated peptides complexed with the H2-M3 MHC class Ib molecule. To enable direct identification of H2-M3 restricted T cells during bacterial infection, tetrameric H2-M3 molecules were complexed with one of the N-formylated L. monocytogenes peptides. These studies demonstrated that H2-M3 restricted T cell responses following primary infection occur more rapidly than H2-KDa restricted T cell responses. H2-M3 restricted T cells are cytolytic and secrete gamma-interferon, suggesting they play an important role in bacterial clearance. Interestingly, H2-M3 restricted memory T cell responses are attenuated compared to H2-KDa restricted responses. The specific aims of this application are: 1) To characterize H2-M3 restricted CTL responses in liver and gut of orally infected mice, providing insights into the role of MHC class Ib restricted T cells responses at a mucosal site following the natural route of L. monocytogenes infection; 2) To determine the mechanisms responsible for accelerated H2-M3 restricted T cell responses during primary infection with L. monocytogenes; and 3) To investigate the basis for attenuated H2-M3 restricted memory T cell responses in mice reinfected with L. monocytogenes. The studies proposed in this application will provide an unprecedented view of MHC class Ib restricted T cell responses to bacterial infection and will test the hypotheses that H2-M3 restricted T cells play a prominent role in intestinal immunity and that intestinal bacterial flora can influence pathogen specific T cell repertoires. Additionally, these experiments may provide novel insights into the factors driving in vivo T cell expansion and memory generation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HOMOCYSTEINE AND COAGULATION IN SICKLE CELL DISEASE Principal Investigator & Institution: Balasa, Vinod; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 452293039 Timing: Fiscal Year 2003; Project Start 11-JUL-2003; Project End 31-MAR-2008 Summary: The coagulation system and endothelial cells are believed to contribute to the vascular pathology of sickle cell disease (SCD). Elevated plasma homocysteine (Hcy) is associated with vascular disease and thrombosis in the general population and is believed to induce endothelial cell dysfunction and activate the coagulation system. Patients with SCD exhibit activation of coagulation and an increase in activated
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circulating endothelial cells (CEC). Preliminary data demonstrate that hyperhomocysteinemia (HHcy) is present in 38% of patients with SCD and that a majority (62%) of these individuals have pyridoxine deficiency, compared to race and age-matched controls. It is hypothesized that HHcy is associated with activation of coagulation and CEC in SCD and that a lowering of Hcy with pyridoxine supplementation will reduce this activation. Therefore, the aims of this study are to determine the following in patients with SCD: (1) prevalence of HHcy and its association with vitamin cofactor deficiencies (2) correlation of HHcy with activation of CEC and coagulation (3) responsiveness of HHcy to pyridoxine supplementation (4) correlation of a decrease in Hcy levels with reduction in the activation of CEC and coagulation. The following laboratory determinations will be made in patients with SCD and in race and age-matched controls: fasting and post-methionine load Hcy, levels of red cell folate, serum vitamin B12, pyridoxal 5'-phosphate, the C677T MTHFR genotype; markers of activation of coagulation (prothrombin fragment 1.2, thrombin:antithrombin complexes), and fibrinolysis (plasmin:antiplasmin complexes, D-dimer); enumeration of CECs and the presence of activation markers VCAM-1 and tissue factor on CECs. SCD patients with HHcy will be randomized to receive a 6-week trial of pyridoxine supplementation or placebo and levels of Hcy, pyridoxine, and determination of markers of activation of coagulation and CECs will be repeated. This study is a collaborative trial open to all the sickle cell centers and at least 248 SCD patients and 248 controls will be recruited. Hey levels will be regressed on age in the controls and 95% confidence intervals will be determined. The chi-square statistic will be used to test the difference. Linear regression will be used to determine the relationship between Hcy and the activation markers. Paired t-tests will be used to test the other hypotheses. Pyridoxine supplementation is a simple therapy with the potential to reduce thrombotic complications of sickle cell disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HOMOCYSTEINE, ER STRESS AND ALCOHOLIC LIVER INJURY Principal Investigator & Institution: Kaplowitz, Neil; Chief, Gastroenterology Section; Medicine; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2004; Project Start 01-MAY-2004; Project End 31-MAR-2009 Summary: (provided by applicant): The pathogenesis of alcoholic liver disease (ALD) remains uncertain despite considerable recent progress. We present a new hypothesis which builds upon the known effect of alcohol on homocysteine metabolism by linking this to the ER stress response and consequent fatty liver, necrosis, and apoptosis which we have observed in the intragastric ethanol fed mouse model. Our preliminary results indicate that feeding betaine reverses the hyperhomocysteinemia, ER stress and liver pathology in response to alcohol. Five aims are proposed which build on this hypothesis and preliminary results. First, we will complete a detailed characterization of ethanolinduced ER stress including the cellular and zonal compartmentation alcoholic mouse liver, the effect of ethanol on the susceptibility to ER stress and apoptotic signaling, and the effect of ER stress on susceptibility to TNF. Second, we will attempt to ascertain the contribution of key components of the ER stress response to alcoholic liver disease by exploiting various mice which have gene deletions of specific components of the ER stress response (e.g. SREBP-1, CHOP, caspase 12) or other signaling mechanisms for regulating SREBP (LXRa null mice). Third, we will determine the mechanism of hyperhomocysteinemia in response to ethanol by assessing substrate pool sizes, homocysteine metabolizing enzyme expression and tracer kinetics. These studies will
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allow us to determine that the liver is the major source of homocysteine and whether decreased remethylation and/or transulfuration are primarily responsible for excess homocysteine. Fourth, we will determine the role of homocysteine in ethanol-induced ER stress. We will employ several different strategies to strengthen the evidence for linkage of homocysteine and the ER stress response to ethanol. We will determine if alcoholic liver injury is potentiated by concomitantly raising homocysteine with either excess dietary methionine or guanidinoacetate or use of cystathionine a- synthase +/mice. In addition, we will assess the effect of SAMe feeding on homocysteine, ER stress and liver injury and determine if TNF acts upstream of homocysteine by assessing homocysteine and ER stress in response to ethanol feeding in TNF-R1 null mice. Fifth, we will determine the mechanism of action of betaine feeding in protecting against ethanol by comparing it to taurine, dimethlysulfoniopropriate, and by determining if betaine protects in MAT1A null mice. In addition, we will assess the global effects of betaine feeding on hepatic gene expression to look for clues of alternative effects of betaine which might also contribute to its protective action. We anticipate that we will obtain important new knowledge which can be applied to the prevention and treatment of ALD Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HYPERHOMOCYSTEINEMIA IN ALZHEIMER'S DISEASE Principal Investigator & Institution: Diaz-Arrastia, Ramon R.; Associate Professor; Neurology; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 15-AUG-2001; Project End 31-JUL-2004 Summary: In the past years, two independent case control studies have established a correlation between elevated homocysteine levels and Alzheimer's Disease (AD). Since vitamin supplementation with folic acid, vitamin B12, and pyridoxine can lower homocysteine levels, this association raises the exciting possibility that polyvitamin therapy may decrease the incidence of AD. The goal of this proposal is to obtain pilot data necessary to design a large multicenter trial to determine whether vitamin therapy lowers the risk of AD. We plan to do this through the following specific aims: (a) Determine whether fasting or post-methionine load (PML) are best associated with AD. The published studies analyzed homocysteine levels in fasting or randomly drawn serum samples. Since many patients have elevations in homocysteine levels only after a methionine load, and both fasting and PML hyperhomocysteinemia may be associated with dementia, we will determine whether fasting hyperhomocysteinemia, PML hyperhomocysteinemia, or both, are linked to a higher risk of AD. We will also determine whether plasma levels of S-adenosylhomocysteine (SAH) and Sadenosylmethionine (SAM) are nire sensitive markers of functional hyperhomocysteinemia (b) Determine the relative importance of nutritional and genetic factors as determinants of hyperhomocysteinemia. Elevated homocysteine levels result from a complex interplay of genetic and acquired factors, and the link between hyperhomocysteinemia and AD has so far been reported only in Europeans. In an attempt to determine which of these factors is most important in an ethnically and culturally heterogeneous US population, we will administer a nutritional questionnaire and measure vitamin levels in our patients, as well as determine the allelic frequency of the C677T polymorphism of MTHFR, a major genetic determinant of hyperhomocysteinemia. (c) Determine whether vitamin therapy is effective in lowering homocysteine levels in patients with hyperhomocysteinemia. All subjects will be treated sequentially for 12 weeks first with low dose vitamin supplementation, followed by high-dose vitamin supplementation. The effectiveness, compliance rates, and potential
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side effects of these therapies will be monitored. Each of these specific aims is essential to rationally design a large multicenter trial to determine whether polyvitamin therapy lowers AD risk. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMAGING OF ONCOGENE ACTIVATION Principal Investigator & Institution: Vande Woude, George F.; Director, Bri Basic Research Program; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 14-JUN-2002; Project End 31-MAR-2007 Summary: (provided by applicant): The primary aim of this study is to develop novel molecular imaging methodologies to visualize and measure the expression and activity of tyrosine kinase growth factor receptor in vivo. The Met tyrosine kinase growth factor receptor and its ligand hepatocyte growth factor/scatter factor (HGF/SF), important genes in development, tumorigenicity and metastasis, will serve as a model. We propose to evaluate and image the expression and activity of Met and HGF/SF both at the cellular and organism levels by comparing different imaging modalities (confocal microscopy, MRI, PET and ultrasound) to conventional biochemical analysis. Using imaging techniques with fluorescence and/or luminescence tagged Met and HGF/SF we will directly image and measure the presence of these important molecules in normal tissues and tumors. We will, in parallel, perform direct analysis of Met and HGF/SF in normal and tumor tissue by IP and western blot. We will use this information together with molecular imaging in animal models to evaluate and quantify the efficacy of both standard therapeutics (e.g. drugs, radiation and hormones) and neutralizing antibodies to Met and HGF/SF for potential utilization of imaging technologies in human cancer. Specific Aims: 1. We will measure Met interaction with its ligand (HGF/SF) and its signal transduction substrates at the sub-cellular level using fluorescence tagged proteins. 2. We will develop molecular imaging techniques to determine in animal models, the presence of Met and HGF/SF, using fluorescence tagged proteins in xenograph tumors and in transgenic and "knocked in" animals. These animals models should allow real-time observation of Met mediated tumorigenesis. 3) We will develop non-invasive "indirect" metabolic molecular imaging methodologies for assessing Met activity at the organism level and in tissues as well as during tumor formation. We wiill be measured real-time in vivo using imaging modalities of MRIBOLD, MRS,PET and Doppler ultrasound to assess their diagnostic potential. 4) We will quantify and characterize the combinatorial effect of a variety of Met signal transduction inhibitors in vivo on tumors and metastasis. The effects will be studied in animal models using direct and indirect molecular imaging modalities during therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: IMPACT OF PAH CARCINOGEN-DNA ADDUCTS ON DNA METHYLATION Principal Investigator & Institution: Geacintov, Nicholas E.; Professor; Chemistry; New York University 15 Washington Place New York, Ny 10003 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-JUL-2004 Summary: (provided by applicant) This research will be done primarily in Russia as an extension of NIH grant # R0l CA 20851. The methylation of DNA plays an important role in the control of gene expression in mammalian cells. The enzymes involved in this process are DNA methyltransferases (MTases) which recognize CpG sequences in DNA
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and catalyze the transfer of methyl group from S-adenosyl-L-methionine to form 5methylcytosine. In different types of tumors, aberrant or accidental methylation of CpG islands in the promoter region has been observed for many cancer-related genes resulting in the silencing of their expression. The polycyclic aromatic hydrocarbons (PAR) such as benzo[a]pyrene or dibenzo[a,1]pyrene are ubiquitous environmental pollutants. They are metabolized in vivo to highly genotoxic dihydrodiol epoxides (DE). Furthermore these diol epoxides bind to cellular DNA causing mutations, thus contributing to the initiation of tumorigenesis. The question how MTases function when carcinogen lesions are present in DNA is still open. It is generally assumed that the target cytosine flipping-out-mechanism, first found for HhaI Mtase occurs in the case of all cytosine-C5-DNAMtases from pro- and eukaryotes. Hence, one of the possibilities may be that distortions of DNA produced by bulky carcinogens which favor extrahelical position of cytosine (displacement of bases, bending, and destabilisation of the double helix) should facilitate DNA methylation. The purpose of this project is to reveal the relationship between DNA methylation and carcinogenic DNA modifications such as PAH lesions, taking prokaryotic cytosine-C5-DNA Mtases EcoRII, SssI and HhaI (recognition sites CCA/TGG, CG, and GCGC, respectively) as models. The general hypothesis to test is that PAR DE-modified DNA can be methylated by DNA MTases with different efficiencies as compared to unmodified DNA. Specific aim I is to obtain experimental evidences of base-flipping mechanism for EcoRII and SssI Mtases using kinetic and fluorescence studies of the interaction of these enzymes with 2-aminopurine or 2-pyrimidinone- containing substrates analogs. Specific aim 2 has several components: (i) synthesize a number of stereoisomeric carcinogen-modified substrate analogs of EcoRII, SssI and HhaI Mtases with PAH-guanine and PAH-adenine lesions positioned within the recognition sites of the enzymes, (ii) study PAR-DNA adduct conformations and thermodynamic stabilities, (iii) examine the binding of the adducts to the enzymes, and (iv) investigate the susceptibilities of carcinogen-modified sequences to methylation by the enzymes. The longer range goal of this project is to discover the relationship between the structural features of carcinogen-DNA lesions and the modified DNA sequences, the catalytic mechanisms of DNA methylation, and the susceptibilities of PAH-modified DNA sequences to methylation. The results should provide novel insights into the mechanisms of carcinogenesis associated with the formation of the stereoisomeric PAR diol epoxide-DNA lesions and their impact on biological methylation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INHIBITION OF ANGIOGENESIS BY TNP 470 AND OVALICIN Principal Investigator & Institution: Liu, Jun O.; Professor; Pharmacol & Molecular Sciences; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 05-AUG-1998; Project End 31-MAY-2008 Summary: (provided by applicant): The post-translational processing of initiator methionine during protein synthesis is a universal biological process that is conserved from prokaryotes to eukaryotes. Methionine aminopeptidases are the enzymes catalyzing the removal of initiator methionine. One gene is known in prokaryotes while two genes are known in eukaryotes encoding methionine aminopeptidases. The importance of initiator methionine processing is underscored by the fact that deletion of the methionine aminopeptidase genes in either prokaryotes or eukaryotes is lethal. Of the two methionine aminopeptidase genes in eukaryotes, the type 2 enzyme (MetAP2) has been shown to be the direct target for the fumagillin family of angiogenesis inhibitors, including its analog TNP-470. Work in the past several years has provided
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Methionine
strong evidence that MetAP2 is a physiologically relevant target for TNP-470. It has also been found that inhibition of endothelial cell proliferation by TNP-470 is mediated by the tumor suppressor gene p53. Thus, TNP-470 is capable of activating p53, which induces the expression of p21that is responsible for the cell cycle blockade of endothelial cells. These studies reveal a unique role of MetAP2 in the progression of the endothelial cell cycle. Recently, a novel anticancer drug entering Phase II clinical trial known as bengamide was found to inhibit both MetAP2 and MetAP1 in vitro and to block cell cycle in both G1 and G2/M phase. It is hypothesized that MetAP1 may play a role in the cell cycle at the G2/M phase. The major objective of the current proposal is to further delineate the physiological functions of MetAP1 and MetAP2 employing yeast as a model system and to identify isoform-specific inhibitors for MetAP1 and MetAP2 by high throughput screens. The functions of the different domains in MetAP1 and MetAP2 will be investigated by creating various yeast mutants expressing different domains of these enzymes and determining the phenotypic changes using DNA microarray. The different known activators of p53 will be systematically examined to identify potential mediators of p53 activation by TNP-470. Molecular probes of bengamide will be prepared to confirm its interaction with MetAP1 and MetAP2. High throughput screens will be conducted to identify specific inhibitors for MetAP1 and MetAP2. The newly identified inhibitors for MetAP1 will be employed to assess the physiological role of MetAP1 in the cell cycle progression in the G2/M phase. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION
INTEGRATIVE
NEUROBIOLOGY
OF
CARDIOVASCULAR
Principal Investigator & Institution: Abboud, Francois M.; Edith K. Pearson Professor; Iowa Cardiovascular Center; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-DEC-1976; Project End 31-DEC-2002 Summary: This Program Project renewal focuses on Integrative Neurobiology of Cardiovascular Regulation. It has represented the major scientific emphasis of the Cardiovascular Research Center at Iowa since 1971. The strong cohesive interactions between senior basic scientists and clinical investigators is complemented by innovative directions with the recruitment of outstanding new scientists. The scope extends from work in cellular/molecular biology to integrative neuroscience; from gene transfer in cultured cells to genetically engineered animals; and from studies in isolated systems to mechanistic research in humans. There are five major Projects, each with tightly related interactive Parts. "Central RAS and Cardiovascular Regulation" defines the central action of angiotensin by selective targeting of central nuclei for gene transfer, regulation of gene expression, chemical ablation and cellular electrophysiology. "Modulation of Sensory Inputs by CGRP" is a coordinated effort to explore the activation of trigeminal afferents by nociceptive stimuli and subarachnoid hemorrhage (SAH). Changes in the expression of CGRP may mediate the disabling autonomic responses to pain and the devastating vasospasm in SAH, and hold the promise of therapeutic gene transfer. In "Leptin and Central Autonomic Drive" the focus is on the effect of leptin, at the level of hypothalamus, in transducing the activation of sympathetic pathways. The availability of genetic models of obesity and the convergence of diverse scientific expertise, provide a unique opportunity to clarify the autonomic-leptin interaction, and to extend the work to obese humans. Our experience in the mechanisms of baroceptor activation and new interests in the biology and biophysics of ion channels will be merged on "Cellular/Molecular Mechanism of Mechanosensation and Excitation of Baroreceptor Neurons." Four separate but interrelated Parts will pursue the concepts that
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ENaC/degenerin family members are the BR sensors, and that methionine oxidationreduction is important in the regulation of BR ion channels by autocrine factors. These are novel and important concepts. "Nitrosyl Factors and Neurovascular Control" Extends ongoing work on the interaction between glutamatergic and nitroxidergic neurons in the NTS, which influences the central mediation of the baroreflex often impaired in hypertension and aging. A second Part addresses the novel hypothesis that "preformed stores"of nitrosyl factors, at the neuro-endothelial-vascular interface, represent a major mechanism of regulation of vascular tone. Essential Core functions will support these projects in the areas of "Imaging," "Transgenic Animals," and "VectorMediated Gene Transfer." The tract record of productivity, creative interactions, innovative concepts and state-of-the-art approaches promise the optimal realization of the work whereby the scientific outcome will be far greater than the sum of the components. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LIPOTROPE STIMULATES BREAST CANCER CELL DEATH Principal Investigator & Institution: Park, Chung S.; Professor; Animal and Range Sciences; North Dakota State University Fargo, Nd 581055756 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): Lipotropes (methyl group containing nutrients including choline, methionine, folic acid, and vitamin B12) have been shown to have oncostatic action on mammary cancer. We hypothesize that excess lipotropes may alter expression of apoptosis-related genes including bcl-2 gene, via alterations in DNA methylation, and consequently increase the sensitivity of cancer cells to programmed cell death. Specific aims of the proposed study are: 1) to confirm if excess lipotropes increase the susceptibility of breast cancer cells to apoptosis, 2) to investigate if lipotrope-supplementation alters the expression of certain genes involved in the regulation of apoptosis, and 3) to examine if an excess of lipotropes affects genomic methylation patterns of apoptosis-related genes. Tamoxifen (TAM), an anti-cancer agent, will be used to induce apoptosis in breast cancer cells. Two breast cancer cell lines, MCF-7 and T47D, as well as a normal mammary cell line, MCF-10A, will be tested in this study. Cells will be cultured in preincubation medium until 80 percent confluent and then switched to apoptosis induction media (TAM added) with (treatment) or without (control) excess lipotropes. Apoptosis will be accessed by immunohistochemistry, electrophoretic DNA fragmentation patterns, and caspase assay. Expression of apoptosis-related genes will be elucidated by gene array methodology and Northern analysis. The genomic DNA methylation patterns of apoptosis-related genes will be analyzed by methylation specific PCR and HPLC. Direct molecular and biochemical information on the possible effect of excess lipotropes upon breast cancer cell death could ultimately lead to the development of dietary compounds and chemotherapeutic agents that would reduce and treat breast cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MECHANISM OF BCL-X EXPRESSION IN LYMPHOCYTES AND CANCER Principal Investigator & Institution: Boise, Lawrence H.; Associate Professor; Microbiology and Immunology; University of Miami-Medical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-MAR-2003
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Methionine
Summary: (Adapted from Investigator's abstract): Programmed cell death or apoptosis is a cellular suicide process that is necessary to maintain homeostasis in multicellular organisms. In recent years several genes have been cloned that function to either induce or inhibit apoptosis. Many of these genes share homology with the anti-apoptotic oncogene bcl-2. One of these genes, bcl-xL, can function in a similar fashion as bcl-2, yet displays a different pattern of expression. Specifically in lymphocytes Bcl-2 is expressed at high levels regardless of the activation state of the cell while Bcl-xL is expressed only upon cell activation. In addition, upregulation of bcl-x but not bcl-2 occurs in tumor cells following irradiation or induction of multidrug resistance. The objectives of this proposal are to determine the molecular mechanisms by which bcl-x expression is regulated. Specifically to characterize the bcl-x promoter and determine the cis elements which are involved in regulation of gene expression during lymphocyte activation as well induction of drug resistance in tumor cells. A fragment of genomic DNA which extends 2.7 kb 5' of the start methionine has been isolated. This fragment has two putative TATA boxes within 1 kb of the start ATG. The first specific aim is to determine usage of these TATA boxes by primer extension analysis and RNase protection analysis. Functional analysis will be carried out by subcloning promoter fragments into reporter constructs and determining regions of the promoter required for responsiveness to different activation signals. In addition, the cloned fragment contains a GC rich region that displays differential methylation in drug sensitive and drug resistant cell lines. The final aim of this proposal is to determine the methylation pattern of the bcl-x CpG island by sequencing of sodium bisulfite-treated DNA to reveal methylation sites. The role of methylation of the CpG island on bcl-x expression will be determined by in vitro methylation of reporter constructs. While bcl-x overexpression has not been shown to lead to any specific tumors, it's expression has been demonstrated in several types of tumors including breast, prostrate and the Reed-Sternberg cells of Hodgkin's lymphoma. Understanding the mechanisms by which bcl-x is controlled may result in the development of ways to increase the efficacy of cancer chemotherapy through decreasing the apoptotic threshold of the tumor cell. In addition determination of the methylation state of bcl-x in tumors may be a good indicator of the outcome of cancer chemotherapy of a given tumor. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISTIC STUDIES OF LIPOIC ACID SYNTHASE Principal Investigator & Institution: Booker, Squire J.; Assistant Professor; Biochem and Molecular Biology; Pennsylvania State University-Univ Park 110 Technology Center University Park, Pa 16802 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant): Lipoic acid is an essential sulfur-containing cofactor of several multienzyme complexes that are involved in primary metabolism. It has been known for a number of years to be derived directly from octanoic acid, but the mechanism of sulfur insertion into the unactivated fatty acid has remained obscure. Recently, a gene has been cloned which appears to be the catalytic core of the enzymatic activity that is involved in the sulfur insertion reaction. Signature motifs within its deduced primary sequence and initial spectroscopic characterization of the protein collectively indicate that this "lipoic acid synthase" belongs to an emerging class of enzymes that contain iron-sulfur clusters, and that use S-adenosyl-L-methionine as a means of generating carbon-centered radical intermediates in enzymatic reactions. The roles of S-adenosyl-L-methionine and iron-sulfur clusters in this class of enzymes represent departures from the roles that they have traditionally been assigned in
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biochemical textbooks. Iron-sulfur clusters have traditionally been thought of as electron transfer agents or Lewis acid catalysts, while S-adenosyl-L-methionine is still considered to be mainly a cellular methylating agent. The experiments proposed herein seek to reveal the "new" molecular enzymology associated with these cofactors. Several experimental mechanisms are discussed, and experiments are proposed that will distinguish among them. Aside from the involvement of lipoic acid as a cofactor in enzyme complexes of energy metabolism, it is known to modulate glucose metabolism in patients with type II diabetes and to serve as a general cellular antioxidant, among many other things. There is significant evidence that lipoic acid can be endogenously synthesized in mammalian cells. Experiments outlined in this proposal will lay a foundation upon which studies to address whether the inability to synthesize lipoic acid endogenously can lead to a compromising of cellular function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MECHANISTIC STUDIES ON A CO2+ DEPENDENT MAP FROM E COLI Principal Investigator & Institution: Holz, Richard C.; Associate Professor; Chemistry and Biochemistry; Utah State University 1415 Old Main Hill Logan, Ut 843221415 Timing: Fiscal Year 2002; Project Start 01-JAN-1999; Project End 31-DEC-2002 Summary: Thee long range goals of this research are to define the reaction mechanism and substrate specificity of the cobalt(II)-dependent methionine aminopeptidase from Escherichia coli (MAP). In eukaryotic as well as in prokaryotic cells, methiomine aminopeptidases selectively cleave methionine residues from the N-termini of terminal polypeptide chains. In the cytosol of eukaryotes, all proteins are initiated with an Nterminal methionine. The composition of mature N-termini play important roles in the directed degradation and cellular targeting of proteins involved in signal transduction, protein trafficking, cancer cell growth, and viral infection. Recently, one of the two MAP's found in yeast was shown to be the target of the angiogenic chemotherapeutic agents fumagilln and its analog AGM 1470. Therefore, MAP's appear to play a critical role in the proliferation of endothelial cells and likely serve as important targets for inhibiting the growth and proliferation of tumors. As isolated from several bacterial and mammalian sources, MAPs are maximally stimulated by two g-atoms of Co(II). On the other hand, the addition of Zn(II) or Mg(II) to apo- MAP's do not provide active enzymes. The MAP from E. coli has been shown by X-ray crystallography to contain a dinuclear cobalt(II) active site. Therefore, MAP is a member of a new class of cobaltcontaining enzymes that includes mammalian MAP' isolated from both porcine liver and humans. Our approach will be to utilize the X-ray crystal structures of the MAP's from E. coli and P. furiosus in conjunction with site mutagenesis, biochemical, and spectroscopic methods to gain fingerprints of each step in the catalytic mechanism. The MAP from E. coli is an ideal enzyme for a study of this type because it is small, highly soluble, readily available in large amounts, and is capable of being genetically manipulated. The specific aims of this proposal are to: 1) define the structural and magnetic properties of the dicobalt(II) an diiron(II) MAP enzymes, 2) characterize how substrate analog inhibitors interact with both the dicobalt(II) and diiron(II) MAP enzymes, 3) determine whether the nucleophilic hydroxide moiety, a key element in the proposed peptide bond cleavage mechanism, is coordinated to one or both metal ions in MAP, 4) prepare and purify variant enzymes with altered active site carboxylic acid, histidine, threonine, and tyrosine residues, 5) provide evidence for and propose a detailed mechanism for MAP. It is anticipated that the successful completion of the studies described in this proposal will provide new insights into the hydrolytic reaction
34
Methionine
catalyzed by MAP and will ultimately assist in the design and synthesis of new chemotherapeutic agents targeted specifically to MAP's. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: METABOLISM AND EXCITABILITY IN RODENT HIPPOCAMPUS Principal Investigator & Institution: Williamson, Anne D.; Assistant Professor; Neurosurgery; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-JAN-2007 Summary: (provided by applicant): Both excitatory and inhibitory synaptic transmission rely on the supply of glutamate. Glutamate is synthesized de novo from glucose and also recycled through the glutamate-glutamine cycle between neurons and astrocytes. GABA used for synaptic transmission is also dependent on neuronal-glial cycling as GABA is synthesized from glutamate which can enter interneurons either via uptake or through glutamine. The main goal of this proposal is to test the broad hypothesis that cellular excitability is intimately tied to the status of glutamate-glutamine-GABA cycling and specifically that GABAergic transmission is more sensitive than excitatory transmission to disruption in cycling during periods of sustained neuronal activity because of the added energy-dependent steps needed for the synthesis of GABA. In Specific Aim 1 we will interrupt cycling a several different levels including blockade of the synthetic enzymes of glutamine, glutamate and GABA as well as by blocking glutamine uptake. The effect of these metabolic inhibitors on synaptic inhibition will be examined physiologically. In Specific Aim 2, we will use mass spectometry to measure the changes in the levels of glutamate, glutamine and GABA induced by alterations in neurotransmitter cycling in both the tissue and in the bathing medium to address the time-dependent changes in transmitter levels. In Specific Aim 3 will use 13C isomer spectroscopy to assess the effect of those compounds that cross the blood brain barrier (the GS inhibitor methionine sulfoximine and the glutamine transporter MeAIB) on glutamate-glutamine-GABA cycling in control animals. These experiments should provide important data on the regulation of normal synaptic transmission as well as an understanding of the pathology of a number of neurological disorders where changes in neural energetics have been seen including epilepsy, ALS and Huntington's disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: METHIONINE RECYCLING PATHWAYS IN KLEBSIELLA Principal Investigator & Institution: Lawrence, Jeffrey G.; Biological Sciences; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2006 Summary: (provided by applicant): Sulfur is a critical component of numerous universally-distributed, indispensable biomolecules. In most bacteria, sulfur is assimilated organically into cysteine, which serves as the sulfur donor for all other sulfurbearing molecules in the cell. Methionine is made is a separately controlled process, using cysteine as a sulfur donor. Klebsiella aerogenes is distinct from the related model organism Escherichia coli in employing at least 2 distinct pathways to recycle methionine-bound sulfur back into the cysteine pool. One pathway appears specific in directing reverse transsulfurylation (creating cysteine from methionine), and the likely generates an inorganic sulfur intermediate from methanethiol. Therefore, sulfur amino-acid metabolism in E. coli - used as a model organism for understanding the physiology of numerous organisms by homology - represents remnant metabolism and provides an incomplete view of this universally distributed physiology. These
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recycling pathways may play a role in Klebsiella exploitation of a pathogenic lifestyle, where sulfur may be limiting, and may play significant roles in recycling abundant global pools of organic sulfur compounds. Using genetic and molecular methods, these recycling pathways will be examined. (1) The identified genes for cysteine and methionine biosyntheses will be characterized physically and genetically via insertion mutagenesis, gene knock-out and gene fusion. (2) Insertion mutagenesis will define each methionine recycling pathway genetically. Both enzyme assays and nutritional testing will elucidate the steps of each recycling pathway. (3) Fusions to the lacZ reporter gene will be used to identify global regulatory proteins, and to infer their synergistic modes of action. In this way, characterization of these pathways sheds light on the evolution of complex metabolism, and on the selective forces that lead to gene acquisition, gene loss, and genome change. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: METHIONINE SULFOXIDE REDUCTION, SELENIUM AND AGING Principal Investigator & Institution: Gladyshev, Vadim N.; Biochemistry; University of Nebraska Lincoln Lincoln, Ne 685880430 Timing: Fiscal Year 2003; Project Start 15-JAN-2003; Project End 31-DEC-2007 Summary: (provided by applicant): Methionine sulfoxide (Met(O)) reduction is an essential metabolic pathway that provides protection against oxidative stress and regulates protein function. Met(O) are formed in the presence of reactive oxygen species and are reduced back to methionine by peptide Met(O) reductases. One Met(O) reductase (MsrA) has been known for decades and has recently been shown to regulate lifespan in animals. MsrA, however, is only specific for methionine-S-sulfoxides. The P.I. identified and characterized a second mammalian Met(O) reductase (SelR1) that is specific for methionine-R-sulfoxides. SelR1 is a selenocysteine-contain Jng protein and dietary selenium affects its expression. This raises a possibility that SelR1 may also be involved in delaying the aging process through reduction in levels of Met(O) and that supplementation of diet with selenium may provide means of extending the lifespan of certain segments of the human population. To directly characterize the role of SelR1 in aging, the pathway of Met(O) reduction in mammals will be analyzed with an emphasis on the function of selenoproteinSelR1 and characterization of the lifespan of animals that are either deficient or enriched in SelR1. A combination of biochemical and cell biology approaches and mouse model systems will be used to address the following specific questions (specific aims): 1) What are the properties and reaction mechanisms of SelR1 and its homologs? Three SelR isozymes have been identified in mammals. Wildtype and mutant forms of these proteins will be characterized and their catalytic activities, substrate specificity, metal-binding properties and the ability to complement yeast strains determined; 2) What are the tissue expression patterns, cellular locations and regulation of expression of Met(O) reductases? Hypotheses will be tested that SelR isozymes are located in different cellular compartments and that a single MsrA gene gives rise to two forms of the enzyme. In addition, efficiency of selenocysteine insertion and regulation of SelR1 expression by dietary selenium will be determined; 3) What is the role of SelR in aging? SelR1 knockout mice will generated and the hypothesis tested that these animals are characterized by a reduced lifespan. Transgenic mice overexpressing SelR1 will also be generated to determine whether these animals have increased lifespan. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Methionine
Project Title: METHOD FOR NEONATAL SCREENING FOR HOMOCYSTINURIA Principal Investigator & Institution: Rozzell, James D.; President; Biocatalytics, Inc. Suite 103 Pasadena, Ca 91106 Timing: Fiscal Year 2002; Project Start 01-SEP-1999; Project End 31-JAN-2003 Summary: (Applicant's description) In Phase 1 an enzymatic assay for homocysteine was developed with sensitivity down to concentrations of 10-20 micromolar, well below the range of 50-500 micromolar that is indicative of homocystinuria. The feasibility of a test strip for homocysteine detection was demonstrated using an immobilized form of the enzyme and a colorimetric visualization method, providing results within 20 minutes. In Phase 2, the test strip assay will be perfected for use in the neonatal screening for homocystinuria to replace the flawed Guthrie test, which cannot detect homocysteine. Immobilization of the enzyme will be optimized for loading and activity, and the visualization chemistry will be refined. Stability and shelf life will be evaluated and improved as necessary. Expression of the methionine gamma-lyase gene will be increased to reduce the cost of enzyme. The solution assay will be further developed to make the assay viable for routine blood testing. Enzyme selectivity for homocysteine will be enhanced by directed evolution of existing clones. Sample preparation procedures will be optimized to remove potentially interfering substances in physiological fluids. Sensitivity will be improved 5 to 10 fold using fluorescent substrates, with the goal of precise, reproducible quantitation of homocysteine down to the range of 5-10 micromolar. PROPOSED COMMERCIAL APPLICATION: Neonatal screening assay for homocystinuria; home and doctor's office test strip for measurement of L-methionine and L-homocysteine concentrations in urine or blood. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: METHYLATION EPIDEMIOLOGY
AND
OXIDATION
IN
BREAST
CANCER
Principal Investigator & Institution: Freudenheim, Jo L.; Professor; Social and Preventive Medicine; State University of New York at Buffalo Suite 211 Ub Commons Buffalo, Ny 14228 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2006 Summary: (provided by applicant): There is considerable epidemiologic evidence that alcohol intake is related to risk of breast cancer and that intake of vegetables and fruits may reduce risk. Utilizing an existing case control study, we propose to examine two etiological mechanisms, one-carbon metabolism and/or oxidative stress and breast cancer. Our first aim is to examine the relation of elements related to one-carbon metabolism with risk. We propose a) to investigate genetic variation in enzymes important in one-carbon metabolism (methylene tetrahydrofolate reductase (MTHFR), methionine synthase (MS) and cystathione B-synthase (CBS)) in relation to risk and to investigate interaction of these genetic factors with dietary folate and alcohol with breast cancer risk; b) to investigate the association of dietary folate and alcohol and these genetic factors with total p53 mutations and with particular p53 mutations and c) to investigate the association of dietary folate and alcohol and these genetic factors with hypermethylation of the p16 gene, the BRCA1 gene and the estrogen receptor gene in breast tumors. Our second aim is to examine elements related to oxidative stress and antioxidants with risk. We propose to a) examine the relation of genetic variation in an enzyme important in the control of oxidative balance (manganese superoxide dismutase (MnSOD)) and to examine interactions of this genetic factor with dietary factors both oxidants and antioxidants; and b) to investigate the association between dietary sources
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of oxidants and antioxidants with total and particular p53 mutations. By combining information on intake, genetic susceptibility and tumor characteristics, it will be possible to make clearer inferences about the role of these two mechanisms in breast cancer etiology, with potentially important public health implications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MINORITY PREDOCTORAL FELLOWSHIP PROGRAM Principal Investigator & Institution: Farias, Martin; Integrative Physiology; University of North Texas Hlth Sci Ctr Fort Worth, Tx 761072699 Timing: Fiscal Year 2002; Project Start 12-JUN-2002; Project End 31-JAN-2003 Summary: (provided by applicant): The long term objective of this proposal is to characterize the paracrine environment of the sinoatrial node of the dog. Specifically, we want to understand the actions of enkephalins and nitric oxide on heart rate control. We will use an innovative cardiac microdialysis technique to achieve this objective. We will also employ various agents such as NOS inhibitors and donors plus opioid agonists and antagonists to accomplish the following specific aims. This proposal will test the hypothesis that: MEAP acting on delta II opioid receptors located prejunctionally in the sinoatrial node suppresses vagal bradycardia by interrupting the NOcGMP pathway. 1. We will demonstrate that the delta II opioid receptor subtype is responsible for the vagolytic effect of nodal enkephalins. 2. That the NO-cGMP pathway in the SA node is required for normal vagal function in the dog. 3. That nodal MEAP suppresses vagal function by interrupting the NO-cGMP pathway. 4. That MEAP interrupts the NOcGMP pathway prejunctionally in order to attenuate vagal bradycardia. Information obtained from this work will provide new insights into cardiac pathologies that involve autonomic dysfunction and may allow the creation of innovative therapies to help treat such pathologies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: FUNCTION
MODIFICATION
OF
ALPHA-CRYSTALLIN
CHAPERONE
Principal Investigator & Institution: Abraham, Edathara C.; Professor; Biochem and Molecular Biology; University of Arkansas Med Scis Ltl Rock Little Rock, Ar 72205 Timing: Fiscal Year 2002; Project Start 01-JUN-1996; Project End 31-MAY-2004 Summary: The objective of this proposal is to elucidate the effect of some common posttranslational modifications of alpha-crystallin (alphaA and alphaB) on the molecular chaperone property, i.e., the ability of alpha-crystallin to protect other proteins from denaturation and aggregation. By choosing biologically relevant modifications different domains of alphaA- and alphaB-crystallins will be targeted for in vitro structural modifications which in turn will be correlated with changes in chaperone function. Studying in vitro modification will facilitate the characterization of in vivo modifications that cause a decline in chaperone like property of human alpha-crystallin. This is the first study ever where posttranslational modifications that occur in vivo and that can be inflicted in vitro will be correlated with chaperone activity and chaperonetarget protein binding. The specific aims of this proposal are based on our most recent findings that glycation, oxidation and mixed disulfide formation have inhibitory effects on alpha-crystallin chaperone function and that both aging and diabetes decrease the chaperone property. The following specific aims are hypothesis driven, each designed to test a specific hypothesis: 1) In vitro modifications of calf or young human alphacrystallin by oxidation with H2O2, by glycation with ascorbic acid and fructose, and by
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Methionine
mixed disulfide formation with GSSG will be used to test the hypothesis that such posttranslational modifications will influence the chaperone function as determined by the ability of alpha-crystallin to protect beta- and gamma-crystallin from thermal denaturation and aggregation. In addition, we will study the combined effect of more than one type of modification hoping to show a synergistic effect by two treatments. 2) With both alphaL and alphaH fractions from 1 month to 90 years old human lenses it will be shown whether with increasing age increasing levels of posttranslationally modified alpha-crystallin with altered chaperone function accumulates. 3) Since diabetic lenses are exposed to higher levels of oxidation and glycation than age-matched nondiabetic lenses we will test the possibility that the alpha-crystallin chaperone function is altered even more in diabetic human or rat lenses. 4) We will identify the protein modifications in alphaA- and alphaB-crystallins that will be introduced in vitro or that occur in vivo by mass spectral analysis and correlate with changes in chaperone function including chaperone-target protein binding. These analyses will identify the types of modifications that produce a decrease in the chaperone property. 5) We will investigate the mechanism of the loss of chaperone function due to in vitro modifications or in vivo modifications during aging or diabetes. We will test the hypothesis that posttranslational modifications affect the chaperone-target protein binding leading to reduced chaperone function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR CARCINOGENESIS
MECHANISMS
OF
DIET-INDUCED
Principal Investigator & Institution: Jacob, Samson T.; Professor and Chairman; Molecular & Cellular Biochemistry; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: Epidemiological and clinical studies have demonstrated that folate deficiency in humans could lead to susceptibility to certain types of cancers. Premalignant dysplasia could be reversed by folate supplementation. Elucidation of the molecular mechanisms underlying folate deficiency and predisposition to cancer is, therefore, of critical importance in determining the role of folate and other dietary elements in cancer prevention. An excellent rat model system is available to study the role of diet low in methionine, choline and folate (lipotrope-deficient or LD diet) on the induction of hepatocarcinogenesis in the absence of any exogenous xenobiotic agents. It is known that a key tumor suppressor (p53) gene is methylated in the hepatoma induced by LD diet. Using this model system, we will (a) explore by Bisulfite genomic sequencing and Ms-SNuPe (Methylation- sensitive single nucleotide primer extension) the methylation status of CpG dinucleotides on p53 promoter at different stages of hepatocarcinogenesis (b) investigate the role of methylation of specific CpG dinucleotides in p53 promoter inactivation by transient transfection assay (c) investigate the mechanism of methylation-mediated alteration in chromatin structure and identify the key factors involved in consequent silencing of p53 promoter with progression of tumorigenesis, by restriction endonuclease accessibility assay and chromatin immunoprecipitation (ChIP) with antibodies specific to methyl CpG binding proteins (MeCPs) (d) study the regulation of expression and activity of different DNA methyltransferase isozymes (involved in maintenance and de novo methylation) during hepatocarcinogenesis induced by LD diet (e) identify the proteins that interact with de novo methylases (f) clone the genes, specifically the three genes that are methylated in preneoplastic liver as detected by RLGS technique, identify them, investigate their expression levels at
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different stages of tumorigenesis and study functional significance of silencing of these genes in tumorigenesis. It is hoped that this study will yield important information concerning the relationship of folate/methyl deficiency to regional hypermethylation of growth/tumor suppressor genes or genes encoding proteins that suppress the growth regulatory genes at different stages of tumorigenesis, and their silencing that lead to tumor formation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CANCER
MOLECULAR-NUTRIENT
INTERACTIONS
IN
INTESTINAL
Principal Investigator & Institution: Augenlicht, Leonard H.; Professor and Director; Montefiore Medical Center (Bronx, Ny) Bronx, Ny 104672490 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): This application is submitted by the New York Colon Cancer Study Group (NYCCSG) investigators who have been exceptionally successful, individually and in collaboration, in studying genetic/molecular and dietary factors, and their interaction, in the development of intestinal cancer. This application brings powerful technologies at the Albert Einstein/Montefiore Cancer Center, the Strang Cancer Prevention Center at Rockefeller University, and the University of Nebraska School of Medicine, to the question of how a Western-style diet that mimics the major risk factors for colon cancer - high in fat and phosphate, low in calcium, vitamin D, choline, methionine, folate and fiber - interacts with genetic factors to increase probability of tumor formation in the intestinal tract. In project 1, novel mouse genetic models of intestinal cancer made at Einstein/Montefiore, including the Apc1636+/- mouse, the Muc2-/- mouse and a new mouse model with a point mutation that mimics a true human pathogenic allele, the Msh2G674S mouse, will be studied for modulation of cell maturation and tumor formation by the Western-style diet and the effects of partial reversal with calcium and vitamin D3. For the Apc1638 mouse, this will be extended to understanding the contribution of each component of the diet. Microarray analysis, utilizing a 27,000 member cDNA array, will establish a matrix of data, which defines the contributions of each dietary and each genetic component to the response, the underlying mechanisms, and how they interact on a molecular level. In Project 2, tissues from Project 1 will be utilized to specifically determine how the genetic and dietary factors, alone and in combination, recruit and modulate the b-catenin-Tcf -c-myc/cyclinD1 -- cdk4/p21/p27 pathway, and Augenlicht, L related signaling and cell cycle machinery. Moreover, we will extend our analysis of the utilization, as well as mechanisms, of a block to c-myc transcription, which may be a key to how some nutritional factors can modulate tumor formation. This will make use of novel transcriptional imaging methods developed at Einstein and used by collaborating investigators in this Program. Project 3 extends the work of Projects 1 and 2 to human subjects, who will be maintained in the Rockefeller General Clinical Research Center (GCRC) and fed diets in which defined components (e.g., calcium and vitamin D3) are modulated. Biopsies taken during, and at completion of cross-over design studies will permit us to dissect how specific dietary components modulate intestinal cell maturation, biomarkers and profiles of gene expression, and how this relates to the alterations by similar dietary components in the mouse models, and to extensive gene expression data bases we have already developed that dissect cell maturation pathways in colonic cells. The four cores are Administration, Histopathology, Genomics, and Biostatistics. The Histopathology Core has extensive experience and standardized methodologies, and also incorporates laser capture microdissection, Real-Time PCR
40
Methionine
analysis, and tissue arrays. The Genomics Core capitalizes on the Einstein Microarray Facility, which is at the forefront of development and implementation of methods of gene expression profiling, and the extensive experience the facility, and members of this program have with such analyses. Moreover, this Core also includes sophisticated and novel methodology for analysis of locus specific and genome wide DNA methylation, transcriptional imaging of multiple genes simultaneously in situ, and high-throughput structural proteomics for determination of three dimensional structure of sequences with particularly interesting profiles of expression, but of currently unknown function. The Biostatistics Core at the North Shore University Hospital has already participated with members of this program on another National Cancer Institute (NCI) supported program that makes extensive use of microarray analysis of gene expression. Finally, a Pilot Project Program will provide new technologies to the Cores and new projects to supplement those proposed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MTHFR POLYMORPHISMS IN PANCREATIC CANCER IN SF BAY AREA Principal Investigator & Institution: Holly, Elizabeth A.; Professor; Epidemiology and Biostatistics; University of California San Francisco 3333 California Street, Suite 315 San Francisco, Ca 941430962 Timing: Fiscal Year 2002; Project Start 03-JAN-2001; Project End 31-DEC-2003 Summary: The capacity for DNA repair is essential to maintain both genetic integrity and normal cellular function and to control abnormal cell growth. Folate is required for biosynthesis of oligonucleotides needed for DNA repair mechanisms and inadequate folate has been associated with human cancer. The methylenetetrahydrofolate reductase (MTHFR) enzyme is critical in the regulation of folate and methionine metabolism. Because folate is important in DNA synthesis, repair and methylation, it may play a role in cancer prevention and recent evidence suggests that this is the case. The overall goal of this study is to determine whether the prevalence of the C677T and A1298C polymorphisms in the MTHTR gene differs between pancreatic cancer patients and control subjects. DNA will be examined from 334 cases and 966 control participants who had blood drawn in the large population-based case-control study that included 550 pancreatic cancer patients and 1600 controls. All genetic testing will be done using the UCSF Comprehensive Cancer Center Genome Core facilities and laboratory personnel. Data analyses for the variables collected in the interviews in the large study and for the MTHFR genetic component also will be completed variables collected in the interviews in the large study and for the MTHFR genetic component also will be completed under the proposed work. The specific aims are to: 1) identify and compare the incidence of MTHFR C677T and A1298C polymorphisms in pancreatic cancer patients and control subjects; 2) evaluate the relationships between MTHFR polymorphisms and other exposures that also may be related to risk for pancreatic cancer such as dietary folate, smoking and alcohol consumption; and 3) perform analyses of other dietary factors and other data collected in the parent study. Data will be analyzed using stratification and multiple logistic regression for all risk factors that could potentially confound or modify the association between the MTHFR polymorphisms and pancreatic cancer such as dietary folate, smoking and alcohol consumption. Data from other risk factors also will be analyzed. While a relationship between low serum folate and risk for pancreatic has been reported there is no data to describe polymorphisms in MTHFR genes among pancreatic cancer patients and control subjects. These questionnaire- and genetics-based
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analyses will provide new and provocative data of public health importance for this devastating disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MYELOPEROXIDASE VASCULATURE
AND
NO
SIGNALING
IN
THE
Principal Investigator & Institution: White, C Roger.; Associate Professor; Medicine; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 20-AUG-2001; Project End 31-JUL-2005 Summary: (provided by the applicant): The heme protein myeloperoxidase (MPO) plays an important role in the host defense response. Myeloperoxidase catalyzes the addition of chloride to hydrogen peroxide, resulting in the formation of the chlorinating species hypochlorous acid (HOCI) Hypochlorous acid reacts avidly with numerous cellular targets including thiols, amines, nucleotides and unsaturated fatty acids. Recent evidence suggests that MPO and HOCI contribute to the pathogenesis of cardiovascular disease. In this application, we present data suggesting that MPO-derived HOCI contributes to the development of endothelial dysfunction by reducing nitric oxide (NO) bioavailability. MPO effectively binds to the arterial wall and is associated with a significant increase in tissue enzymatic activity. Results of in vitro studies showed that MPO-derived HOCI impairs acetylcholine-induced relaxation but does not affect relaxation induced by an NO donor. These data suggest that the endothelium is a target of MPO-dependent injury. HOCI mediates the inhibitory effects of MPO since endothelial dysfunction could be prevented by addition of the HOC scavenger Lmethionine. There are several components of the endothelial NO synthetic pathway that may be modified by HOCI including NO synthase (NOS III) activity, L-arginine substrate and NOS Ill-dependent cofactors. In this proposal, we will identify mechanisms underlying the inhibitory effects of MPO-derived HOCI on NO bioavailability by 1) defining the effects of MPO on endothelial NO signaling processes; 2) characterizing the role of L-arginine derived N-chloramines in MPO-dependent endothelial cell injury; and 3) by determining whether inhibitors of MPO prevent endothelial dysfunction in a rodent model of ischemia-reperfusion. The HOCIdependent modification of L-arginine may represent a common pathogenic mechanism underlying endothelial dysfunction in diverse cardiovascular diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEW AMINO ACIDS FOR PROTEIN ENGINEERING Principal Investigator & Institution: Tirrell, David A.; Professor; None; California Institute of Technology Mail Code 201-15 Pasadena, Ca 91125 Timing: Fiscal Year 2002; Project Start 01-JAN-2001; Project End 31-DEC-2003 Summary: Protein engineering is a powerful tool for design if novel liquid crystal phases, macromolecular surface arrays, reversible hydrogels, and artificial extracellular matrices for use in tissue regeneration and repair. In vivo microbial expression of artificial genes provides a means of preparing such non-natural proteins in high yields. The target structure is encoded into an artificial gene, and the gene is expressed in an appropriate microbial host. However, in vivo protein engineering poses a challenge in that the pool of potential monomers is restricted to the natural proteinogenic amino acids and those analogs that can be activated and charged to transfer RNAs. Tirrell and others have successfully incorporated analogs of methionine, isoleucine, leucine, and phenylalanine through the action of their respective aminoacyl-tRNA synthases.
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Methionine
Analogs with olefinic and acetylenic functional groups have been shown to serve as methionine surrogates in bacterial protein synthesis. Incorporation of such functional groups creates important new opportunities for chemical derivatization, extending the range of materials properties that can be designed into protein-based polymers. For example, recent advances in the chemistry of olefin metathesis have led to the development of transition metal carbenes that catalyze efficient cyclization of peptides containing olefinic side chains. The objective of this proposal is to combine fast computational analog screening methods and experiments - both in vivo and in vitro to find new amino acids for use in protein engineering. This collaboration will lead to fast and efficient discovery of non-natural amino acid analogs with new and useful functionality and will provide a basis for building novel protein-like polymers with desired properties. The computational methods to be used here have already been tested for design of analogs for phenylalanine and will be extended to new substrates for Phe, Met, Ile, Leu, and Val tRNA synthetases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NITROUS OXIDE AND WOUND INFECTIONS Principal Investigator & Institution: Sessler, Daniel I.; None; University of Louisville Jouett Hall, Belknap Campus Louisville, Ky 40292 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2007 Summary: (provided by applicant): Nitrous oxide remains the most commonly used anesthetic and has been given to several billion patients. In vitro, even brief exposure to nitrous oxide inactivates methionine synthetase, which reduces induction of enzymes required for immune function. Nitrous oxide also reduces chemotactic migration by monocytes. However, nitrous oxide improves neutrophil chemotaxis and facilitates oxygen radical formation, and may therefore augment the efficacy of oxidative killing by neutrophils - the primary defense against pathogenic bacteria. Preliminary results in 200 patients suggest that the beneficial effects of nitrous oxide on wound healing outweigh its toxicities. We will thus test the hypothesis that the incidence of postoperative wound infection will be less in patients given 60% nitrous oxide than in those given 60% nitrogen during elective colon surgery. We propose to study up to 1000 patients undergoing elective colon resection. Perioperative antibiotic, anesthetic, fluid, and oxygen management will be set by protocol. Patients will be anesthetized with isoflurane in 40% inspired oxygen, with the remaining ventilatory mixture randomly assigned as nitrous oxide or nitrogen. Surgical wounds will be evaluated daily by a physician blinded to group assignment. Wounds will be considered infected when they meet CDC criteria or pus is detected and they are culture-positive for pathogenic bacteria. As a secondary outcome, incidence of nosocomial pneumonia in the two groups will be determined. Results will be analyzed by Fisher Exact and unpaired, twotailed t-tests; P < 0.05 will be considered statistically significant. We anticipate showing that substituting nitrous oxide for nitrogen reduces the incidence of surgical wound infection. Confirming our hypothesis would thus allow clinicians to make a minor modification in anesthetic practice that might reduce the incidence of a complication responsible for considerable perioperative morbidity and cost. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NOVEL ANTIMICROBIAL AGENTS AGAINST M. TUBERCULOSIS Principal Investigator & Institution: Horwitz, Marcus A.; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024
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Timing: Fiscal Year 2004; Project Start 15-JUL-2004; Project End 31-OCT-2008 Summary: (provided by applicant): M. tuberculosis is the world's leading cause of death from a single infectious agent and the leading cause of death in AIDS patients. The emergence of multidrug resistant tuberculosis poses a major threat to the public health, giving new urgency to research aimed at combating this ancient scourge. Moreover, multidrug resistant strains of M. tuberculosis (MDRTB) are a potential weapon of bioterrorism, and such strains have been classified as NIAID/CDC Category C Bioterrorism Agents. Studies proposed in this grant application build upon advances made in collaborative efforts between the Horwitz laboratory at UCLA and the Griffith laboratory at the U. of Wisconsin over the past two years to develop novel antimicrobials against M. tuberculosis for treatment of drug resistant organisms. During the past several years, the Horwitz and Griffith laboratories have laid the groundwork for the development of a new antimicrobial strategy against M. tuberculosis - targeting M. tuberculosis glutamine synthetase (GS). Thus, Horwitz et al. demonstrated that M. tuberculosis GS is a promising antimicrobial target, and that the high production of this enzyme is correlated with pathogenicity in mycobacteria and with the presence of a poly-L-glutamate/glutamine structure in the cell wall of pathogenic mycobacteria. Horwitz et al. showed further that inhibition of GS with L-methionine-SR-sulfoximine (MSO) inhibits M. tuberculosis growth in cell-free culture, in human macrophages, and in vivo in guinea pigs challenged by aerosol with M. tuberculosis. In combination with ascorbate, MSO is almost as potent as isoniazid, the leading antituberculous drug. Importantly, working in a collaboration during the past year, the Horwitz and Griffith laboratories have identified analogs of MSO that are highly potent against M. tuberculosis in vitro but lack certain drawbacks of MSO. This application has two major goals: 1) Develop novel MSO analogs that are better drug candidates than MSO because they are a) more selective for glutamine synthetase (GS) vs gamma-glutamylcysteine synthetase (gamma -GCS); and/or b) less well taken up into the brain where MSO exerts its major toxicity in sensitive species; and/or c) even more selective for M. tuberculosis GS vs. mammalian GS, and test the toxicity of the analogs in mice. 2) Test the novel MSO analogs for their capacity to inhibit M. tuberculosis growth in broth culture, in human macrophages, and in guinea pigs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ORAL ANTIOXIDANT/ANTICYTOKINE THERAPY FOR ALD Principal Investigator & Institution: Hill, Daniell B.; Associate Professor of Medicine; Medicine; University of Louisville Jouett Hall, Belknap Campus Louisville, Ky 40292 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2006 Summary: (provided by applicant): Alcoholic liver disease (ALD) remains the leading major cause of liver disease and liver related mortality in the United States. Alcohol metabolism and ALD are associated with lipid peroxidation and oxidative stress with decreased levels of nutritional antioxidants such as reduced glutathione (GSH) and vitamin E. Animal studies have clearly shown that treatment with GSH precursors, such as N-.acetylcysteine (NAC) and S-adenosyl- L-methionine (Adomet or SAMe), ameliorates alcohol/endotoxin liver injury. We postulate that chronic alcohol abuse causes increased gut permeability and endotoxemia, depletion of nutritional antioxidants (e.g., GSH, Vit E), generation of reactive oxygen intermediates, activation of NFKB, increased TNF production, increased IL-8 production with neutrophil infiltration, Adomet deficiency, mitochondrial GSH depletion, increased susceptibility to hepatic TNF cytotoxicity, and liver injury. We have chosen a combination of two nutritional supplements which inhibit cytokine production in effector cells (e.g. Kupffer
44
Methionine
cells) and which attenuate liver metabolic abnormalities and enhance cytoprotection in target cells (e.g. hepatocytes). Because there is no ideal model system and animal studies to date all support beneficial effects of Adomet/NAC therapy, we are proposing human studies. The two agents to be used, NAC and SAMe, are already commercially available as over-the-counter nutritional supplements. The specific objectives of this proposal are to: I) Determine an oral dose of Adomet in stable alcoholic cirrhotics that when given for 21 days significantly improves methionine clearance, increases Adomet levels, and attenuates cytokine production; 2) Determine in stable alcoholic cirrhotics an oral dose of NAC that when given for 21 days significantly increases whole blood GSH levels and decreases cytokine production; and 3) Determine in stable alcoholic cirrhotics whether giving Adomet and NAC together for a 21 day period provides a degree of improvement in methionine clearance, whole blood GSH values and cytokine levels at least as significant as with either drug alone, and determine that this combination is well tolerated. The data from these studies will be useful in designing clinical trials using these agents in the treatment of acute alcoholic hepatitis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OXIDATIVE STRESS IN ALZHEIMER'S DISEASE Principal Investigator & Institution: Markesbery, William R.; Professor of Pathology & Neurology; Sanders-Brown Ky Res Ctr/Aging; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2002; Project Start 01-DEC-1994; Project End 31-JAN-2007 Summary: Alzheimer's disease is a major health problem affecting 4 million persons in the USA. The key to understanding AD is determining the etiology and pathogenesis of neuron degeneration in specific brain regions. This application is for a five year renewal of the Program Project Grant (P01AG05119) at the University of Kentucky (UK) SandersBrown Center on Aging. The major goal of this program proje4ct is to gain an understanding of brain oxidation in AD. The program project is composed of two cores and four closely interrelated projects. Each project has human (AD and control), genealtered animal and cell culture components. Each project has published and preliminary data relevant to specimens from longitudinally followed AD and control subjects that have short post-mortem interval autopsies. Project by Markesbery examines the hypothesis that oxidation of DNA and RNA oxidation. Project by Butterfield is aimed at defining the molecular mechanisms and sequela of Abeta-associated oxidative stress in AD. Special emphasis will be placed on the action of methionine in Abeta (1- 42) in oxidative stress and neuron toxicity. Project by St. Clair examines the hypothesis that the ability of mitochondria to remove superoxide radicals without inflicting self injury plays a central role in regulating free radical mediated neurodegeneration in AD. This study will investigate the mechanism by which increased expression of manganese superoxide dismutase can be safely achieved in the brain. Project by Kindy is designed to understand the interaction between the receptor for advanced glycation endproducts, Abeta and oxidative stress. A coordination and administration Core will provide supervision and coordination of the research projects, financial management, statistical support, internal and external scientific review and procurement of tissue from the Uk ADRC. The Animal Core provides transgenic, knockout and knockin mice for all four projects. This program project has the potential of identifying molecular targets for development of therapeutic agents aimed at decreasing neuron injury and improving the outcome of AD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: OXIDATIVE STRESS, HOMOCYSTEINE AND ALZHEIMER'S DISEASE Principal Investigator & Institution: Pratico, Domenico; Assistant Professor; Pharmacology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2004; Project Start 15-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Alzheimer's disease (AD) is the most common form of dementia for which there is no effective therapy. Although the causative events(s) responsible for the disease is not known, it is evident that some environmental elements by interacting with endogenous factors could play a role in its pathogenesis. Epidemiological studies have shown that high blood levels of homocysteine (Hcy), a condition known as hyperhomocysteinemia (HHcy) is a risk factor for developing AD. Hcy derives from the conversion of methionine through reactions that are dependent on the presence of necessary vitamins (i.e., B6, B12 and folate). Since cellular exposure in vitro to Hcy induces oxidative stress and inflammatory reactions, we want to test the hypothesis that these mechanisms mediate in vivo the link between AD and HHcy. Previously, we have shown that lipid peroxidation is increased in selective areas of AD brains, and in AD patients where it correlates with disease severity. Inflammation also occurs in AD, and it does do with the full complexity of local and peripheral inflammatory responses. Transgenic mice over-expressing the Swedish mutation of the amyloid precursor protein (Tg2576) manifest signs of brain lipid peroxidation and inflammation. Our longterm goal is to define the effects of long-term exposure to HHcy in two different models of AD-like amyloidosis (Tg2576 and the APP/YAC Tg mice). First, we will test the hypothesis that diet-induced HHcy exacerbates brain oxidative stress and inflammation, accelerates behavioral impairments and brain amyloid/3 peptide deposition in these mice. Second, by cross-breeding AD Tg mice with Tg mice that are deficient for a key enzyme in Hcy metabolism, we will investigate whether genetic-induced HHcy exacerbates brain oxidative stress, inflammatory responses, behavioral impairments, and amyloid beta peptide levels and deposition. In summary, this proposal tests the hypothesis that long-term exposure to high Hcy levels exacerbates ADlike phenotype in two different mouse models of AD-like amyloidosis, and investigates some of the molecular and cellular mechanisms that could account for this effect. These studies will be a necessary basis before prevention studies aimed to reduce Hcy levels are initiated in patients at risk for AD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: AMYLOIDOSIS
PATHOGENESIS
OF
HEREDITARY
TRANSTHYRETIN
Principal Investigator & Institution: Benson, Merrill D.; Professor; Medical and Molecular Genetics; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002; Project Start 01-AUG-1990; Project End 31-MAR-2004 Summary: (from abstract): The overall objective of this proposal is to define the pathophysiology of the autosomal dominant transthyretin amyloidoses. These diseases, while considered rare, are actually being recognized in increased numbers of kindreds throughout the world and especially in the United States. Transthyretin amyloidosis is usually associated with peripheral neuropathy, nephropathy, and cardiomyopathy which present as late-onset (adult) disease with high degrees of morbidity and mortality. To date at least 72 variants of transthyretin (TTR) have been found to be associated with systemic amyloidosis which is inherited as an autosomal dominant
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Methionine
disease. Of particular concern is the fact that: 1) it has recently been shown that there are elderly individuals who develop transthyretin amyloid cardiomyopathy (senile cardiac amyloldosis) in the absence of any detectible mutation in transthyretin; and, 2) there is a high prevalence of one particular transthyretin mutation (isoleucine 122) in the American Black population and this is manifest as amyloid cardiomyopathy. These two findings suggest that, as the population ages, amyloid heart disease will become of greater significance to the American population. Previous studies have centered on determining structural changes of transthyretin which are related to amyloid formation. Structures of amyloid forming variants methionine 30, serine 84, alanine 60, arginine 10, tyrosine 77 have been compared to structures of non amyloid forming threonine 109, serine 6, methionine 119 and normal transthyretin. No common structural change has been found to explain initiation of the fibril forming process but preliminary data suggest that solvent accessability to variant transthyretin dimers may allow a proteolysis event which could lead to the initiation of fibril formation. Metabolic studies using radiolabelled variant and normal transthyretins have suggested increased plasma clearance of variant proteins. The Specific Aims will test the hypothesis that single amino acid substitutions in transthyretin result in changes in tertiary structure of the transthyretin molecule which allow alterations in metabolism of the variant molecule and its associated normal monomers to lead to amyloid formation. Transthyretin proteins isolated from tissues of patients with amyloidosis will be studied to characterize proteolytic peptides and determine if partial proteolysis with generation of carboxyl terminal peptides is a factor in amyloid fibril formation. Fibril forming potential of these fragments will be tested by producing recombinant protein of residues 49 - 127 and testing fibril formation with and without full-length transthyretin in vitro. A new Specific Aim will test the hypothesis that the ratio of the various tetrameric forms of transthyretin affects the propensity to form amyloid fibrils. To accomplish this aim a dual expression system in baculovirus coexpressing normal TTR and variant TIR has been developed. These studies are directed at developing methods to prevent amyloid formation from variant TTR proteins and, thereby providing therapeutic options for a disease which at the present time has no specific therapy other than liver transplantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PHARMACOGENETICS OF METHOTREXATE IN RHEUMATOID ARTHRITIS Principal Investigator & Institution: Bridges, S Louis.; Associate Professor; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 15-MAR-2002; Project End 31-DEC-2006 Summary: Methotrexate (MTX) is one of the most effective drugs for RA, but 20- 30% of patients have suboptimal clinical responses to MTX, and 15-25% have side effects limiting its use. Thus, it is important to elucidate influences on MTX efficacy and toxicity. We will test the hypothesis that single nucleotide polymorphisms (SNPs) in genes encoding key enzymes involved in folate or MTX metabolism or in the mechanism of actions of MTX (e.g. the adenosine pathway) influence clinical responses to MTX. We are uniquely positioned to utilize clinical outcomes (ACR response criteria, radiographic progression and toxicities) and genomic DNA from patients in two completed clinical trials: 153 MTX-treated RA patients from an Immunex trial comparing MTX and etanercept, and 79 MTX-treated RA patients from a UAB trial of folic acid supplementation. HLA DRB1 alleles and a total of 5 known SNPs in the following 4 key genes will be genotyped: 1) 5,10- methylenetetrahydrofolate reductase
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(MTHFR); 2) 5-methyl- tetrahydrofolate-homocysteine methyltransferase (methionine synthase) (MTR); 3) methionine synthase reductase (MTRR); and 4) adenosine receptor A2A [A(2A)R]. These SNPs were chosen on the basis of being common enough in the general population to allow meaningful analyses, their key roles in relevant pathways, and evidence of their biological activity. Through the MCRC Methodology Core, we will look for associations between SNP alleles and MTX efficacy or toxicity. Although these known SNPs are important, SNP haplotypes may be even more informative, aqs they allow characterization of the effect of multiple SNPs working in concert. Therefore, we will use both "in silico" in sequencing approaches to identify novel SNP haplotypes in these 4 and 3 other critical genes: dihydrofolate reductase (DHFR), 5- aminoimidazole-4carboxamide ribonucleotide transformylase (AICAR- T), and aldehyde oxidase (AO). In addition to data mining of public domain and proprietary (i.e. Celera) SNP databases, we will perform SNP discovery on 40 individuals from two racial/ethnic groups [20 African-American (A-A) and 20 Caucasian]. Differences in frequencies of novel haplotype related to disease status or race/ethnicity will be sought by analysis of 108AA Ra patients and 53-AA controls; 336 RA patients (mostly Caucasian); and 800 controls (mostly Caucasian) from established cohorts. Based on results from these studies, the role of selected novel SNP haplotypes on MTX efficacy and toxicity will be tested in patients from the folic acid and Immunex trials. We will compare the predictive power of two approaches to genetic profiling: the single SNP approach and the SNP haplotype approach. These studies may provide clinically useful markers of MTX efficacy or toxicity in RA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PILOT--DEVELOP MTHFR NULL AND C677T POLYMORPHIC MICE Principal Investigator & Institution: Kucherlapati, Raju S.; Professor; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 18-SEP-2003; Project End 31-AUG-2008 Summary: Methylenetetrahydrofolate reductase (MTHFR) is a protein that is important in folate metabolism. Its enzymatic activity is to convert 5, 10-methylenetetrahydrofolate to 5'-methyl tetrahydrofolate, which in turn is important in the methylation of homocysteine to methionine. Several variants and mutations in the gene for MTHFR have been described. Moderate or severe deficiencies of this enzyme lead to a number of disorders including hyperhomocystenuria and homocystenuria. The clinical outcome of the deficiency include peripheral neuropathy, developmental delay, hypotonia and seizures [1]. Mild forms of the reduced MTHFR activity are present in high frequencies in the general population. These variant forms of these enzymes lead to mild homocystinuria. High level of homocysteine is a risk factor for arterial disease [2-4]. The genes for human and mouse MTHFR have been isolated and characterized [4-7]. The human gene encodes a protein 656 amino acids in length and the mouse gene encodes a 654 aa protein. There is a high level of conservation between the human and mouse genes. At the amino acid level, the two proteins are 90% identical [5]. The exon-intron organization of the two genes is also identical. Both genes have 11 exons. Although several different size transcripts have been described [6, 7], all of them encode the identical protein. Several variants of the human MTHFR gene have been described. Of these, the C677T variant that converts an alanine codon to valine is the most studied. This is a very common polymorphism and has an allele frequency of approximately 35% in the North American population. The amino acid change leads to a thermolabile enzyme that causes a predisposition of homocystenuria when folate levels are low [4, 8, 9]. In this developmental project, we propose to make mice that have a null allele of the
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Mthfr gene and a second mouse that carries the homologous C677T variation. Based on the high level of identity between the two proteins and the complete conservation of the 10 amino acids on either side of the variation in the mouse and human genes suggests that the mouse will truly mimic the functional aspects of the C677T polymorphism in humans. Availability of these mice would help us in better defining the role of MTHFR and C677T variant on folate metabolism and how these genetic changes would affect colon cancer susceptibility under different nutritional folate levels. The steps that are involved in generating the mice are as follows: 1. Isolation of a mouse BAC from the 129/SvEvTac strain genomic library, 2. Modification of the gene, 3. Transfection of mouse ES cells with the gene modification construct and screening the colonies for the desired modification, 4. Injection of the modified ES cells into blastocysts to generate chimeras and 5. Mate the chimeras for germ-line transmission of the modified allele. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PILOT--IMAGING OF METASTASIS Principal Investigator & Institution: Tsarfaty, Galia; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 14-JUN-2002; Project End 31-MAR-2007 Summary: Pilot Project 2--The primary aim of this study is to develop novel molecular imaging methodology to visualize and quantify the expression and activity of tyrosine kinase growth factor receptor and mitochondria uncoupling proteins in metastasis. The Met tyrosine kinase growth factor receptor, its ligand hepatocyte and Mimp (ref), a novel Met-HGF/SF-induced protein will serve as a model. Using novel molecular imaging modalities we will analyze the effects of Met and HGF/SF overexpression on mammary tumors and metastasis formation. Subsequently, using a Tet inducible Mimp we will examine the effects of Mimp expression on Met-HGF/SF-induced metastasis. Preliminary results suggest that Mimp reduces Met-HGF/SF-induced metastasis. The combined expression of Met and Mimp which is inhibitory and its down-stream effects may shed light on the involvement of mitochondrial uncoupling activities in regulating HGF/SF-induced metastasis. Our specific aims are: 1) to image overexpression of Met and HGF/SF in an in vitro invasion process and in tumor and metastasis formation. 2) to characterize the effect of Mimp induction on the tumorigenic/metastatic potential in in-vitro and in vivo systems. 3) to develop molecular imaging modalities for Mimpluciferase and Mimp-DsRed in tumorigenicity and metastasis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PILOT--PREDICT PLASMA FOLATE AND HOMOCYSTEINE BY SNPS IN FOLATE METABOLISM Principal Investigator & Institution: Rimm, Eric B.; Associate Professor; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 18-SEP-2003; Project End 31-AUG-2008 Summary: We propose to assess the genotype-phenotype relation of variants in five genes that synthesize or metabolize 5-methylTHF or homocysteine. The five genes are: MTHFD1 (5,10 methylenetetrahydrofolate dehydrogenase), MTHFR (methylenetetrahydrofolate reductase), MTR (Methionine Synthase), MTRR (Methionine Synthase Reductase), and SAHH (S-adenosylhomocysteine hydrolase). We will explore SNPs or newly defined haplotypes in these genes in relation to plasma folate and homocysteine already assessed among 943 men and women; a population over-sampled to represent a wide range of alcohol consumption.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PLACEBO-CONTROLLED STUDY OF SAME VS.ESCITALOPRAM IN MDD Principal Investigator & Institution: Fava, Maurizio; Professor of Psychiatry Harvard Medical; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2004; Project Start 15-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Major depressive disorder (MDD) is a common, typically recurrent and disabling disorder, costing the U.S. over $44 billion/year in direct and indirect costs, and with point prevalence rates estimated at 5%-9% for women, and 2%-3% for men. More than one third of patients suffering from MDD appear to use alternative therapies in the U.S. Routinely prescribed in Europe for nearly 30 years and released four years ago in the U.S. as an over-the-counter dietary supplement, s-adenosyl-l-methionine (SAMe) has gained significant popularity as an agent marketed for improving mood and emotional well being. A number of relatively small double-blind studies have shown that parenteral or oral preparations of SAMe, compared with a number of standard tricyclic antidepressants, were generally equally effective, and tended to produce fewer side effects A relatively smaller number of studies have also examined the efficacy of SAMe compared to placebo, with the majority of these studies showing a significant advantage of SAMe over placebo. The recent report of the Southern California Evidence-Based Practice Center for the U.S. Department of Health and Human Services [Agency for Healthcare Research and Quality (AHRQ Publication 2002; http://www.ahrq.gov) ] states that "The results of these studies justify additional randomized clinical trials to evaluate the efficacy and tolerability of SAMe for treatment of depression." No adequately powered placebocontrolled study of SAMe in depression has ever been conducted in the U.S. We therefore propose a five-year, placebo-controlled, two-site study to assess the efficacy and safety of SAMe and of a standard selective serotonin reuptake inhibitor (SSRI), escitalopram in outpatients with MDD. This proposal is a parallel comparison of the efficacy and safety of SAMe, escitalopram, and placebo, with a crossover phase during which non-responders to any of these three treatments receive open-label treatment with the combination of escitalopram and SAMe. It is important to assess the efficacy of this combination therapy because patients frequently self-medicate with SAMe during standard antidepressant treatment. The primary aim of the proposed study is to test the acute antidepressant efficacy and tolerability of both SAMe and escitalopram, each compared to placebo, for the treatment of MDD. Secondary aims are to assess the acute effects of SAMe or escitalopram vs. placebo on remission rates, quality of life, and psychosocial functioning. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PROTEIN/RNA INTERACTIONS IN SPLICE SITE SELECTION Principal Investigator & Institution: Xu, Rui-Ming; Associate Professor; Cold Spring Harbor Laboratory 1 Bungtown Road Cold Spring Harbor, Ny 11724 Timing: Fiscal Year 2003; Project Start 01-JAN-1998; Project End 31-MAR-2007 Summary: (provided by applicant): Most human genes are interrupted by non-coding sequences known as introns. The nascent transcript must be processed to remove the introns and to join the coding sequence into a contiguous mature mRNA molecule. The human genome project provided an estimate that only 1 to 1.5% of the approximately 3x10/9 base pair (bp) genome is spanned by coding sequences or exons, whereas introns
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occupy approximately 24% of the genome. It is apparent that the cellular machinery is presented with a formidable task to precisely locate the splice sites within a gene's transcript. Another dimension of complexity is added when certain exon sequences are skipped or included, a phenomenon known as alternative splicing. Alternative splicing occurs in a large number of human genes and it plays important roles in regulating gene expression during development and differentiation. Alternative splicing is also responsible for generating molecular diversity in certain cells, such as neurons. Splicing of pre-mRNA involves an ordered assembly of components, including small nuclear ribonucleoprotein particles (snRNP) and additional protein splicing factors, resulting in the formation of a large 50-60S complex, termed the spliceosome. We are interested in understanding the molecular mechanism of splice site recognition from a structural standpoint. In this proposal, we focus our study on several well characterized human splicing factors that are important for splice site selection, namely, SR proteins, heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) and the U2 auxiliary factor (U2AF). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RCT OF SAME IN ALCOHOLIC LIVER DISEASE Principal Investigator & Institution: Mendler, Michel H.; Medicine; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2004; Project Start 01-JUN-2004; Project End 31-MAY-2007 Summary: (provided by applicant): Background: Alcoholic liver disease is one of the most important causes of chronic liver disease in this country. There is currently no treatment for chronic alcoholic liver disease other than abstinence. Hepatic methionine metabolism is abnormal in these patients and one of the consequences is depletion of Sadenosylmethionine (SAMe) levels, which can affect numerous important cellular processes. SAMe has been increasingly utilized for the treatment of liver diseases although the protective mechanisms remain unclear. A recent randomized double-blind trial using SAMe in patients with alcoholic liver disease and found improvement in 2year survival in those with less advanced liver disease. However, important changes in methionine metabolism and histological changes were not included in the study. Aim: The goal of this study is to determine the effect of SAMe administration on key metabolic abnormalities of the methionine cycle and on the recovery from alcoholic liver disease. Methods: This is a randomized, double blind, placebo-controlled trial. Thirty patients with stable alcoholic hepatitis (Maddrey Score < 32) without cirrhosis who meet entry criteria will receive either 400 mg of SAMe (n=15) or placebo (n=15) three times a day for the duration of one year. History, physical assessment, various blood tests and a liver biopsy will be performed prior to treatment. Patients will have repeat blood tests on subsequent follow-up visits every month for the first two months, then every two months thereafter. They will also be encouraged to abstain from alcohol during these visits. A post-treatment liver biopsy will be obtained at the end of the trial. The primary outcome parameters include serum homocysteine, SAMe and TNFalpha levels, and the expression of key hepatic enzymes of the methionine cycle and of hepatic SAMe and glutathione levels. Histological progression of alcoholic liver disease, clinical and biochemical indices of liver disease, and quality of life assessment will also be examined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REACTION MECHANISMS OF MAMMALIAN B12-DEPENDENT ENZYMES Principal Investigator & Institution: Banerjee, Ruma; Willa Cather Professor of Biochemistry; Biochemistry; University of Nebraska Lincoln Lincoln, Ne 685880430 Timing: Fiscal Year 2002; Project Start 01-FEB-1993; Project End 31-JAN-2003 Summary: (adapted from the applicant's abstract) Mammals have two known B12dependent enzymes that conduct essential housekeeping functions: methionine synthase and methylmalonyl-CoA mutase. Impairments in methionine synthase lead to megaloblastic anemia and hyperhomocysteinemia, the latter being a graded risk factor for atherosclerotic cardiovascular diseases. Dysfunction of methylmalonyl-CoA mutase leads to methylmalonic aciduria, leading to metabolic aberrations that can be fatal. This proposal focuses on elucidating the reaction mechanisms of these two enzymes, as well as the mechanism by which the cofactor regulates the activity of methionine synthase. Chemically, B12 is a novel cofactor, and catalyzes distinct biochemical transformations in association with these two enzymes. Thus, methionine synthase catalyzes a displacement reaction in which the cobalt-carbon bond of B12 breaks heterolytically, while the mutase catalyzes a rearrangement reaction in which the cobalt-carbon bond breaks homolytically. A combination of spectroscopic, kinetic and molecular genetic techniques will be used to explore the mechanisms of these reactions, and to map and characterize the mutations in patients with inborn errors affecting these enzymes. The redox-active proteins that activate mammalian methionine synthase under physiological conditions will be identified and characterized, as these represent additional targets for mutations that could lead to hyperhomocysteinemia. The level at which B12 exerts control over methionine synthase and causes the observed induction in enzyme activity when presented to cells in culture will also be examined. These studies on the native and mutant B12 enzymes will make inroads into our understanding of novel reaction mechanisms of clinically important enzymes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REACTIONS OF VIT B12 COMPOUNDS & ENZYMES WITH NO AND N2O Principal Investigator & Institution: Birke, Ronald L.; Professor; City College of New York 138Th St and Convent Ave New York, Ny 10031 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2007 Summary: Our long-term objectives are to understand the functions of vitamin B 12 compounds in enzymatic reactions and as therapeutic agents in terms of their chemical properties. Some specific goals of this research project are to investigate the interactions of nitrogen oxides, NO and N20, and nitrite anion with vitamin B12 (cobalamin) compounds in vitro in order to understand their effects on enzymatic reactions of methionine synthase, B 12-MS, and their effectiveness for sequestering trauma induced NO in vivo. One hypothesis is that redox reactions of NO and N20 with the Co(II) and Co(I) forms of cobalamin can effect enzyme functioning. Specifically, we plan to study the complexes formed and the redox behavior of systems of NO, N20, and the nitrite anion with various cobalamin compounds in their three cobalt oxidation states using electrochemical measurements, UV-VIS spectroscopy, resonance Raman spectroscopy (RRS), surface enhanced resonance Raman spectroscopy (SERRS), and electron paramagnetic resonance (EPR) spectroscopy. Nitrogen species formed as reaction products will be investigated by gas chromatography-mass spectrometry (GC-MS), We will also study the reductive cleavage mechanism for the activation of methylcobalamin
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and adenosylcobalamin. Our aim is to measure equilibrium binding constants, redox reaction rates, and electrochemical reduction potentials for cobalamin redox couples and also to determine the structure of NO binding in their nitrosyl complexes. Experiments will also investigate the solvent and pH effects on the equilibrium and kinetic properties of the complexes. In addition, we will investigate the inactivation of pure methionine synthase obtained from a recombinant strain of E. Coil which overproduces the enzyme. We will compare NO and N20 inactivation by various means including deactivation in an electrochemical cell which produces the cob(I)alamin form of the enzyme, analysis of the inactivated enzyme by twodimensional polyacrylamide gel electrophoresis, and stopped-flow kinetic measurements of enzyme catalysis in the presence of NO and N20. Additionally, we will correlate our chemical studies with the effect of various cobalamin compounds on NO generated at the surface of endothelium cells in physiological experiments to be done at Ohio University. These results should help in understanding how NO and N20 work in inhibiting B 12-MS function, if NO can act as a regulator for MS-B 12, and how cobalamins can detoxify organisms with elevated levels of NO which cause the condition of hypotension. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REACTIVE OXYGEN SPECIES AND AGING Principal Investigator & Institution: Michaelis, Elias K.; Professor and Chairman; Medicinal Chemistry; University of Kansas Lawrence Youngberg Hall Lawrence, Ks 660457563 Timing: Fiscal Year 2002; Project Start 01-SEP-1995; Project End 31-MAR-2006 Summary: Aging in mammals is associated with progressive loss of muscle mass, bone demineralization, vascular calcification and progressive hypertension, sensory perception deficits, hypo functioning immune systems, and loss of tissue elasticity. The original program project proposal five years ago was based on the two hypotheses of cell aging, the free radical theory and the Ca2+ hypothesis of aging, that we believe explain many of the cell and molecular changes that occur with aging. Chronic imbalances between oxidant and anti-oxidant processes in cells cause oxidative stress during aging and progressive deterioration of macromolecular structures such as proteins, DNA, and lipids. Progressive deterioration of processes that control [Ca2+]i leads down a path of cellular deterioration and organ malfunction. One of the operating mechanisms for the loss of the capacity of cells to handle the rise in [Ca2}]i may be oxidant-induced protein and membrane damage, especially of proteins that regulate Ca2+ entry into cells, transport out of cells, transport into intracellular organelles, or release from such organelles. The research performed in our laboratories under the auspices of the program project has contributed substantial and detailed new information to support the two major hypotheses of aging. We have provided chemical evidence for the presence of post-translational modification of proteins brought about by ROS. These modifications occur in proteins that regulate intracellular Ca2+ and the function of Ca2+ as an intracellular messenger. The current program project renewal application expands upon the work already accomplished and attempts to define not only the chemical and biochemical modifications due to increasing oxidative stress during aging, but also the cellular and physiological consequences of such modifications. An additional focus of the proposed work is that of cellular mechanisms for protein repair or degradation following insults produced by oxidation. The areas of focus in the continuation of this program project are: a) characterization of the pathways of repair or degradation of calmodulin and the Ca-ATPases b) mechanisms of protein repair by methionine sulfoxide reductase c) age-dependent changes in NMDA receptor
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function, intracellular calcium channels, protein phosphatases and kinases, and the multi- catalytic proteases d) chemical sensitivity of tyrosine nitration, sulfhydryl group oxidation, and the chemical nature of protein carbonyl groups. To accomplish these goals we will continue to use the expertise of the protein and peptide analysis core. We have also established a new core in cell culture and molecular biology that will assist us in our investigations of changes in cell biology, cell physiology and molecular biology. It is our hope and expectation that the studied proposed in this program will provide us with new insights into basic biological and chemical processes associated with aging. And, that this program will also provide us with targets for potential therapeutic intervention to ameliorate the gradual deterioration in cell and organ functions that occur with aging. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REGULATION OF FOLATE METABOLISM Principal Investigator & Institution: Matthews, Rowena G.; Professor; Biological Chemistry; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-APR-1978; Project End 31-MAR-2005 Summary: (Verbatim from the Applicant's Abstract):One carbon units bound to tetrahydrofolate are utilized for the de novo biosynthesis of purines and thymidylate and for the provision of methyl groups for the biological methylation reactions that involve adenosylmethionine as the methyl donor. The long term goals of this research are to study the catalytic mechanisms of enzymes that use tetrahydrofolate derivatives as cofactors, and to study the regulation of one carbon metabolism. Because the availability of one carbon units is one of the factors that limits the rate of growth of cells, these studies are relevant to the design of chemotherapeutic inhibitors of folatedependent enzymes. They are also relevant to our understanding of the factors that control the level of plasma homocysteine, an independent risk factor for the development of cardiovascular disease. The proposed studies focus on three folatedependent enzymes: human methylenetetrahydrofolate reductase (MTHFR), which catalyzes the reduction of methylenetetrahydrofolate to methyltetrahydrofolate in a reaction which commits one-carbon units to provision of methyl groups for adenosylmethionine-dependent methylations, and cobalamin-dependent and cobalamin-independent methionine synthases from Escherichia coli. Methionine synthases catalyze methyl transfer from methyltetrahydrofolate to homocysteine, to produce tetrahydrofolate and methionine. Based on research with MTHFR from E. coli, a model has been developed in which enzyme activity is regulated by the availability of folate derivatives; this model will be tested for its applicability to the regulation of the human MTHFR. Studies of the catalytic mechanisms of cobalamin-dependent and cobalamin-independent methionine synthases from Escherichia coli are also proposed. These studies will focus on the mechanism of activation of the substrate, methyltetrahydrofolate, for transfer of the methyl group and on the catalytic role of the essential zinc ions in these two enzymes, and will employ a wide variety of kinetic, spectroscopic, and stereochemical techniques. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: REGULATION OF METHIONINE METABOLISM IN BACILLUS SUBTILIS Principal Investigator & Institution: Henkin, Tina M.; Professor; Microbiology; Ohio State University 1960 Kenny Road Columbus, Oh 43210
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Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2005 Summary: (provided by applicant): A novel global regulation system for control of genes involved in methionine metabolism has been uncovered in Bacillus subtilis. Genes utilizing this mechanism, designated the S box family, contain in their mRNA leader regions a complex set of conserved primary sequence and structural elements, including a transcriptional terminator, competing antiterminator, and antiantiterminator. Genetic analyses indicate that during growth in methionine, sequences in the leader are required for stabilization of the anti-antiterminator, which prevents formation of the antiterminator, which in turn allows termination. The molecular mechanism for control of the leader RNA structure in response to methionine levels is unknown, although preliminary studies suggest that binding of a regulatory factor is required to prevent readthrough. This system is widely used for control of methioninerelated genes in a variety of Gram-positive bacteria, including important pathogens such as Staphylococcus aureus, and is also found in the Gram-negative bacteria Chlorobium tepidum and Geobacter sulforreducens. Eleven transcriptional units are controlled by this mechanism in B. subtilis alone, so the total number of genes involved is high. The major goal of this study is to further investigate the molecular mechanism of transcription termination control, and to elucidate the physiological role of this system, using a combination of genetic and biochemical approaches. The required cis-acting sequence elements will be identified by site-directed mutagenesis. The trans-acting regulatory factors required for the methionine response will be identified, and the system will be examined both in vivo and in vitro. A requirement for ppGpp for efficient readthrough in vivo has been demonstrated, and the molecular basis for this requirement will be examined. Finally, the physiological role of genes of unknown function which appear to be regulated by this mechanism will be examined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REPAIR, DEGRADATION, AND CALCIUM REGULATION IN MUSCLE Principal Investigator & Institution: Bigelow, Diana; Professor; University of Kansas Lawrence Youngberg Hall Lawrence, Ks 660457563 Timing: Fiscal Year 2002; Project Start 15-JUN-2002; Project End 31-MAR-2003 Summary: Our long term goal is to understand the cellular processes that are responsible for the accumulation of oxidized calcium regulatory proteins in senescent muscle and how these related to their prolonged contraction and relaxation times. Here, we focus on the ryanodine receptor (RyR) and the sarcoplasmic reticulum (SR) CaATPase, two calcium regulatory proteins that, together, play a major role in eliciting intracellular calcium transients in muscle. Their respective roles consist of calcium release to initiate muscle contraction, and the rate-limiting active resequestration of cytosolic calcium into the SR lumen to allow relaxation. Our previous work has shown specific and substantive levels of 3-nitrotyrosine (3Ngamma) modification of the SERCA2a isoform of the Ca-ATPase in heart and skeletal muscle which increases with age of the animal. 3NY is a characteristic product of peroxynitrite (ONOO-), and suggests the simultaneous generation of superoxide (O2.-) and nitric oxide (NO.) in myocytes. We hypothesize that accumulation of 3Ngamma modification of SERCA2a during aging is due to defects in cellular mechanisms designed to minimize reactive oxygen species (ROS), or those involved in the degradation of oxidized proteins. We therefore propose to focus on gaining a detailed understanding of degradation pathways or whether increased levels of ROS overwhelm the normal functioning of these pathways. We further hypothesize that the presence of the strong thiol oxidant,
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ONOO-, in myocytes will functionally alter the cysteine-rich RyR and its methionine rich regulator, calmodulin. The latter protein has been previously shown to be oxidized in aging. In addition, ONOO-, formation may deplete NO> which regulates the RyR., both directly and through the FK binding protein. Therefore, we propose the following specific aims: (1) Identify cellular pathways for the degradation of SERCA2a, and possible defects in aging; and (2) Characterize the regulation of the RyR by oxidized CaM, and other regulatory molecules in senescent muscle. Knowledge of cellular mechanisms that lead to accumulation, and altered regulation by oxidized proteins will be essential for the design of therapeutic approaches for maintenance of optimal heart and skeletal muscle function during aging. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: REVERSIBLE OXIDATION OF METHIONINE IN AGING Principal Investigator & Institution: Hoshi, Toshinori; Physiology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2004; Project Start 15-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Oxidation of amino acids by reactive oxygen species is considered to accelerate aging. The amino acid methionine is readily oxidized to form two epimers of methionine sulfoxide, methionine-R-sulfoxide (met-R-O) and methionine-S-sulfoxide (met-S-O). The enzyme methionine sulfoxide reductase A (MSRA) reduces met-S-O while the enzyme methionine sulfoxide reductase B (MSRB) reduces met-R-O. Multiple forms of MSRA and MSRB that differ in tissue and subcellular distributions are now known. Increasing evidence suggests that methionine oxidation may be an important determinant of the time course of normal aging. However, there is no systematic information available how the met-R/S-contents and MSRA/B activities change with age. Furthermore, it is not known whether different MSR forms play similar roles in aging. Using the model organism Drosophila, the study proposed here will provide a comprehensive view of the roles of methionine oxidation and MSRs in normal biology of aging. Age-dependent changes in the oxidized methionine contents and MSR activities in different tissues and subcellular fractions are systematically measured. Different forms of MSRs are overexressed in different tissues and subcellular regions to compare their efficacies in lifespan extension and delaying the onset of decline in the physical activity level and reproductive vigor. Furthermore, gene expression profiles in the long-living MSRA flies are systematically compared with those of control flies. The study will also test whether a food supplement, S-methyI-Lcysteine, could act to extend the animal lifespan by participating in the reversible methionine oxidation cycle involving the MSR system. The results expected should prove valuable in designing interventions to extend lifespan. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: S SANGUIS ADHESION--MOLECULAR BASIS OF SPECIFICITY Principal Investigator & Institution: Herzberg, Mark C.; Professor; Polymer Science & Engineering; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 01-APR-1990; Project End 31-MAR-2004 Summary: Density-dependent surface growth may switch sessile phenotypes to planktonic. During years 08-13, sessile and planktonic S. sanguis and S. gordonii cells will be compared to test the hypothesis that expression of adhesin proteins is regulated by the process of adhesion. Specifically, we will (1) compare the adhesion specificities of
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PAAP+ S. sanguis and PAAP- S. gordonii in a biofilm model that facilitates adhesion, protein biosynthesis and growth at 37 C for 6 hours in chemically-defined synthetic medium. In this model, the two wild-type strains and selected mutants will tagged with different antibiotic resistance markers. The strains will be incubated alone or together to determine if adhesion is competitive when binding to saliva-coated hydroxyapatite in the presence or absence of specific antibodies against salivary antigens, or simulated pellicles formed from purified salivary macromolecules. Since preferred binding sites show discrete distributions on coated enamel chips, the two strains will be compared microscopically for topological distribution of binding. To learn if they express different adhesin phenotypes, (2) sessile and planktonic cells will be recovered periodically from the biofilm model and altered expression of streptococcal surface macromolecules will be analyzed by pulse-labeling, autoradiography and Western immunoblotting with antibodies against known proteins. Novel surface proteins regulated during adhesion will be analyzed by amino acid microsequencing, PCR synthesis of the target gene, insertional inactivation, analysis of the mutant for defects in adhesion and finally cloning and sequencing of the complete gene. Selected experiments will be simulated on enamel chips to determine the ultrastructural morphology of resultant biofilms. The specificity of adhesin proteins requires protection against oxidative stress. Preliminary data show partial cloning of the S. gordonii msrA gene, which encodes methionine sulfoxide reductase, a purported adhesin maintenance factor. To analyze posttranslational modification and functional maintenance of adhesin proteins, (3) an msrAnegative mutant will be constructed and the methionine-rich diversity region of the adhesin, antigen I/II (SspA/SspB) will be analyzed for altered structure and function. These studies will serve as a definitive test of the hypothesis that the process of adhesion regulates expression of required proteins in a biofilm model. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SAME AND FOLATE DEFICIENCY IN ALCOHOLIC MIRCROPIGS Principal Investigator & Institution: Halsted, Charles H.; Professor; Internal Medicine; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 956165200 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2007 Summary: (provided by applicant): The overall hypothesis of the proposed research is that the pathogenesis of alcoholic liver disease (ALD) is regulated by changes in intrahepatic methionine metabolism that result from chronic ethanol consumption. Previously, we found that the combination of dietary ethanol and a folate deficient diet both maximized perturbations in methionine metabolism and accelerated the development of ALD in micropigs. The objective of the proposed research is to prove the hypothesis by demonstrating that the biochemical and histopathological features of ALD can be prevented or reversed by provision of supplemental S-adenosylmethionine (SAM) or folic acid to pigs maintained on chronic ethanol feeding with and without folate deficient diet. The first specific aim is to determine the efficacy and metabolic effects of intervention with SAM or folic acid in the prevention and treatment of ALD in micropigs. The second specific aim is to study the effects of abnormal methionine metabolism on known mediators and signal pathways of alcoholic liver injury. Micropigs will be fed diets with ethanol that are either folate sufficient or deficient and with or without supplemental SAM during development of liver injury, and with or without supplemental SAM or folic acid after development of alcoholic liver injury. Data collection will include methionine metabolites in plasma and liver, liver histopathology, markers of inflammation, necrosis, and apoptosis, products of lipid,
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protein, and DNA oxidation, antioxidant enzymes, and signal pathways of apoptosis. The data will be interpreted to confirm the role and establish potential mechanisms for abnormal methionine metabolism in the pathogenesis of ALD. While furthering understanding of interactions of methionine metabolites on pathways of liver injury, the project may establish novel approaches to the prevention and treatment of ALD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SAME, RXRALPHA-MEDIATED PATHWAYS AND ALD Principal Investigator & Institution: Wan, Yu-Jui Y.; Professor; Harbor-Ucla Research & Educ Inst 1124 W Carson St Torrance, Ca 905022052 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): The goal of this project is to study the mechanism underlying nuclear receptor retinoid x receptor et (RXR-alpha)-mediated pathways on regulating S-adenosyl-L-methionine (SAMe) homeostasis. The main hypothesis is that RXR-alpha-mediated pathways either directly or indirectly control SAMe synthesis and alter the levels of glutathione and phosphatidylcholine in the liver, which consequently play a crucial role in the development of alcoholic liver disease (ALD). Most of the retinol and alcohol studies rely on either feeding animals with excess amount of retinoids or introducing animals with retinol deficient diet. Feeding animals with retinoids can be toxic. Retinol deficiency can also cause many unwanted effects. Knockout technology avoids these potential problems. Tissue specific knockout further allows studying the function of the gene in a cell type specific manner without affecting the gene function systemically. We have established an animal model in that the RXRalpha gene is knocked out only in the hepatocyte. RXR-alpha is highly expressed in the liver and is required for almost all the nuclear receptor-mediated pathways. Therefore, hepatocyte RXR-alpha deficient mouse serves as an excellent model for studying retinoid signaling in alcoholic liver disease. When hepatocyte RXR-alpha is deficient, liver retinoic acid is elevated, alcohol elimination rate is increased and alcohol-induced liver damage becomes more severe. In addition, the expression of more than ten genes encoding enzymes involved in the SAMe pathway is altered. Those data indicate that RXR-alpha, SAMe and ALD are intricately interlinked. Two specific aims are proposed to study the direct and indirect effect of RXR-alpha on SAMe homeostasis. First is to examine how RXR-alpha-mediated pathways regulate alcohol metabolism, which may indirectly control SAMe synthesis and affect the development of ALD. Second is to characterize how RXR-alpha-mediated pathways regulate genes encoding enzymes in the SAMe pathway and directly control SAMe homeostasis. RXR-alpha-mediated pathways including PPARcz and 3' and RXR-alpha homodimer and others will be studied. The effect of those nuclear receptor ligands on regulating SAMe synthesis will be analyzed. The proposed study not only allows us to understand how nuclear receptors regulate SAMe homeostasis, it also provides an opportunity to identify potential therapeutical targets and treatment agents for ALD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: STRUCTURAL BASIS--ALTERED CALCIUM HOMEOSTASIS OF AGING Principal Investigator & Institution: Squier, Thomas C.; Associate Professor; Battelle Pacific Northwest Laboratories Box 999, 902 Battelle Blvd Richland, Wa 99352 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2004
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Summary: (Abstract from the Application). The long term goal is to identify the molecular mechanisms that result in the age-dependent loss of critical cellular functions, which correlate with an increased sensitivity to stress and diminished capabilities of the elderly. These investigators have focused on identification of the proposed linkage between oxidative stress and decreased calcium regulation observed during aging. Based on previous findings which demonstrate that during aging, multiple methionines in the calcium regulatory protein calmodulin (CaM) are oxidatively modified to their corresponding sulfoxides resulting in a reduced ability to activate the PM-Ca-ATPase, and the key role that CaM plays in intracellular signaling, they hypothesize that agerelated decreases in CaM function are responsible for the loss of calcium homeostasis observed in senescent cells. The accumulation of oxidatively modified CaM (CaMox) that is functionally inactive during aging is consistent with a decreased function of cellular repair and degradative enzymes in senescent animals. Thus the specific activity of methionine sulfoxide reductase (MsrA), which is able to repair oxidized CaM in vitro and fully restore CaMox function, may be compromised during aging. Likewise, the age relationship decreases in the function of the proteasome, which normally selectively degrades oxidized proteins, may result in the accumulation of inactive CaMox. Therefore, to identify the molecular mechanisms that result in the loss of CaM function, and recognition features that normally promote Cal repair and turnover, they propose the following specific aims: (1) Identify how methionine oxidation in CaM alters target protein activation, (2) Determine recognition elements in CaMox (oxidized) that promote methionine sulfoxide repair by MsrA, and (3) Discover mechanisms of degradation of CaMox by the proteasome. These measurements will involve a multidisciplinary approach that will combine biochemical measurements of the function of genetically engineered CaM mutants with altered sensitivities to oxidative stress and spectroscopic measurements of CaMox structure using FT-IR, flex, and NMR spray. Additional single-molecule measurements will permit the resolution of structural heterogeneity in individual CaMox molecules and identification of the mechanisms of CaM, recognition by MsrA and the proteasome. An understanding of the cellular mechanisms that modify calcium homeostasis under conditions of oxidative stress and the role of CaM oxidation in modifying target protein activation will be important to the development of new therapies to alleviate the decline in cellular functions associated with aging. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SUBTLE DISTURBANCES OF COBALAMIN STATUS Principal Investigator & Institution: Carmel, Ralph; Director of Research; New York Methodist Hospital 506 60Th St New York, Ny 11215 Timing: Fiscal Year 2003; Project Start 01-SEP-1983; Project End 31-AUG-2008 Summary: (provided by applicant): Low cobalamin (vitamin B12) levels are frequent, especially in the elderly, several million of whom are affected. Most often the low levels reflect "subclinical cobalamin deficiency", an asymptomatic state marked only by metabolic evidence of cobalamin insufficiency. It is unclear if these persons need intervention because progression to clinical deficiency may be uncommon, and many people with low levels have no deficiency at all. The proposal aims to study whether nitrous oxide (N2O), used in most general anesthesia in the US, worsens cobalamin status in elderly people who have unrecognized subclinical cobalamin deficiency. The reason for concern is that N2O inactivates cobalamin and therefore can cause neurological dysfunction in some patients with underlying clinically expressed cobalamin deficiency. The elderly are known to have an increased risk of postoperative
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cognitive complications. The study will recruit patients >60 years old who are scheduled for elective surgery in which N2O use for more than 1 hour is planned. Patients will be randomized in a blinded fashion to receive a standard anesthetic regimen of several agents, in which N2O is either included or replaced by air; the two regimens are equally safe and effective. They will undergo cognitive function and depression scale testing, blood testing of cobalamin-related metabolism, and clinical evaluation before surgery and at 48 hours, 14 days and 28 days after surgery. Those with cognitive changes will be treated with cobalamin and reevaluated after 3 months. Statistical analysis will compare the subgroups' metabolic, neuropsychological, demographic, genetic and clinical data. The primary question is what effect routine N2O anesthesia has on metabolic and clinical status related to subclinical cobalamin deficiency. It will also resolve whether or not the combination of N2O and the deficiency can explain the increased rate of postoperative cognitive problems in the elderly, and thus if preoperative or postoperative attention to cobalamin is needed in the elderly. A secondary goal is to extensively study cobalamin-related and homocysteine-related metabolism in these patients and their conditions, particularly as changes evolve after N2O use and later improvement. The clinical study provides a unique opportunity to establish these metabolic details and to compare their interactions with common genetic mutations in the patients that affect enzymes relevant to cobalamin deficiency, N2O effects, and their contribution to the clinical outcomes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SULFUR-CENTERED CRYSTALLIN MODIFICATIONS & LENS OPACITY Principal Investigator & Institution: Pande, Jayanti; Research Associate; Physics; Massachusetts Institute of Technology Room E19-750 Cambridge, Ma 02139 Timing: Fiscal Year 2002; Project Start 01-JUN-1994; Project End 31-MAY-2003 Summary: Sulfur-centered post-transitional modifications of the crystallins are a recurring feature in many cataractous lenses. This is especially true of maturity-onset human nuclear cataract, in which the cysteine and methionine residues of the beta and gamma crystallins are found to be chemically modified. It is generally assumed that all such modifications are cataractogenic, despite the vast chemical differences between them. In this proposal a strategy is presented to identify the general chemical determinants of cataractogenicity in a variety of crystallin modifications at the cysteine and methionine residues. This strategy is based on the hypothesis that: polar or charged modifications decrease the net attraction between proteins, and are therefore "cataractinhibiting". Conversely, marginally polar and hydrophobic modifications increase the net attraction between proteins and are therefore "cataractogenic." The following Specific Aims are proposed to test this hypothesis. 1. Introduce in vitro, oxidative modifications normally found in the lens, at the sulfur centers of the beta and gamma crystallins individually and in mixtures, and measure the "cataractogenic" or "cataractinhibiting" properties of the modified proteins, as defined above. 2. Examine the influence of charge, hydrophilicity and stearic effects on the cataractogenic or cataractinhibiting tendency of the gamma crystallins and beta-gamma crystallin mixtures modified at the cysteine or methionine residues, using selected chemical modifiers. 3. Evaluate the role of alpha-crystallin and its subunits alpha-A and alpha-B in inhibiting protein aggregation due to sulfur-centered modifications of the gamma crystallins and beta gamma crystallin mixtures. 4. Determine the role of individual cysteine and methionine residues in cataractogenesis by introducing point mutations at these residues using site-directed mutagenesis. The long-term objectives are to devise
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strategies to prevent cataractogenic modifications in vivo. The proposed studies in Aim 2 are expected to eventually guide the development of anticataract drug candidates. Changes in the net attraction between lens crystallins will be determined by measuring Tph, the phase separation temperature and protein aggregation. SDS-PAGE, size exclusion HPLC, quasielastic light scattering and protein clouding measurements to determine Tph. Ion-exchange HPLC, low pressure chromatography, isoelectricfocusing, Raman and mass spectroscopies will be used as analytical methods for protein characterization. Molecular modeling studies will guide the selection of reagents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: SYNERGISTIC NUTRACEUTICAL EFFECTS OF DLPC AND SAME Principal Investigator & Institution: Lieber, Charles S.; Professor of Medicine & Pathology; Medicine; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2004; Project Start 15-APR-2004; Project End 31-MAR-2008 Summary: (provided by applicant): Our long-term objective is to develop effective prevention and therapy for liver cirrhosis. One of its nutritional consequences is decreased enzymatic transformation of essential nutrients to their active form, including defective activation of methionine to s-adenosylmethionine (SAMe), with loss of many of methionine's vital functions. This deficiency responds only partially to SAMe supplementation because optimal [cellular function] also requires integrity of the membranes, which are injured by free radical attack on their phosphatidylcholine (PC) infrastructure. This can be overcome through phospholipid replenishment with dilinoleoylphosphatidylcholine (DLPC), a highly bioavailable PC, but SAMe is also required because it is a crucial co-factor in the regeneration of PC through methylation of phosphatidylethanolamine. A major cause of oxidative stress and liver injury is cytochrome P4502E1 (CYP2E1) when induced by either ethanol (in alcoholic liver disease), lipids (in obesity) and ketones (in diabetes). Available CYP2E1 inhibitors are too toxic for clinical use, except for DLPC recently discovered to inhibit CYP2E1. Our immediate aim is to test the synergistic effects of the administration of SAMe + DLPC, using rodent models of precirrhotic alcoholic and nonalcoholic steatohepatitis and CCI4induced cirrhosis. Mechanisms of the beneficial interaction between SAMe and DLPC will be studied in vivo and also in vitro in cultured rodent hepatic stellate cells, Kupffer cells and macrophages, with focus on the preservation of the physiologic anti-oxidant glutathione, the restoration of phosphatidylethanolamine methyltransferase activity, the attenuation of oxidative stress and the resulting NF-?B activation, with lipid peroxidation and rise in the pathogenic cytokines TNF-?, TGF-?1, IL-1? and IL-6. Decreased fibrosis may be achieved through diminished stellate cell activation, enhanced collagenase activity and lowered leptin production. In summary, the synergistic effects of SAMe and DLPC, two innocuous and hepatoprotective nutraceuticals, will be tested against key modalities of experimental liver injury, including non-alcoholic and alcoholic steatohepatitis and CCI4 induced cirrhosis, thereby providing preclinical data needed to ultimately verify, in a clinical trial, the effectiveness of this nutraceutical combination in the prevention and treatment of liver cirrhosis, a common cause of mortality for which effective therapy is presently not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TARGETS OF AMINO ACID RESTRICTION IN PROSTATE CANCER Principal Investigator & Institution: Meadows, Gary G.; Dorothy O. Kennedy Professor & Director,; Pharmaceutical Sciences; Washington State University 423 Neill Hall Pullman, Wa 99164 Timing: Fiscal Year 2004; Project Start 02-JUN-2004; Project End 31-MAY-2009 Summary: (provided by applicant) The objective of this application is to identify the molecular target(s) by which specific amino acid dependency modulates the viability and invasiveness of human androgen-independent prostate cancer calls. We hypothesize that specific amino acid-regulated invasion is dependent on the inhibition of FAK and its binding partners. We further hypothesize that specific amino acidregulated induction of apoptosis is due to the modulation and/or interference in cross talk between the MEKJERK survival pathway and the Akt pathway leading to loss of mitochondrial integrity with consequent activation of effector caspases. The specific aims are: 1) Identify if FAK/Cas/Crk or Rho/Ras pathway is the molecular target(s) of specific amino acid restriction in integrin-mediated attachment/invasion. 2) Determine how specific amino acid restriction modulates and/or interferes with the cross talk between the MEK/ERK and Akt survival pathways. 3) Determine the role(s) of BH123 and/or BH3 proteins of the Bcl-2 protein family on mitochondrial outer membrane permeabilization (MOMP), mitochondrial release of cytochrome c, and apoptosisinducing factor (AIF), and subsequent activation of caspases, and 4) Determine if dietary tyrosine and phenylalanine restriction and methionine restriction will inhibit growth and metastasis of prostate cancer xenografts. Specialized techniques utilized in the application involve cell attachment, migration/invasion, and wounding assays and immunoprecipitation and Western blot analysis. The cellular location of various signaling molecules will be examined with confocal immunofluorescence microscopy. Gene transfection experiments will be used to determine the role of certain cell signaling molecules. Intracellular amino acids will be determined by high pressure liquid chromatography and apoptosis will be measured by flow cytometry. A major benefit from the proposed research proposed is that it will expand knowledge into newer pathways of apoptosis research specific for prostate cancer cells as well as enhance understanding of the mechanisms underlying the anticancer activity of tyrosine/phenylalanine and methionine restriction. This is especially important research since there still is no satisfactory drug for treatment of androgen-independent, metastatic human prostate cancer. This research could serve as the basis for future development of more specific antimetastatic, anti-invasive, apoptosis-based therapies for human prostate cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: THE RELATIONSHIP OF PROTEIN DYNAMICS TO ENZYME CATALYSIS Principal Investigator & Institution: Reich, Norbert O.; Professor; Chemistry and Biochemistry; University of California Santa Barbara 3227 Cheadle Hall Santa Barbara, Ca 93106 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2004 Summary: (provided by the applicant): The principal investigator and his collaborators propose to investigate the importance of protein dynamics on the catalytic rate enhancement of enzymatic methyl transfer. While much attention in the field of enzymatic catalysis is given to transition state stabilization or to entropic arguments, evidence in support of the importance of protein dynamics to catalysis is scant. Proteins
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are certainly known to undergo various types of conformational changes; for example, evidence in support of correlated motions contributing to ligand binding is available. Similar correlated motions have been identified for several enzyme-catalyzed reactions using molecular dynamic simulations. The investigators propose to apply a combination of x-ray crystallography, MD simulations, and functional analyses to provide an experimental and theoretical basis for relating protein dynamics and enzyme reaction rates. They propose to investigate M.HhaI, a bacterial S-adenosyl methionine-dependent DNA cytosine C5 methyltransferase. S-adenosyl methionine-dependent enzymes are widespread in biology and modify nucleic acids, proteins, lipids, carbohydrates, as well as drugs. Mammalian and bacterial DNA methyltransferases are important drug targets for anticancer and antibiotic drugs, respectively. M.HhaI is the best understood Sadenosyl methionine-dependent methyltransferase of any type, since numerous highresolution cocrystal structures are available and both the kinetic and chemical mechanisms are well known. The principal investigator and his collaborators identified structural elements that appear to be important for protein dynamics through inspection of both the M.HhaI-DNA cocrystal structure and MD analysis of the same structure. Several mutants have been prepared and are undergoing crystallographic, multiple conformer (MCA), and MD analyses. They propose to compare this structural and dynamic information with measurements of the methyl transfer rate. Data analysis will focus on correlations between methylation and 1) protein flexibility, 2) interatomic distances, 3) correlated motions, 4) frequency of near attack conformations (NACs), and 5) distribution if conformers. Multiple conformer analysis of the WT M.HhaI-DNA and mutant cocrystal structures will be used to design additional mutants to test the relationship between methylation and correlated motions. An extract-based screen will follow random mutagenesis of segments implicated in correlated motions; candidate mutants will be submitted to the structural and functional analyses. The combination of structural, molecular dynamic, and functional analyses should provide unique insights with potentially broad impact, into how correlated conformational changes contribute to catalysis. M.HhaI represents a class of enzymes with significant medical applications, and a better mechanistic property. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: THE ROLE OF H2-M3 IN T CELL DEVELOPMENT AND IMMUNITY Principal Investigator & Institution: Wang, Chyung-Ru; Associate Professor; Pathology; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002; Project Start 01-JUL-1996; Project End 31-MAY-2006 Summary: (provided by applicant): H2-M3 is an MHC class Ib molecule which preferentially binds N-Formylated peptides. Since all prokaryotes initiate protein synthesis with N-formylated methionine, the peptide binding specificity of M3 is especially suited for presenting these unique microbial antigens to T cells. Consistent with this notion, mice infected with Listeria monocytogenes, generate CD8+ CTLs that recognize N-formylated Listeria peptides presented by M3. Recent studies have shown that M3-restricted T cells expand rapidly during primary Listeria infection, prior to the expansion of class Ia-restricted T cells. However, the expansion of M3-restricted T cells following secondary Listeria infection was rather limited compared with the vigorous recall response of class Ia-restricted T cells. The mechanisms underlying the distinct kinetics of the M3-restricted response are not clear and the significance of M3-restricted T cells in bacterial infection remains to be defined. This application seeks to understand how M3 presents bacterial antigens and how M3 contributes to shaping the T cell repertoire during bacterial infections. First, we will use biochemical and cell biology
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approaches to examine the structural requirements for controlling intracellular trafficking of M3 and to elucidate the pathway for presentation of both endogenous and exogenous listerial antigens by M3. Secondly, we will compare T cell development in the M3-deficient and control mice to determine whether M3 is responsible for selecting unique subset(s) of T cells. Adoptive transfer of naive and memory T cells from D7 transgenic mice, expressing TCR specific for M3/LemA complexes, will be performed to investigate whether M3-restricted T cells have requirements similar to class Ia-restricted T cells for the maintenance of the periphery T cell pools. Thirdly, we will infect M3deficient, class Ia-deficient and control mice with Listeria to examine the relative contribution of class Ia-restricted and M3-restricted responses during Listeria infection, and to determine whether lack of an early M3 response could alter the kinetics and magnitude of class Ia-restricted response. Finally, we will extend our study to explore the functional role of M3-restricted T cells in immunity against Mycobaterium tuberculosis. Study of M3-restricted T cells responses against two distinct groups of intracellular bacteria would shed light on whether early and potent M3-restricted T cell response is unique to Listeria infection or is a general host defense mechanism against intracellular bacterial infection. Understanding the inter-relationship between class Iarestricted and class Ib-restricted responses during the generation of specific immunity may facilitate the development of more effective vaccines. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRANSCRIPTOME OF METASTATIC PROSTATE CANCER Principal Investigator & Institution: Glinsky, Gennadi V.; Associate Professor; Sidney Kimmel Cancer Center San Diego, Ca 921211181 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: (Investigator's Abstract): The goal of this project is to discover genes that are differentially expressed during metastasis of prostate cancer. Potentially such transcripts and their products will be useful in detection, prognosis and ultimately, understanding and treatment of the disease. Because metastasis is a transient and rare event, it is difficult to study. We will concentrate on systems that reveal stark and potentially relevant phenotypic differences among cells of differing metastatic potential in vitro or which appear to model parts of the process in vivo. We have found that cell lines from a variety of different tumor types that differ in their metastatic potential generally demonstrated (i) differential clonogenic growth potential, (ii) strikingly different survival in serum starvation experiments, and (iii) phenotypic reversal of the metastatic phenotypein vitro and in vivo aft treatment with synthetic glycoamines, which are potential anti-metastatic drugs. We have shown that prostate cancer cell lines that differ in metastatic ability are also transcriptionally distinct, monitored on cDNA array. Remarkably, when cells selected for high metastatic ability are serum-starved and treated with glycoamines most of the transcriptional changes that would otherwise occur upon serum removal do not occur. These observations suggest that we can reveal functionally relevant differences in mode1 systems of the process of metastasis. We will study gene expression in an orthotopic human prostate cancer model in nude mice. Gene expression will also be measured during efficacy experiments of the leading clinic drug candidate, the Lac-L-Leu glycosarnine analog. To model one stage of metastasis we will inject cells of differing metastatic potential into the circulation of rabbits, recover cells by magnetic cell sorting base on an epithelial surface antigen, and then monitor changes in gene expression. We will also study leukapheresis-enriched disseminated cancer cells from human volunteers with advanced disease. To determine which, if any, of the gene status changes are likely to be diagnostic, prognostic, or of potential
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mechanistic or therapeutic value, we will examine a selected subset of genes in fresh pathology samples and in the blood-borne human prostate cancer cells using mRNA and protein expression-based assays. A set of 20-30 of the most relevant gene will be selected from the differential gene expression list and the levels of the corresponding proteins will be evaluated in time-course S35-methionine labeling and Western blot experiments. Subsequently the expression profile of these protein products will be studied in human prostate tumor samples by immunofluorescence analysis and immunohistochemistry to better correlate gene expression changes with phenotype. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TRANSLATIONAL REGULATION IN SENDAI VIRUS Principal Investigator & Institution: Peeples, Mark E.; Professor; Rush University Medical Center Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-MAY-2007 Summary: (provided by applicant): The long-term goal of this proposal is to understand the regulation of protein synthesis in mammalian viruses. Our laboratory has focused on the role of mRNA structure on translation. The P/C mRNA of Sendai virus provides an excellent model to dissect translation machinery. It uses five translation start sites to express five proteins (P, C, C', Yl and Y2) in differential amounts. Expression of these proteins is not in accordance with the tenets of ribosome scanning, internal ribosome entry, or the ribosome shunting model. Our studies indicated that the C-AUG must occur in +1 orientation in relation to the P-AUG for the efficient synthesis of C protein. Importantly, all the known viral bicistronic mRNAs with overlapping reading frames have their second AUG in +1 orientation. Thus, one aim of the proposal is to test the hypothesis that the +1 orientation of the downstream reading frame in a bicistronic mRNA is crucial for its efficient initiation. This concept will be examined by constructing mRNAs with three overlapping open reading frames. Appropriate placement of AUG start sites will test the validity of this hypothesis. Second, non-AUG start sites are used efficiently in the P/C mRNA. The 5' UTR of the mRNA appears to be important for translation initiation at non-AUG codons. Third, the Y2 start site (fourth AUG) locus has a high propensity for translation initiation. Chimeric mRNAs will be constructed to define the loci that enhance translation of C' and Y2 proteins. Preliminary results have indicated that long-range interactions in the mRNA play a role in the initiation of all P/C mRNA encoded proteins. To test this, secondary structure of the entire P/C mRNA will be analyzed using both secondary and higher order structureprobing reagents to establish structure-function relationships. Creating deletions within the coding regions of P and C proteins will localize internal regulatory sequences. Fourth, synthesis of C' and certain cellular proteins is resistant to cycloheximide inhibition. Elements and mechanism that allow cycloheximide resistance will be defined. Finally, P/C mRNA binding proteins that are involved in translation regulation will be identified and characterized. Recent studies have shown that the internal initiation can occur on the A site of the ribosome without the initiator methionine tRNA, eIF2 or GTP hydrolysis. This initiation mechanism can explain some of our results. We will test this model for the P/C mRNA. In essence, the proposed studies will define the mechanisms that allow the regulated expression of the polycistronic P/C mRNA. Moreover, these studies will provide insights as to how mRNA structure and its interacting proteins regulate the protein synthesis machinery in mammalian cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: TRANSMISSION OF PRIONS WITHIN AND BETWEEN SPECIES Principal Investigator & Institution: Harrington, Robert D.; Vet Microbiology and Pathology; Washington State University 423 Neill Hall Pullman, Wa 99164 Timing: Fiscal Year 2004; Project Start 01-JUL-2004; Project End 31-MAR-2007 Summary: (provided by applicant): Research Proposal: Transmissible Spongiform Encephalopathies (TSE) are a group of chronic invariably fatal neurodegenerative diseases. Chronic Wasting Disease (CWD) is a form of TSE in wild and captive elk, mule deer, and white tail deer. Oral transmission has been documented in many TSE's, and has been experimentally reproduced in deer given CWD infectious material. The oral transmissibility of CWD to other species remains uncertain. Potential hosts for CWD includehumans that consume venison, wild carnivores, and agriculturally important ruminants. Genetic polymorphismsthat effect TSE susceptibility have been identified for some species and may effect transmission of CWD. I will test the oral infectivityof CWD in a transgenic model to determine the effect of an amino acid polymorphism on disease susceptibility. I will test oral infectivity in a natural TSE host to further define the host range of TSE between species. Such studies are timely and topical due to the geographic spread of CWD positive animals and evidence that Bovine Spongiform Encephalopathy, the TSE affecting cattle, has zoonotic potential. The Candidate: The candidate is a veterinarian who has recently completed a residency in Comparative Medicine at the University of Washington School of Medicine. He has matriculated into the Washington State University Department of Veterinary Microbiology and Pathology for additional research training to culminate in the Doctor of Philosophy degree. The continuation of mentored training in biomedical research, with particular emphasis on continued investigation into the pathogenesis of TSE's, is necessary for development as an independent and collaborative investigator. The Environment: The research project will create a unique collaborative opportunity drawing on the resources and relevant expertise of both Washington State University and the University of Washington. Washington State University will provide interaction with internationally recognized faculty who have expertise in the study of Transmissible Spongiform Encephalopathies. The University of Washington and associated Comparative Medicine Transgenic Resource Laboratory will provide interaction with faculty and staff who have extensive experience in transgenic technology and the use of mutant mice in modern biomedical research. Both universities have established educational programs with a productive history of training veterinarians in biomedical research. Activities include weekly literature review, clinical-pathologic conferences, and research seminars. Participation in educational and training opportunities from these multiple sources will provide Dr. Harrington with a well rounded scientific background and allow specific research training pertinent to his area of research interest. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: X-RAY STRUCTURES OF EUKARYOTIC TRANSLATION FACTORS Principal Investigator & Institution: Bonanno, Jeffrey B.; Lab/Molecular Biophysics; Rockefeller University New York, Ny 100216399 Timing: Fiscal Year 2002; Project Start 01-MAR-2000; Project End 31-DEC-2002 Summary: The long-term goal of the proposed research is a detailed structural and mechanistic understanding of the enormously complex macromolecular machine that controls translation initiation in eukaryotes. The proposed work builds on our structural and functional studies of mRNA selection by the cap-binding protein, eukaryotic initiation factor 4E or eIF4E. X-ray crystallography will be combined with chemical
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methods to study the structures and mechanisms of action of an important subset of the remaining translation initiation factors [eIF4G, eIF4A, eIF2, IF2, eIF3, eIF1A, eIF2B, eIF5, the poly (A)-binding protein (PABP), and a PABP-interacting protein]. These translation factors participate in the following biochemical steps: (a) resolving secondary structural features in the 5' untranslated region of the mRNA, (b) delivering the methionyl initiator tRNA to the 40S subunit, (d) recycling the G protein that loads the methionyl initiator tRNA onto the 40S subunit, (d) recruitment of the 40S subunit, the methionyl initiator tRNA and various accessory factors to the 5' untranslated region of cellular mRNAs bearing 5' 7-methyl-G caps, (e) recruitment of the same components to the 5' untranslated region of an uncapped viral RNA, (f) 60S ribosomal subunit joining, and (g) synergy of transcription initiation via mRNA circularization by the PABP. The specific aims of the research are as follows: Specific Aim 1. Determine X-ray structures of the RNA helicase eIF4A, and its complexes with ADP, a non-hydrolyzable ATP analog, and single-stranded RNA. Specific Aim 2. Determine X-ray structures of eIF2, and its complexes with GDP, a non-hydrolyzable GTP analog, and methionyl initiator tRNA. Specific Aim 3. Determine the X-ray structure of eukaryotic IF2. Specific Aim 4. Determine X-ray structures of a C-terminal fragment of eIF4G, and its complex with a picornavirus internal ribosome entry site. Specific Aim 5. Determine X-ray structures of eIF5 and eIF2Bepsilon, and their complexes with eIF2beta. Specific Aim 6. Determine Xray structures of PABP recognizing poly (A) RNA, and various binary and ternary complexes with a PABP-interacting protein and eIF4G. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “methionine” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for methionine in the PubMed Central database: •
A Gene Controlling Variation in Arabidopsis Glucosinolate Composition Is Part of the Methionine Chain Elongation Pathway. by Kroymann J, Textor S, Tokuhisa JG, Falk KL, Bartram S, Gershenzon J, Mitchell-Olds T.; 2001 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=129277
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A homologue of elongation factor 1[gamma] regulates methionine sulfoxide reductase A gene expression in Saccharomyces cerevisiae. by Hanbauer I, Boja ES, Moskovitz J.; 2003 Jul 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=166206
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Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.
With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.
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A new methionine locus, metR, that encodes a trans-acting protein required for activation of metE and metH in Escherichia coli and Salmonella typhimurium. by Urbanowski ML, Stauffer LT, Plamann LS, Stauffer GV.; 1987 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=211958
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A Test of the ``Jigsaw Puzzle" Model for Protein Folding by Multiple Methionine Substitutions within the Core of T4 Lysozyme. by Gassner NC, Baase WA, Matthews BW.; 1996 Oct 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=37959
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Acidic sphingomyelinase downregulates the liver-specific methionine adenosyltransferase 1A, contributing to tumor necrosis factor --induced lethal hepatitis. by Mari M, Colell A, Morales A, Paneda C, Varela-Nieto I, Garcia-Ruiz C, Fernandez-Checa JC.; 2004 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=362116
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Altered regulation of the glnRA operon in a Bacillus subtilis mutant that produces methionine sulfoximine-tolerant glutamine synthetase. by Schreier HJ, Rostkowski CA, Kellner EM.; 1993 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=196239
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Aminoacylation Identity Switch of Turnip Yellow Mosaic Virus RNA from Valine to Methionine Results in an Infectious Virus. by Dreher TW, Tsai C, Skuzeski JM.; 1996 Oct 29; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=37969
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An anticodon change switches the identity of E. coli tRNA(mMet) from methionine to threonine. by Schulman LH, Pelka H.; 1990 Jan 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=330265
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Antisense Inhibition of Threonine Synthase Leads to High Methionine Content in Transgenic Potato Plants. by Zeh M, Casazza AP, Kreft O, Roessner U, Bieberich K, Willmitzer L, Hoefgen R, Hesse H.; 2001 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=129252
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Aromatic Amino Acid Transamination and Methionine Recycling in Trypanosomatids. by Berger BJ, Dai WW, Wang H, Stark RE, Cerami A.; 1996 Apr 30; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=39498
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Bacterial variations on the methionine salvage pathway. by Sekowska A, Denervaud V, Ashida H, Michoud K, Haas D, Yokota A, Danchin A.; 2004; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=395828
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Biochemical and regulatory effects of methionine analogues in Saccharomyces cerevisiae. by Colombani F, Cherest H, de Robichon-Szulmajster H.; 1975 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=246067
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Carbon dioxide stimulates peroxynitrite-mediated nitration of tyrosine residues and inhibits oxidation of methionine residues of glutamine synthetase: Both
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modifications mimic effects of adenylylation. by Berlett BS, Levine RL, Stadtman ER.; 1998 Mar 17; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19646 •
Characterization of Salmonella typhimurium Strains Sensitive and Resistant to Methionine Sulfoximine. by Steimer-Veale K, Brenchley JE.; 1974 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=245690
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Cobalamin inactivation decreases purine and methionine synthesis in cultured lymphoblasts. by Boss GR.; 1985 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=423748
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Constitutive Overexpression of Cystathionine [gamma]-Synthase in Arabidopsis Leads to Accumulation of Soluble Methionine and S-Methylmethionine. by Kim J, Lee M, Chalam R, Martin MN, Leustek T, Boerjan W.; 2002 Jan 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=148947
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Control of protein life-span by N-terminal methionine excision. by Giglione C, Vallon O, Meinnel T.; 2003 Jan 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140049
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Corynebacterium glutamicum Utilizes both Transsulfuration and Direct Sulfhydrylation Pathways for Methionine Biosynthesis. by Hwang BJ, Yeom HJ, Kim Y, Lee HS.; 2002 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=134843
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Decreased methionine synthesis in purine nucleoside-treated T and B lymphoblasts and reversal by homocysteine. by Boss GR, Pilz RB.; 1984 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=425293
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Dimethylsulfoniopropionate and Methanethiol Are Important Precursors of Methionine and Protein-Sulfur in Marine Bacterioplankton. by Kiene RP, Linn LJ, Gonzalez J, Moran MA, Bruton JA.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=91606
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Direct Sulfhydrylation for Methionine Biosynthesis in Leptospira meyeri. by Belfaiza J, Martel A, Margarita D, Saint Girons I.; 1998 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=106879
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DNA binding of CPF1 is required for optimal centromere function but not for maintaining methionine prototrophy in yeast. by Mellor J, Rathjen J, Jiang W, Barnes CA, Dowell SJ.; 1991 Jun 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=328258
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Effects of methionine on the cytoplasmic distribution of actin and tubulin during neural tube closure in rat embryos. by Moephuli SR, Klein NW, Baldwin MT, Krider HM.; 1997 Jan 21; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=19549
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Effects of Regulatory Mutations upon Methionine Biosynthesis in Saccharomyces cerevisiae: Loci eth2-eth3-eth10. by Cherest H, Surdin-Kerjan Y, Antoniewski J, de Robichon-Szulmajster H.; 1973 Sep; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=246357
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Enhanced methionine levels and increased nutritive value of seeds of transgenic lupins (Lupinus angustifolius L.) expressing a sunflower seed albumin gene. by Molvig L, Tabe LM, Eggum BO, Moore AE, Craig S, Spencer D, Higgins TJ.; 1997 Aug 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22931
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Enzymatic reduction of protein-bound methionine sulfoxide. by Brot N, Weissbach L, Werth J, Weissbach H.; 1981 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=319302
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Escherichia coli peptide methionine sulfoxide reductase gene: regulation of expression and role in protecting against oxidative damage. by Moskovitz J, Rahman MA, Strassman J, Yancey SO, Kushner SR, Brot N, Weissbach H.; 1995 Feb; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=176620
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Existence of two levels of repression in the biosynthesis of methionine in Saccharomyces cerevisiae: effect of lomofungin on enzyme synthesis. by SurdinKerjan Y, de Robichon-Szulmajster H.; 1975 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=246066
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Exogenous methionine increases levels of mRNAs transcribed from pcbAB, pcbC, and cefEF genes, encoding enzymes of the cephalosporin biosynthetic pathway, in Acremonium chrysogenum. by Velasco J, Gutierrez S, Fernandez FJ, Marcos AT, Arenos C, Martin JF.; 1994 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=205148
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Extracting biological information from DNA arrays: an unexpected link between arginine and methionine metabolism in Bacillus subtilis. by Sekowska A, Robin S, Daudin JJ, Henaut A, Danchin A.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33395
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Factors Affecting Virulence of Shigella flexneri: Defective Methionine Synthesis in an Escherichia coli-Shigella Hybrid. by Rothman SW, Corwin LM.; 1972 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=251393
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Factors modulating conformational equilibria in large modular proteins: A case study with cobalamin-dependent methionine synthase. by Bandarian V, Ludwig ML, Matthews RG.; 2003 Jul 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=166199
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Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig. by Halsted CH, Villanueva JA, Devlin AM, Niemela O, Parkkila S, Garrow TA, Wallock LM, Shigenaga MK, Melnyk S, James SJ.; 2002 Jul 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=126626
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High in vivo rates of methionine biosynthesis in transformed human and malignant rat cells auxotrophic for methionine. by Hoffman RM, Erbe RW.; 1976 May; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=430329
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Homoserine O-acetyltransferase, involved in the Leptospira meyeri methionine biosynthetic pathway, is not feedback inhibited. by Bourhy P, Martel A, Margarita D, Saint Girons I, Belfaiza J.; 1997 Jul; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=179265
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Identification of L-Methionine-S-Sulfoximine as the Convulsant Isomer of Methionine Sulfoximine. by Rowe WB, Meister A.; 1970 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=283073
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In Vitro and In Vivo Oxidation of Methionine Residues in Small, Acid-Soluble Spore Proteins from Bacillus Species. by Hayes CS, Illades-Aguiar B, Casillas-Martinez L, Setlow P.; 1998 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107222
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In vivo growth characteristics of leucine and methionine auxotrophic mutants of Mycobacterium bovis BCG generated by transposon mutagenesis. by McAdam RA, Weisbrod TR, Martin J, Scuderi JD, Brown AM, Cirillo JD, Bloom BR, Jacobs WR Jr.; 1995 Mar; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=173102
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Induction and Repression in the S-Adenosylmethionine and Methionine Biosynthetic Systems of Saccharomyces cerevisiae. by Ferro AJ, Spence KD.; 1973 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=285450
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Insertional Inactivation of the Methionine S-Methyltransferase Gene Eliminates the S-Methylmethionine Cycle and Increases the Methylation Ratio. by Kocsis MG, Ranocha P, Gage DA, Simon ES, Rhodes D, Peel GJ, Mellema S, Saito K, Awazuhara M, Li C, Meeley RB, Tarczynski MC, Wagner C, Hanson AD.; 2003 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=166937
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Interference by methionine on valine uptake in Acremonium chrysogenum. by Alonso MJ, Luengo JM.; 1987 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=174728
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Involvement of folic acid and methionine in the synthesis of certain membraneassociated nucleotide sugars by Enterococcus hirae. by Wood RC.; 1994 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=196834
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Mapping the interactions between flavodoxin and its physiological partners flavodoxin reductase and cobalamin-dependent methionine synthase. by Hall DA, Vander Kooi CW, Stasik CN, Stevens SY, Zuiderweg ER, Matthews RG.; 2001 Aug 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=55485
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Methionine sulfoxide is transported by high-affinity methionine and glutamine transport systems in Salmonella typhimurium. by Ayling PD.; 1981 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=216234
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Modification of protein surface hydrophobicity and methionine oxidation by oxidative systems. by Chao CC, Ma YS, Stadtman ER.; 1997 Apr 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=20306
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Modulation of potassium channel function by methionine oxidation and reduction. by Ciorba MA, Heinemann SH, Weissbach H, Brot N, Hoshi T.; 1997 Sep 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23300
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Molecular Characterization and Sequence of a Methionine Biosynthetic Locus from Pseudomonas syringae. by Andersen GL, Beattie GA, Lindow SE.; 1998 Sep 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107460
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Molecular mechanisms of an inborn error of methionine pathway. Methionine adenosyltransferase deficiency. by Ubagai T, Lei KJ, Huang S, Mudd SH, Levy HL, Chou JY.; 1995 Oct; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=185831
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MtaR, a Regulator of Methionine Transport, Is Critical for Survival of Group B Streptococcus In Vivo. by Shelver D, Rajagopal L, Harris TO, Rubens CE.; 2003 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=262094
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Mutation in the Threonine Synthase Gene Results in an Over-Accumulation of Soluble Methionine in Arabidopsis. by Bartlem D, Lambein I, Okamoto T, Itaya A, Uda Y, Kijima F, Tamaki Y, Nambara E, Naito S.; 2000 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=58986
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Mutations affecting regulation of methionine biosynthetic genes isolated by use of met-lac fusions. by Mulligan JT, Margolin W, Krueger JH, Walker GC.; 1982 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=220301
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Myeloperoxidase-Mediated Oxidation of Methionine and Amino Acid Decarboxylation. by Tsan MF.; 1982 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=351195
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N-terminal RAG1 frameshift mutations in Omenn's syndrome: Internal methionine usage leads to partial V(D)J recombination activity and reveals a fundamental role in vivo for the N-terminal domains. by Santagata S, Gomez CA, Sobacchi C, Bozzi F, Abinun M, Pasic S, Cortes P, Vezzoni P, Villa A.; 2000 Dec 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=18960
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One- and two-electron oxidations of methionine by peroxynitrite. by Pryor WA, Jin X, Squadrito GL.; 1994 Nov 8; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=45189
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Oxidation of methionine residues in proteins of activated human neutrophils. by Fliss H, Weissbach H, Brot N.; 1983 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=390013
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Partial purification and some properties of homoserine O-acetyltransferase of a methionine auxotroph of Saccharomyces cerevisiae. by Yamagata S.; 1987 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=212417
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Peptide methionine sulfoxide reductase from Escherichia coli and Mycobacterium tuberculosis protects bacteria against oxidative damage from reactive nitrogen intermediates. by John GS, Brot N, Ruan J, Erdjument-Bromage H, Tempst P, Weissbach H, Nathan C.; 2001 Aug 14; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=55550
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Peroxynitrite-mediated modification of proteins at physiological carbon dioxide concentration: pH dependence of carbonyl formation, tyrosine nitration, and methionine oxidation. by Tien M, Berlett BS, Levine RL, Chock PB, Stadtman ER.; 1999 Jul 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22143
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Physical mapping of the scattered methionine genes on the Escherichia coli chromosome. by Old IG, Saint Girons I, Richaud C.; 1993 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=204776
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Probing the molecular mechanism of action of co-repressor in the E. coli methionine repressor-operator complex using surface plasmon resonance (SPR). by Parsons ID, Persson B, Mekhalfia A, Blackburn GM, Stockley PG.; 1995 Jan 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=306656
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Processing of the initiation methionine from proteins: properties of the Escherichia coli methionine aminopeptidase and its gene structure. by Ben-Bassat A, Bauer K, Chang SY, Myambo K, Boosman A, Chang S.; 1987 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=211843
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Properties of Mutant SHV-5 [beta]-Lactamases Constructed by Substitution of Isoleucine or Valine for Methionine at Position 69. by Giakkoupi P, Miriagou V, Gazouli M, Tzelepi E, Legakis NJ, Tzouvelekis LS.; 1998 May; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=105805
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Reduced availability of endogenously synthesized methionine for Sadenosylmethionine formation in methionine-dependent cancer cells. by Coalson DW, Mecham JO, Stern PH, Hoffman RM.; 1982 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=346647
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Reduction of methionine sulfoxide to methionine by Escherichia coli. by Ejiri SI, Weissbach H, Brot N.; 1979 Jul; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=216841
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Regulation of methionine transport activity in Escherichia coli. by Kadner RJ.; 1975 Apr; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=235647
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Regulation of the Methionine Feedback-Sensitive Enzyme in Mutants of Salmonella typhimurium. by Lawrence DA.; 1972 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=247244
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Repression of the tyrosine, lysine, and methionine biosynthetic pathways in a hisT mutant of Salmonella typhimurium. by Brown BA, Lax SR, Liang L, Dabney BJ, Spremulli LL, Ravel JM.; 1977 Feb; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=235064
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Role of methionine and formylation of initiator tRNA in initiation of protein synthesis in Escherichia coli. by Varshney U, RajBhandary UL.; 1992 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=207498
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Role of methionine in bacterial chemotaxis: requirement for tumbling and involvement in information processing. by Springer MS, Kort EN, Larsen SH, Ordal GW, Reader RW, Adler J.; 1975 Nov; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=388779
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Role of Methionine in Biosynthesis of Prodigiosin by Serratia marcescens. by Qadri SM, Williams RP.; 1973 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=246475
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S-Adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: A double-blind cross-over trial. [ISRCTN36233495]. by Najm WI, Reinsch S, Hoehler F, Tobis JS, Harvey PW.; 2004; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=387830
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S-adenosyl methionine alters the DNA contacts of the EcoKI methyltransferase. by Powell LM, Murray NE.; 1995 Mar 25; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=306793
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S-Adenosyl Methionine-Mediated Repression of Methionine Biosynthetic Enzymes in Saccharomyces cerevisiae. by Cherest H, Surdin-Kerjan Y, Antoniewski J, De Robichon-Szulmajster H.; 1973 Jun; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=285346
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Selenoprotein R is a zinc-containing stereo-specific methionine sulfoxide reductase. by Kryukov GV, Kumar RA, Koc A, Sun Z, Gladyshev VN.; 2002 Apr 2; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=123633
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Sinorhizobium meliloti Cells Require Biotin and either Cobalt or Methionine for Growth. by Watson RJ, Heys R, Martin T, Savard M.; 2001 Aug; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=93089
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Structure of Mycobacterium tuberculosis Methionine Sulfoxide Reductase A in Complex with Protein-Bound Methionine. by Taylor AB, Benglis, Jr. DM, Dhandayuthapani S, Hart PJ.; 2003 Jul 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=164888
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Synergistic activity of 5-trifluoromethylthioribose and inhibitors of methionine synthesis against Klebsiella pneumoniae. by Tower PA, Johnson LL, Ferro AJ, Fitchen JH, Riscoe MK.; 1991 Aug; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=245218
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Targeted Disruption of the Methionine Synthase Gene in Mice. by Swanson DA, Liu ML, Baker PJ, Garrett L, Stitzel M, Wu J, Harris M, Banerjee R, Shane B, Brody LC.; 2001 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=99560
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Targeted Inactivation of the mecB Gene, Encoding Cystathionine-[gamma]-Lyase, Shows that the Reverse Transsulfuration Pathway Is Required for High-Level Cephalosporin Biosynthesis in Acremonium chrysogenum C10 but Not for Methionine Induction of the Cephalosporin Genes. by Liu G, Casqueiro J, Banuelos O, Cardoza RE, Gutierrez S, Martin JF.; 2001 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=95063
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The Abundance of Met30p Limits SCFMet30p Complex Activity and Is Regulated by Methionine Availability. by Smothers DB, Kozubowski L, Dixon C, Goebl MG, Mathias N.; 2000 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=86396
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The anticodon triplet is not sufficient to confer methionine acceptance to a transfer RNA. by Senger B, Despons L, Walter P, Fasiolo F.; 1992 Nov 15; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=50423
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The atherogenic effect of excess methionine intake. by Troen AM, Lutgens E, Smith DE, Rosenberg IH, Selhub J.; 2003 Dec 9; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=299913
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The effect on endothelial function of vitamin C during methionine induced hyperhomocysteinaemia. by Hanratty CG, McGrath LT, McAuley DF, Young IS, Johnston DG.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34516
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The Folate Branch of the Methionine Biosynthesis Pathway in Streptomyces lividans: Disruption of the 5,10-Methylenetetrahydrofolate Reductase Gene Leads to Methionine Auxotrophy. by Blanco J, Coque JJ, Martin JF.; 1998 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=107064
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The methionine salvage pathway in Bacillus subtilis. by Sekowska A, Danchin A.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=113757
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The N-Terminal Region of Arabidopsis Cystathionine [gamma]-Synthase Plays an Important Regulatory Role in Methionine Metabolism. by Hacham Y, Avraham T, Amir R.; 2002 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=148908
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The specific features of methionine biosynthesis and metabolism in plants. by Ravanel S, Gakiere B, Job D, Douce R.; 1998 Jun 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22764
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The UL3 Protein of Herpes Simplex Virus 1 Is Translated Predominantly from the Second In-Frame Methionine Codon and Is Subject to at Least Two Posttranslational Modifications. by Markovitz NS, Filatov F, Roizman B.; 1999 Oct; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=112816
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Transport and utilization of D-methionine and other methionine sources in Escherichia coli. by Kadner RJ.; 1977 Jan; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=234917
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Trifluoromethionine, a Prodrug Designed against Methionine [gamma]-LyaseContaining Pathogens, Has Efficacy In Vitro and In Vivo against Trichomonas vaginalis. by Coombs GH, Mottram JC.; 2001 Jun; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90540
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Tyrosine Aminotransferase Catalyzes the Final Step of Methionine Recycling in Klebsiella pneumoniae. by Heilbronn J, Wilson J, Berger BJ.; 1999 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=93571
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Unique efficiency of methionine metabolism in premenopausal women may protect against vascular disease in the reproductive years. by Boers GH, Smals AG, Trijbels FJ, Leermakers AI, Kloppenborg PW.; 1983 Dec; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=437037
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Use of 13C Nuclear Magnetic Resonance and Gas Chromatography To Examine Methionine Catabolism by Lactococci. by Gao S, Mooberry ES, Steele JL.; 1998 Dec; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=90907
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Yeast mitochondrial methionine initiator tRNA: characterization and nucleotide sequence. by Canaday J, Dirheimer G, Martin RP.; 1980 Apr 11; http://www.pubmedcentral.gov/picrender.fcgi?tool=pmcentrez&action=stream&blobt ype=pdf&artid=324008
The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with methionine, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “methionine” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for methionine (hyperlinks lead to article summaries): •
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A 2-step strategy to reduce the need for methionine-loading tests to diagnose hyperhomocysteinemia. Author(s): van de Laak MF, Grobbee DE, van der Griend R, de Valk HW, Algra A, Banga JD, van der Graaf Y; Smart study group. Source: The Journal of Laboratory and Clinical Medicine. 2003 August; 142(2): 121-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12960959
PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.
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A critical role of water in the specific cleavage of the anticodon loop of some eukaryotic methionine initiator tRNAs. Author(s): Perbandt M, Barciszewska MZ, Betzel C, Erdmann VA, Barciszewski J. Source: Molecular Biology Reports. 2003 March; 30(1): 27-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12688532
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A double-blind, randomized parallel-group, efficacy and safety study of intramuscular S-adenosyl-L-methionine 1,4-butanedisulphonate (SAMe) versus imipramine in patients with major depressive disorder. Author(s): Pancheri P, Scapicchio P, Chiaie RD. Source: The International Journal of Neuropsychopharmacology / Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum (Cinp). 2002 December; 5(4): 287-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12466028
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A methionine aminopeptidase-2 inhibitor, PPI-2458, for the treatment of rheumatoid arthritis. Author(s): Bernier SG, Lazarus DD, Clark E, Doyle B, Labenski MT, Thompson CD, Westlin WF, Hannig G. Source: Proceedings of the National Academy of Sciences of the United States of America. 2004 July 20; 101(29): 10768-73. Epub 2004 Jul 12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15249666
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A novel inborn error of metabolism detected by elevated methionine and/or galactose in newborn screening: neonatal intrahepatic cholestasis caused by citrin deficiency. Author(s): Ohura T, Kobayashi K, Abukawa D, Tazawa Y, Aikawa J, Sakamoto O, Saheki T, Iinuma K. Source: European Journal of Pediatrics. 2003 May; 162(5): 317-22. Epub 2003 February 27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12692712
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A novel methionine-based signaling mechanism regulating the expression of thymidylate synthase. Author(s): Chu E. Source: Cancer Biology & Therapy. 2003 July-August; 2(4): 370-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14508107
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A randomised controlled trial of ursodeoxycholic acid and S-adenosyl-l-methionine in the treatment of gestational cholestasis. Author(s): Roncaglia N, Locatelli A, Arreghini A, Assi F, Cameroni I, Pezzullo JC, Ghidini A. Source: Bjog : an International Journal of Obstetrics and Gynaecology. 2004 January; 111(1): 17-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14687046
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A single amino acid residue defines the difference in ovalicin sensitivity between type I and II methionine aminopeptidases. Author(s): Brdlik CM, Crews CM. Source: The Journal of Biological Chemistry. 2004 March 5; 279(10): 9475-80. Epub 2003 December 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14676204
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A valine to methionine polymorphism at codon 83 in the 8-oxo-dGTPase gene MTH1 is not associated with sporadic Parkinson's disease. Author(s): Satoh J, Kuroda Y. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. 2000 November; 7(6): 673-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11136354
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Activity of Se-allylselenocysteine in the presence of methionine gamma-lyase on cell growth, DNA integrity, apoptosis, and cell-cycle regulatory molecules. Author(s): Zhu Z, Jiang W, Ganther HE, Ip C, Thompson HJ. Source: Molecular Carcinogenesis. 2000 December; 29(4): 191-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11170256
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Activity, tissue distribution and site-directed mutagenesis of a human peptide methionine sulfoxide reductase of type B: hCBS1. Author(s): Jung S, Hansel A, Kasperczyk H, Hoshi T, Heinemann SH. Source: Febs Letters. 2002 September 11; 527(1-3): 91-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12220640
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Acute methionine loading does not alter arterial stiffness in humans. Author(s): Wilkinson IB, Megson IL, MacCallum T, Rooijmans DF, Johnson SM, Boyd JL, Cockcroft JR, Webb DJ. Source: Journal of Cardiovascular Pharmacology. 2001 January; 37(1): 1-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11152366
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Alcohol, folate, methionine, and risk of incident breast cancer in the American Cancer Society Cancer Prevention Study II Nutrition Cohort. Author(s): Feigelson HS, Jonas CR, Robertson AS, McCullough ML, Thun MJ, Calle EE. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2003 February; 12(2): 161-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12582027
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Alzheimer's amyloid beta-peptide (1-42): involvement of methionine residue 35 in the oxidative stress and neurotoxicity properties of this peptide. Author(s): Butterfield DA, Bush AI. Source: Neurobiology of Aging. 2004 May-June; 25(5): 563-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15172731
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An unusual peptide deformylase features in the human mitochondrial N-terminal methionine excision pathway. Author(s): Serero A, Giglione C, Sardini A, Martinez-Sanz J, Meinnel T. Source: The Journal of Biological Chemistry. 2003 December 26; 278(52): 52953-63. Epub 2003 October 07. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14532271
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Arterial stiffness is rapidly induced by raising the plasma homocysteine concentration with methionine. Author(s): Nestel PJ, Chronopoulos A, Cehun M. Source: Atherosclerosis. 2003 November; 171(1): 83-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14642409
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Association of IL-1 RN*2 allele and methionine synthase 2756 AA genotype with dementia severity of sporadic Alzheimer's disease. Author(s): Bosco P, Gueant-Rodriguez RM, Anello G, Romano A, Namour B, Spada RS, Caraci F, Tringali G, Ferri R, Gueant JL. Source: Journal of Neurology, Neurosurgery, and Psychiatry. 2004 July; 75(7): 1036-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15201366
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Asymmetric dimethylarginine and total homocysteine in plasma after oral methionine loading. Author(s): Wanby P, Brattstrom L, Brudin L, Hultberg B, Teerlink T. Source: Scandinavian Journal of Clinical and Laboratory Investigation. 2003; 63(5): 34753. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14599157
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Basal and post-methionine serum homocysteine and lipoprotein abnormalities in patients with chronic liver disease. Author(s): Ben-Ari Z, Tur-Kaspa R, Schafer Z, Baruch Y, Sulkes J, Atzmon O, Greenberg A, Levi N, Fainaru M. Source: Journal of Investigative Medicine : the Official Publication of the American Federation for Clinical Research. 2001 July; 49(4): 325-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11478408
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Beneficial effect of S-adenosyl-L-methionine in lead intoxication. Another approach to clinical therapy. Author(s): Paredes SR, Juknat de Geralnik AA, Batlle AM, Conti HA. Source: Int J Biochem. 1985; 17(5): 625-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2863186
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Beta adrenergic modulation of formyl-methionine-leucine-phenylalanine-stimulated secretion of eosinophil peroxidase and leukotriene C4. Author(s): Munoz NM, Vita AJ, Neeley SP, McAllister K, Spaethe SM, White SR, Leff AR. Source: The Journal of Pharmacology and Experimental Therapeutics. 1994 January; 268(1): 139-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8301549
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Beta-endorphin-, leucine enkephalinand methionine enkephalin-like immunoreactivity in human cerebrospinal fluid. Simultaneous determination and relation to neurological disorders. Author(s): Neuser D, Lesch KP, Stasch JP, Przuntek H. Source: European Neurology. 1984; 23(2): 73-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6327313
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Binding of alpha-hydroxy-beta-amino acid inhibitors to methionine aminopeptidase. The performance of two types of scoring functions. Author(s): Jorgensen AT, Sorensen MD, Bjorkling F, Liljefors T. Source: Journal of Computer-Aided Molecular Design. 2003 May-June; 17(5-6): 383-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14635729
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Biochemical analysis of the role of transmethylation in the methionine dependence of tumor cells. Author(s): Judde JG, Ellis M, Frost P. Source: Cancer Research. 1989 September 1; 49(17): 4859-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2503245
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Biochemical aspect of dimethyl sulfide breath test in the studies on methionine metabolism. Author(s): Kaji H, Hisamura M, Saito N, Murao M. Source: Res Commun Chem Pathol Pharmacol. 1981 June; 32(3): 515-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7268195
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Biochemical basis for the dominant inheritance of hypermethioninemia associated with the R264H mutation of the MAT1A gene. A monomeric methionine adenosyltransferase with tripolyphosphatase activity. Author(s): Perez Mato I, Sanchez del Pino MM, Chamberlin ME, Mudd SH, Mato JM, Corrales FJ. Source: The Journal of Biological Chemistry. 2001 April 27; 276(17): 13803-9. Epub 2001 January 30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11278456
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Biochemical marker in familial amyloidotic polyneuropathy, Portuguese type. Family studies on the transthyretin (prealbumin)-methionine-30 variant. Author(s): Saraiva MJ, Costa PP, Goodman DS. Source: The Journal of Clinical Investigation. 1985 December; 76(6): 2171-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3908483
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Biochemistry and pharmacology of S-adenosyl-L-methionine and rationale for its use in liver disease. Author(s): Chawla RK, Bonkovsky HL, Galambos JT. Source: Drugs. 1990; 40 Suppl 3: 98-110. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2081485
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Blood S-adenosyl-L-methionine levels in psychiatric disorders. Author(s): Cohen BM, Lipinski JF, Vuckovic A, Prosser E. Source: The American Journal of Psychiatry. 1982 February; 139(2): 229-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7055296
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Blood viscosity and red cell morphology in subjects suffering from cirrhosis before and after treatment with S-adenosyl-L-methionine (SAM). Author(s): Turchetti V, Bellini MA, Leoncini F, Petri F, Trabalzini L, Guerrini M, Forconi S. Source: Clinical Hemorheology and Microcirculation. 2000; 22(3): 215-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10976715
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Brady-tachycardia syndrome after radiotherapy for lung cancer. Assessment by computed tomography and carbon-11 methionine positron emission tomography. Author(s): Watanabe T, Okazaki O, Izumo K, Michihata T, Katagiri T, Harumi K. Source: Japanese Heart Journal. 1999 September; 40(5): 677-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10888388
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Brain ATP:L-methionine S-adenosyltransferase (MAT), S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH): regional distribution and age-related changes. Author(s): Trolin CG, Lofberg C, Trolin G, Oreland L. Source: European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology. 1994 December; 4(4): 469-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7894257
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Brain methionine- and leucine-enkephalin receptors in patients with dementia. Author(s): Rinne JO, Lonnberg P, Marjamaki P, Molsa P, Sako E, Paljarvi L. Source: Neuroscience Letters. 1993 October 14; 161(1): 77-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8255552
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Brain tumor imaging using C-11-labeled L-methionine and D-methionine. Author(s): Schober O, Meyer GJ, Stolke D, Hundeshagen H. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 1985 January; 26(1): 98-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3965661
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Brain tumor protein synthesis and histological grades: a study by positron emission tomography (PET) with C11-L-Methionine. Author(s): Bustany P, Chatel M, Derlon JM, Darcel F, Sgouropoulos P, Soussaline F, Syrota A. Source: Journal of Neuro-Oncology. 1986; 3(4): 397-404. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3485705
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Brain uptake of 11C-methionine in phenylketonuria. Author(s): Comar D, Saudubray JM, Duthilleul A, Delforge J, Maziere M, Berger G, Charpentier C, Todd-Pokropek A. Source: European Journal of Pediatrics. 1981 March; 136(1): 13-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7215387
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Brittle and sparse hair with normal cystine content caused by methionine deficiency? Author(s): Goerz G, Behrens W, Megahed M, Kuester W, Fohles J, Tsambaos D, Nikiforidis G, Balas C. Source: Acta Dermato-Venereologica. 1996 January; 76(1): 62-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8721497
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C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene: incidence and effect of combined genotypes on plasma fasting and post-methionine load homocysteine in vascular disease. Author(s): Hanson NQ, Aras O, Yang F, Tsai MY. Source: Clinical Chemistry. 2001 April; 47(4): 661-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11274015
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Can dietary methionine restriction increase the effectiveness of chemotherapy in treatment of advanced cancer? Author(s): Epner DE. Source: Journal of the American College of Nutrition. 2001 October; 20(5 Suppl): 443S449S; Discussion 473S-475S. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11603655
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CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in two families. Author(s): Zavadakova P, Fowler B, Zeman J, Suormala T, Pristoupilova K, Kozich V, Zavad'akova P. Source: Journal of Inherited Metabolic Disease. 2002 October; 25(6): 461-76. Erratum In: J Inherit Metab Dis. 2003; 26(1): 95. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12555939
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Certain metals trigger fibrillation of methionine-oxidized alpha-synuclein. Author(s): Yamin G, Glaser CB, Uversky VN, Fink AL. Source: The Journal of Biological Chemistry. 2003 July 25; 278(30): 27630-5. Epub 2003 May 16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12754258
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Changes in pulmonary vascular function after acute methionine loading in normal men. Author(s): O'Dochartaigh C, Ong H, Lovell S, Donnelly R, Hanratty C, Riley M, Frenneaux M, Young I, Nicholls P. Source: Clinical Science (London, England : 1979). 2004 April; 106(4): 413-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14709159
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Chemoprevention of hepatocarcinogenesis: S-adenosyl-L-methionine. Author(s): Pascale RM, Simile MM, De Miglio MR, Feo F. Source: Alcohol (Fayetteville, N.Y.). 2002 July; 27(3): 193-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12163149
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Clinical application of (11)C-methionine positron emission tomography for evaluation of pancreatic function. Author(s): Kono T, Okazumi S, Mochizuki R, Ootsuki K, Shinotou K, Matsuzaki H, Natsume T, Kenmochi T, Nakagohri T, Asano T, Ochiai T. Source: Pancreas. 2002 July; 25(1): 20-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12131766
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Clinical relevance of the methionine loading test for assessment of hyperhomocysteinaemia. Author(s): van der Griend R, Biesma DH, Banga JD. Source: The Netherlands Journal of Medicine. 2000 October; 57(4): 174-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11185483
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Cobalamin deficiency with and without neurologic abnormalities: differences in homocysteine and methionine metabolism. Author(s): Carmel R, Melnyk S, James SJ. Source: Blood. 2003 April 15; 101(8): 3302-8. Epub 2002 December 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12515717
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Coexpression of proteins with methionine aminopeptidase and/or Nmyristoyltransferase in Escherichia coli to increase acylation and homogeneity of protein preparations. Author(s): Van Valkenburgh HA, Kahn RA. Source: Methods Enzymol. 2002; 344: 186-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11771383
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Combined 18F-FDG and 11C-methionine PET scans in patients with newly progressive metastatic prostate cancer. Author(s): Nunez R, Macapinlac HA, Yeung HW, Akhurst T, Cai S, Osman I, Gonen M, Riedel E, Scher HI, Larson SM. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 2002 January; 43(1): 46-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11801702
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Comment: the methionine 196 arginine polymorphism in exon 6 of the TNF receptor 2 gene (TNFRSF1B) is associated with the polycystic ovary syndrome and hyperandrogenism. Author(s): Peral B, San Millan JL, Castello R, Moghetti P, Escobar-Morreale HF. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 August; 87(8): 3977-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12161545
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Comorbidity of 5,10-methylenetetrahydrofolate reductase and methionine synthase gene polymorphisms and risk for neural tube defects. Author(s): Johanning GL, Tamura T, Johnston KE, Wenstrom KD. Source: Journal of Medical Genetics. 2000 December; 37(12): 949-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11186937
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Convenient synthesis of human calcitonin and its methionine sulfoxide derivative. Author(s): Shi T, Rabenstein DL. Source: Bioorganic & Medicinal Chemistry Letters. 2002 August 19; 12(16): 2237-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12127546
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Cranial neuronavigation with direct integration of (11)C methionine positron emission tomography (PET) data -- results of a pilot study in 32 surgical cases. Author(s): Braun V, Dempf S, Weller R, Reske SN, Schachenmayr W, Richter HP. Source: Acta Neurochirurgica. 2002 August; 144(8): 777-82; Discussion 782. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12181686
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CSF-methionine is elevated in psychotic patients. Author(s): Regland B, Abrahamsson L, Blennow K, Grenfeldt B, Gottfries CG. Source: Journal of Neural Transmission (Vienna, Austria : 1996). 2004 May; 111(5): 63140. Epub 2004 March 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15088156
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Cyclic oxidation and reduction of methionine residues of proteins in antioxidant defense and cellular regulation. Author(s): Stadtman ER. Source: Archives of Biochemistry and Biophysics. 2004 March 1; 423(1): 2-5. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14989257
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Cyclic oxidation and reduction of protein methionine residues is an important antioxidant mechanism. Author(s): Stadtman ER, Moskovitz J, Berlett BS, Levine RL. Source: Molecular and Cellular Biochemistry. 2002 May-June; 234-235(1-2): 3-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12162447
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Cystatin C is an independent predictor of fasting and post-methionine load total homocysteine concentrations among stable renal transplant recipients. Author(s): Aras O, Tsai MY, Hanson NQ, Bailey R, Rao G, Hunninghake DB. Source: Clinical Chemistry. 2001; 47(7): 1263-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11427458
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D919G polymorphism of methionine synthase gene is associated with blood pressure response to benazepril in Chinese hypertensive patients. Author(s): Zhang Y, Zhang M, Niu T, Xu X, Zhu G, Huo Y, Chen C, Wang X, Xing H, Peng S, Huang A, Hong X, Xu X. Source: Journal of Human Genetics. 2004; 49(6): 296-301. Epub 2004 May 18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15148588
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Daily methionine requirements of healthy Indian men, measured by a 24-h indicator amino acid oxidation and balance technique. Author(s): Kurpad AV, Regan MM, Varalakshmi S, Vasudevan J, Gnanou J, Raj T, Young VR. Source: The American Journal of Clinical Nutrition. 2003 May; 77(5): 1198-205. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12716672
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Deaths from low dose paracetamol poisoning. Use of oral methionine for overdose below threshold for acetylcysteine. Author(s): Wright B, Crowe M. Source: Bmj (Clinical Research Ed.). 1998 December 12; 317(7173): 1656-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9917155
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Decrease in peptide methionine sulfoxide reductase in Alzheimer's disease brain. Author(s): Gabbita SP, Aksenov MY, Lovell MA, Markesbery WR. Source: Journal of Neurochemistry. 1999 October; 73(4): 1660-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10501213
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Defects in auxiliary redox proteins lead to functional methionine synthase deficiency. Author(s): Gulati S, Chen Z, Brody LC, Rosenblatt DS, Banerjee R. Source: The Journal of Biological Chemistry. 1997 August 1; 272(31): 19171-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9235907
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Defects in methylthioadenosine phosphorylase are associated with but not responsible for methionine-dependent tumor cell growth. Author(s): Tang B, Li YN, Kruger WD. Source: Cancer Research. 2000 October 1; 60(19): 5543-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11034100
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Deficiencies of folate and vitamin B(6) exert distinct effects on homocysteine, serine, and methionine kinetics. Author(s): Cuskelly GJ, Stacpoole PW, Williamson J, Baumgartner TG, Gregory JF 3rd. Source: American Journal of Physiology. Endocrinology and Metabolism. 2001 December; 281(6): E1182-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11701432
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Delayed cerebral radionecrosis with a high uptake of 11C-methionine on positron emission tomography and 201Tl-chloride on single-photon emission computed tomography. Author(s): Tashima T, Morioka T, Nishio S, Hachisuga S, Fukui M, Sasaki M. Source: Neuroradiology. 1998 July; 40(7): 435-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9730342
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Depletion of methionine aminopeptidase 2 does not alter cell response to fumagillin or bengamides. Author(s): Kim S, LaMontagne K, Sabio M, Sharma S, Versace RW, Yusuff N, Phillips PE. Source: Cancer Research. 2004 May 1; 64(9): 2984-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15126329
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Determinants of fasting and post-methionine homocysteine levels in families predisposed to hyperhomocysteinemia and premature vascular disease. Author(s): de Jong SC, Stehouwer CD, van den Berg M, Kostense PJ, Alders D, Jakobs C, Pals G, Rauwerda JA. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 1999 May; 19(5): 1316-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10323785
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Dietary cysteine reduces the methionine requirement in men. Author(s): Di Buono M, Wykes LJ, Ball RO, Pencharz PB. Source: The American Journal of Clinical Nutrition. 2001 December; 74(6): 761-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11722957
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Dietary treatment of tyrosinemia type I: importance of methionine restriction. Author(s): Michals K, Matolon R, Wong PW. Source: Journal of the American Dietetic Association. 1978 November; 73(5): 507-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=701680
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Differences in the efficiency of reductive activation of methionine synthase and exogenous electron acceptors between the common polymorphic variants of human methionine synthase reductase. Author(s): Olteanu H, Munson T, Banerjee R. Source: Biochemistry. 2002 November 12; 41(45): 13378-85. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12416982
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Differential diagnosis of thymic tumors using a combination of 11C-methionine PET and FDG PET. Author(s): Sasaki M, Kuwabara Y, Ichiya Y, Akashi Y, Yoshida T, Nakagawa M, Murayama S, Masuda K. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 1999 October; 40(10): 1595-601. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10520697
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Differential effects of leucine and methionine enkephalin on morphine-induced analgesia, acute tolerance and dependence. Author(s): Vaught JL, Takemori AE. Source: The Journal of Pharmacology and Experimental Therapeutics. 1979 January; 208(1): 86-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=569699
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Differential expression of methionine adenosyltransferase genes influences the rate of growth of human hepatocellular carcinoma cells. Author(s): Cai J, Mao Z, Hwang JJ, Lu SC. Source: Cancer Research. 1998 April 1; 58(7): 1444-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9537246
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Differential regulation of methionine adenosyltransferase in superantigen and mitogen stimulated human T lymphocytes. Author(s): LeGros HL Jr, Geller AM, Kotb M. Source: The Journal of Biological Chemistry. 1997 June 20; 272(25): 16040-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9188509
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Diseases of sulphur metabolism: implications for the methionine-homocysteine cycle, and vitamin responsiveness. Author(s): Mudd SH. Source: Ciba Found Symp. 1979; (72): 239-58. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=398765
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Disruption of a regulatory system involving cobalamin distribution and function in a methionine-dependent human glioma cell line. Author(s): Fiskerstrand T, Riedel B, Ueland PM, Seetharam B, Pezacka EH, Gulati S, Bose S, Banerjee R, Berge RK, Refsum H. Source: The Journal of Biological Chemistry. 1998 August 7; 273(32): 20180-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9685364
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Early response to chemotherapy in hypopharyngeal cancer: assessment with (11)Cmethionine PET, correlation with morphologic response, and clinical outcome. Author(s): Chesnay E, Babin E, Constans JM, Agostini D, Bequignon A, Regeasse A, Sobrio F, Moreau S. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 2003 April; 44(4): 526-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12679395
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EEG and clinical profile of a synthetic analogue of methionine-enkephalin - FK 33824. Author(s): Krebs E, Roubicek J. Source: Pharmakopsychiatr Neuropsychopharmakol. 1979 January; 12(1): 86-93. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=368820
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Effect of heterozygosity for the methionine synthase 2756 A-->G mutation on the risk for recurrent cardiovascular events. Author(s): Hyndman ME, Bridge PJ, Warnica JW, Fick G, Parsons HG. Source: The American Journal of Cardiology. 2000 November 15; 86(10): 1144-6, A9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11074217
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Effect of intravenous injection of CDP-choline, S-adenosyl-methionine and citiolone in subjects with hyperlipemia. Author(s): Galeone F, Salvadorini F, Guarguaglini M, Saba P. Source: Artery. 1979 February; 5(2): 157-69. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=231953
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Effect of opioid peptide methionine-enkephalin in long-term cultures of human bone marrow. Author(s): Janda SS, Boranic M, Skodlar J, Petrovecki M, Nemet D, Labar B. Source: Acta Med Croatica. 2000; 54(3): 99-105. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11268793
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Effect of protein and methionine intakes on plasma homocysteine concentrations: a 6mo randomized controlled trial in overweight subjects. Author(s): Haulrik N, Toubro S, Dyerberg J, Stender S, Skov AR, Astrup A. Source: The American Journal of Clinical Nutrition. 2002 December; 76(6): 1202-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12450883
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Effects of acute methionine loading and vitamin C on endogenous fibrinolysis, endothelium-dependent vasomotion and platelet aggregation. Author(s): Labinjoh C, Newby DE, Wilkinson IB, Megson IL, MacCallum H, Melville V, Boon NA, Webb DJ. Source: Clinical Science (London, England : 1979). 2001 February; 100(2): 127-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11171280
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Effects of polymorphisms of methionine synthase and methionine synthase reductase on total plasma homocysteine in the NHLBI Family Heart Study. Author(s): Jacques PF, Bostom AG, Selhub J, Rich S, Ellison RC, Eckfeldt JH, Gravel RA, Rozen R; National Heart, Lung and Blood Institute, National Institutes of Health. Source: Atherosclerosis. 2003 January; 166(1): 49-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12482550
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Efficacy and tolerability of oral and intramuscular S-adenosyl-L-methionine 1,4butanedisulfonate (SAMe) in the treatment of major depression: comparison with imipramine in 2 multicenter studies. Author(s): Delle Chiaie R, Pancheri P, Scapicchio P. Source: The American Journal of Clinical Nutrition. 2002 November; 76(5): 1172S-6S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12418499
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Electron transfer in human methionine synthase reductase studied by stopped-flow spectrophotometry. Author(s): Wolthers KR, Scrutton NS. Source: Biochemistry. 2004 January 20; 43(2): 490-500. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14717604
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Elevated plasma total homocysteine in severe methionine adenosyltransferase I/III deficiency. Author(s): Stabler SP, Steegborn C, Wahl MC, Oliveriusova J, Kraus JP, Allen RH, Wagner C, Mudd SH. Source: Metabolism: Clinical and Experimental. 2002 August; 51(8): 981-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12145770
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Engineering of cysteine and methionine biosynthesis in potato. Author(s): Nikiforova V, Kempa S, Zeh M, Maimann S, Kreft O, Casazza AP, Riedel K, Tauberger E, Hoefgen R, Hesse H. Source: Amino Acids. 2002; 22(3): 259-78. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12083069
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Essential role of methionine residues in calmodulin binding to Bordetella pertussis adenylate cyclase, as probed by selective oxidation and repair by the peptide methionine sulfoxide reductases. Author(s): Vougier S, Mary J, Dautin N, Vinh J, Friguet B, Ladant D. Source: The Journal of Biological Chemistry. 2004 July 16; 279(29): 30210-8. Epub 2004 May 17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15148319
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Evaluation of the effect of high-energy proton irradiation treatment on meningiomas by means of 11C-L-methionine PET. Author(s): Gudjonsson O, Blomquist E, Lilja A, Ericson H, Bergstrom M, Nyberg G. Source: European Journal of Nuclear Medicine. 2000 December; 27(12): 1793-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11189942
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Evaluation of treatment effects in brain abscess with positron emission tomography: comparison of fluorine-18-fluorodeoxyglucose and carbon-11-methionine. Author(s): Tsuyuguchi N, Sunada I, Ohata K, Takami T, Nishio A, Hara M, Kawabe J, Okamura T, Ochi H. Source: Ann Nucl Med. 2003 February; 17(1): 47-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12691130
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Evidence against oxidative stress as mechanism of endothelial dysfunction in methionine loading model. Author(s): Nightingale AK, James PP, Morris-Thurgood J, Harrold F, Tong R, Jackson SK, Cockcroft JR, Frenneaux MP. Source: American Journal of Physiology. Heart and Circulatory Physiology. 2001 March; 280(3): H1334-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11179081
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False-positive parathyroid scan leading to sternotomy: incidental detection of a thymoma by C-11 methionine positron emission tomography. Author(s): Adler LP, Akhrass R, Ma D, Bloom AD. Source: Surgery. 1997 July; 122(1): 116-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9225925
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Fast atom bombardment mass spectrometric quantitative analysis of methionineenkephalin in human pituitary tissues. Author(s): Kusmierz JJ, Sumrada R, Desiderio DM. Source: Analytical Chemistry. 1990 November 1; 62(21): 2395-400. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2291485
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Fasting and post-methionine homocyst(e)ine levels in a healthy Australian population. Author(s): Silberberg J, Crooks R, Fryer J, Wlodarczyk J, Nair B, Finucane P, Guo XW, Xie LJ, Dudman N. Source: Aust N Z J Med. 1997 February; 27(1): 35-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9079251
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Fasting and post-methionine homocysteine levels in NIDDM. Determinants and correlations with retinopathy, albuminuria, and cardiovascular disease. Author(s): Smulders YM, Rakic M, Slaats EH, Treskes M, Sijbrands EJ, Odekerken DA, Stehouwer CD, Silberbusch J. Source: Diabetes Care. 1999 January; 22(1): 125-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10333913
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Fasting and post-methionine load homocyst(e)ine values are correlated with microalbuminuria and could contribute to worsening vascular damage in noninsulin-dependent diabetes mellitus patients. Author(s): Lanfredini M, Fiorina P, Peca MG, Veronelli A, Mello A, Astorri E, Dall'Aglio P, Craveri A. Source: Metabolism: Clinical and Experimental. 1998 August; 47(8): 915-21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9711985
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Fasting and post-methionine loading concentrations of homocysteine, vitamin B2, and vitamin B6 in patients on antiepileptic drugs. Author(s): Apeland T, Mansoor MA, Pentieva K, McNulty H, Strandjord RE. Source: Clinical Chemistry. 2003 June; 49(6 Pt 1): 1005-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12766014
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Fasting, postprandial, and post-methionine-load homocysteinaemia and methylenetetrahydrofolate reductase polymorphism in vascular disease. Author(s): Candito M, Bedoucha P, Gibelin P, Jambou D, de Franchis R, Sadoul JL, Chatel M, Van Obberghen E. Source: Journal of Inherited Metabolic Disease. 1999 June; 22(5): 588-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10399090
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Fatal submassive hepatic necrosis associated with tyrosine-methionine-aspartateaspartate-motif mutation of hepatitis B virus after long-term lamivudine therapy. Author(s): Kim JW, Lee HS, Woo GH, Yoon JH, Jang JJ, Chi JG, Kim CY. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2001 August 1; 33(3): 403-5. Epub 2001 July 07. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11438912
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Fluctuations in dietary methionine intake do not alter plasma homocysteine concentration in healthy men. Author(s): Ward M, McNulty H, Pentieva K, McPartlin J, Strain JJ, Weir DG, Scott JM. Source: The Journal of Nutrition. 2000 November; 130(11): 2653-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11053502
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Fluorine-18-fluorodeoxyglucose and carbon-11-methionine evaluation of lymphadenopathy in sarcoidosis. Author(s): Yamada Y, Uchida Y, Tatsumi K, Yamaguchi T, Kimura H, Kitahara H, Kuriyama T. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 1998 July; 39(7): 1160-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9669387
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fMLP-OMe analogs substituted at the methionine residue: an insight into the receptor properties. Author(s): Cavicchioni G, Monesi LG, Ferretti ME, Fabbri E, Rizzuti O, Spisani S. Source: Archiv Der Pharmazie. 1998 November; 331(11): 368-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9881061
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Folate deficiency, methionine metabolism, and alcoholic liver disease. Author(s): Halsted CH, Villanueva JA, Devlin AM. Source: Alcohol (Fayetteville, N.Y.). 2002 July; 27(3): 169-72. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12163145
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Folate depletion induced by methotrexate affects methionine synthase activity and its susceptibility to inactivation by nitrous oxide. Author(s): Fiskerstrand T, Ueland PM, Refsum H. Source: The Journal of Pharmacology and Experimental Therapeutics. 1997 September; 282(3): 1305-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9316839
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Folate, homocysteine and methionine loading in patients on carbamazepine. Author(s): Apeland T, Mansoor MA, Strandjord RE, Vefring H, Kristensen O. Source: Acta Neurologica Scandinavica. 2001 May; 103(5): 294-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11328204
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Folate, methionine, alcohol, and colorectal cancer in a prospective study of women in the United States. Author(s): Flood A, Caprario L, Chaterjee N, Lacey JV Jr, Schairer C, Schatzkin A. Source: Cancer Causes & Control : Ccc. 2002 August; 13(6): 551-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12195645
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Folate, methionine, and alcohol intake and risk of colorectal adenoma. Author(s): Giovannucci E, Stampfer MJ, Colditz GA, Rimm EB, Trichopoulos D, Rosner BA, Speizer FE, Willett WC. Source: Journal of the National Cancer Institute. 1993 June 2; 85(11): 875-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8492316
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Folate-responsive homocystinuria and megaloblastic anaemia in a female patient with functional methionine synthase deficiency (cblE disease). Author(s): Fowler B, Schutgens RB, Rosenblatt DS, Smit GP, Lindemans J. Source: Journal of Inherited Metabolic Disease. 1997 November; 20(6): 731-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9427140
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Functional expression of human methionine aminopeptidase type 1 in Saccharomyces cerevisiae. Author(s): Dummitt B, Fei Y, Chang YH. Source: Protein and Peptide Letters. 2002 August; 9(4): 295-303. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12144506
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Functional methionine synthase deficiency due to cblG disorder: a report of two patients and a review. Author(s): Harding CO, Arnold G, Barness LA, Wolff JA, Rosenblatt DS. Source: American Journal of Medical Genetics. 1997 September 5; 71(4): 384-90. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9286442
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Functionally null mutations in patients with the cblG-variant form of methionine synthase deficiency. Author(s): Wilson A, Leclerc D, Saberi F, Campeau E, Hwang HY, Shane B, Phillips JA 3rd, Rosenblatt DS, Gravel RA. Source: American Journal of Human Genetics. 1998 August; 63(2): 409-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9683607
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Gas chromatographic and gas chromatographic--mass spectrometric studies on alphaketo-gamma-methylthiobutyric acid in urine following ingestion of optical isomers of methionine. Author(s): Kaji H, Saito N, Murao M, Ishimoto M, Kondo H, Gasa S, Saito K. Source: Journal of Chromatography. 1980 November 14; 221(1): 145-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7451616
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Gas chromatographic-sensory parallel chracterisation of methionine-glucose reaction products and their relation to meat aroma. Author(s): Barylko-Pikielna N, Daniewski M, Mielniczuk Z. Source: Die Nahrung. 1974; 18(2): 125-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=4838297
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Gender differences and other determinants of the rise in plasma homocysteine after L-methionine loading. Author(s): Silberberg J, Crooks R, Fryer J, Wlodarczyk J, Nair B, Guo XW, Xie LJ, Dudman N. Source: Atherosclerosis. 1997 August; 133(1): 105-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9258413
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Gene cloning and characterization of Pseudomonas putida L-methionine-alphadeamino-gamma-mercaptomethane-lyase. Author(s): Hori H, Takabayashi K, Orvis L, Carson DA, Nobori T. Source: Cancer Research. 1996 May 1; 56(9): 2116-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8616859
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Genetic basis of neural tube defects. II. Genes correlated with folate and methionine metabolism. Author(s): Gos M Jr, Szpecht-Potocka A. Source: Journal of Applied Genetics. 2002; 43(4): 511-24. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12441636
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Genetic determinants of fasting and post-methionine hyperhomocysteinemia in patients with retinal vein occlusion. Author(s): Marcucci R, Giusti B, Betti I, Evangelisti L, Fedi S, Sodi A, Cappelli S, Menchini U, Abbate R, Prisco D. Source: Thrombosis Research. 2003 April 15; 110(1): 7-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12877902
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Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects. Author(s): Christensen B, Arbour L, Tran P, Leclerc D, Sabbaghian N, Platt R, Gilfix BM, Rosenblatt DS, Gravel RA, Forbes P, Rozen R. Source: American Journal of Medical Genetics. 1999 May 21; 84(2): 151-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10323741
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Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) in ethnic populations in Texas; a report of a novel MTHFR polymorphic site, G1793A. Author(s): Rady PL, Szucs S, Grady J, Hudnall SD, Kellner LH, Nitowsky H, Tyring SK, Matalon RK. Source: American Journal of Medical Genetics. 2002 January 15; 107(2): 162-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11807892
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Germ-line mosaicism for a valine-to-methionine substitution at residue 553 in the glycoprotein Ib-binding domain of von Willebrand factor, causing type IIB von Willebrand disease. Author(s): Murray EW, Giles AR, Lillicrap D. Source: American Journal of Human Genetics. 1992 January; 50(1): 199-207. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1729889
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Gerstmann-Straussler-Scheinker disease with mutation at codon 102 and methionine at codon 129 of PRNP in previously unreported patients. Author(s): Young K, Jones CK, Piccardo P, Lazzarini A, Golbe LI, Zimmerman TR Jr, Dickson DW, McLachlan DC, St George-Hyslop P, Lennox A, et al. Source: Neurology. 1995 June; 45(6): 1127-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7783876
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Globin-methionine complexes formed during labelling studies. Author(s): Beutler E, Gelbart T. Source: Clinical and Laboratory Haematology. 1984; 6(3): 257-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6518729
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Glucose and methionine uptake and proliferative activity in meningiomas. Author(s): Iuchi T, Iwadate Y, Namba H, Osato K, Saeki N, Yamaura A, Uchida Y. Source: Neurological Research. 1999 October; 21(7): 640-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10555183
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Glucose consumption and methionine uptake in low-grade gliomas after iodine-125 brachytherapy. Author(s): Wurker M, Herholz K, Voges J, Pietrzyk U, Treuer H, Bauer B, Sturm V, Heiss WD. Source: European Journal of Nuclear Medicine. 1996 May; 23(5): 583-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8698067
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Growth of methionine-dependent human prostate cancer (PC-3) is inhibited by ethionine combined with methionine starvation. Author(s): Poirson-Bichat F, Gonfalone G, Bras-Goncalves RA, Dutrillaux B, Poupon MF. Source: British Journal of Cancer. 1997; 75(11): 1605-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9184175
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Haemolytic uraemic syndrome and pulmonary hypertension in a patient with methionine synthase deficiency. Author(s): Labrune P, Zittoun J, Duvaltier I, Trioche P, Marquet J, Niaudet P, Odievre M. Source: European Journal of Pediatrics. 1999 September; 158(9): 734-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10485306
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High expression of methionine aminopeptidase type 2 in germinal center B cells and their neoplastic counterparts. Author(s): Kanno T, Endo H, Takeuchi K, Morishita Y, Fukayama M, Mori S. Source: Laboratory Investigation; a Journal of Technical Methods and Pathology. 2002 July; 82(7): 893-901. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12118091
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High uptake on 11C-methionine positron emission tomographic scan of basal ganglia germinoma with cerebral hemiatrophy. Author(s): Sudo A, Shiga T, Okajima M, Takano K, Terae S, Sawamura Y, Ohnishi A, Nagashima K, Saitoh S. Source: Ajnr. American Journal of Neuroradiology. 2003 October; 24(9): 1909-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14561627
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High-performance liquid chromatography determination of methionine adenosyltransferase activity using catechol-O-methyltransferase-coupled fluorometric detection. Author(s): Wang SH, Kuo SC, Chen SC. Source: Analytical Biochemistry. 2003 August 1; 319(1): 13-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12842102
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Histamine chloramine reactivity with thiol compounds, ascorbate, and methionine and with intracellular glutathione. Author(s): Peskin AV, Winterbourn CC. Source: Free Radical Biology & Medicine. 2003 November 15; 35(10): 1252-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14607524
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HIV-2 protease is inactivated after oxidation at the dimer interface and activity can be partly restored with methionine sulphoxide reductase. Author(s): Davis DA, Newcomb FM, Moskovitz J, Wingfield PT, Stahl SJ, Kaufman J, Fales HM, Levine RL, Yarchoan R. Source: The Biochemical Journal. 2000 March 1; 346 Pt 2: 305-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10677347
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Homocysteine concentrations and methionine loading in patients on antiepileptic drugs. Author(s): Apeland T, Mansoor MA, Strandjord RE, Kristensen O. Source: Acta Neurologica Scandinavica. 2000 April; 101(4): 217-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10770516
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Homocysteine levels during fasting and after methionine loading in adolescents with diabetic retinopathy and nephropathy. Author(s): Chiarelli F, Pomilio M, Mohn A, Tumini S, Vanelli M, Morgese G, Spagnoli A, Verrotti A. Source: The Journal of Pediatrics. 2000 September; 137(3): 386-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10969265
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Homocysteinemia and endothelial damage after methionine load. Author(s): Hladovec J, Sommerova Z, Pisarikova A. Source: Thrombosis Research. 1997 November 15; 88(4): 361-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9526959
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Homology modeling and calculation of the cobalt cluster charges of the Encephazlitozoon cuniculi methionine aminopeptidase, a potential target for drug design. Author(s): Bontems F, le Floch P, Duffieux F, Biderre C, Peyret P, Lallemand JY. Source: Biophysical Chemistry. 2003 August 1; 105(1): 29-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12932577
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Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders. Author(s): Leclerc D, Campeau E, Goyette P, Adjalla CE, Christensen B, Ross M, Eydoux P, Rosenblatt DS, Rozen R, Gravel RA. Source: Human Molecular Genetics. 1996 December; 5(12): 1867-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8968737
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Hydrogen peroxide for disulfide bridge formation in methionine-containing peptides. Author(s): Kudryavtseva EV, Sidorova MV, Ovchinnikov MV, Bespalova ZD. Source: Journal of Peptide Science : an Official Publication of the European Peptide Society. 2000 May; 6(5): 208-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10823489
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Hyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adults. Author(s): Bellamy MF, McDowell IF, Ramsey MW, Brownlee M, Bones C, Newcombe RG, Lewis MJ. Source: Circulation. 1998 November 3; 98(18): 1848-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9799203
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Hyperhomocysteinemia following oral methionine load is associated with increased lipid peroxidation. Author(s): Domagala TB, Libura M, Szczeklik A. Source: Thrombosis Research. 1997 August 15; 87(4): 411-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9271819
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Identification of conserved amino acid residues in rat liver carnitine palmitoyltransferase I critical for malonyl-CoA inhibition. Mutation of methionine 593 abolishes malonyl-CoA inhibition. Author(s): Morillas M, Gomez-Puertas P, Bentebibel A, Selles E, Casals N, Valencia A, Hegardt FG, Asins G, Serra D. Source: The Journal of Biological Chemistry. 2003 March 14; 278(11): 9058-63. Epub 2002 December 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12499375
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Identification of methionine-rich clusters that regulate copper-stimulated endocytosis of the human Ctr1 copper transporter. Author(s): Guo Y, Smith K, Lee J, Thiele DJ, Petris MJ. Source: The Journal of Biological Chemistry. 2004 April 23; 279(17): 17428-33. Epub 2004 February 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14976198
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Identification of the authentic varicella-zoster virus gB (gene 31) initiating methionine overlapping the 3' end of gene 30. Author(s): Maresova L, Pasieka T, Wagenaar T, Jackson W, Grose C. Source: Journal of Medical Virology. 2003; 70 Suppl 1: S64-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12627491
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Identification, expression and chromosome localization of a human gene encoding a novel protein with similarity to the pilB family of transcriptional factors (pilin) and to bacterial peptide methionine sulfoxide reductases. Author(s): Huang W, Escribano J, Sarfarazi M, Coca-Prados M. Source: Gene. 1999 June 11; 233(1-2): 233-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10375640
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Impaired hepatic mitochondrial oxidation using the 13C-methionine breath test in patients with macrovesicular steatosis and patients with cirrhosis. Author(s): Spahr L, Negro F, Leandro G, Marinescu O, Goodman KJ, Rubbia-Brandt L, Jordan M, Hadengue A. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2003 January; 9(1): Cr6-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12552242
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Impairment of cerebrovascular reactivity by methionine-induced hyperhomocysteinemia and amelioration by quinapril treatment. Author(s): Chao CL, Lee YT. Source: Stroke; a Journal of Cerebral Circulation. 2000 December; 31(12): 2907-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11108747
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Importance of a deficiency in S-adenosyl-L-methionine synthesis in the pathogenesis of liver injury. Author(s): Martinez-Chantar ML, Garcia-Trevijano ER, Latasa MU, Perez-Mato I, Sanchez del Pino MM, Corrales FJ, Avila MA, Mato JM. Source: The American Journal of Clinical Nutrition. 2002 November; 76(5): 1177S-82S. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12418501
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Increased plasma homocysteine and S-adenosylhomocysteine and decreased methionine is associated with altered phosphatidylcholine and phosphatidylethanolamine in cystic fibrosis. Author(s): Innis SM, Davidson AG, Chen A, Dyer R, Melnyk S, James SJ. Source: The Journal of Pediatrics. 2003 September; 143(3): 351-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14517519
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Increased susceptibility to Kuru of carriers of the PRNP 129 methionine/methionine genotype. Author(s): Lee HS, Brown P, Cervenakova L, Garruto RM, Alpers MP, Gajdusek DC, Goldfarb LG. Source: The Journal of Infectious Diseases. 2001 January 15; 183(2): 192-196. Epub 2000 December 21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11120925
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Increased viability of PC12 cells exposed to amyloid-beta peptide by transduction with human TAT-methionine sulfoxide reductase. Author(s): Jung B, Lee EH, Chung WS, Lee SJ, Shin SH, Joo SH, Kim SK, Lee JH. Source: Neuroreport. 2003 December 19; 14(18): 2349-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14663189
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Induction of caspase-dependent and -independent apoptosis in response to methionine restriction. Author(s): Lu S, Hoestje SM, Choo E, Epner DE. Source: International Journal of Oncology. 2003 February; 22(2): 415-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12527942
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Influence of a methionine synthase (D919G) polymorphism on plasma homocysteine and folate levels and relation to risk of myocardial infarction. Author(s): Chen J, Stampfer MJ, Ma J, Selhub J, Malinow MR, Hennekens CH, Hunter DJ. Source: Atherosclerosis. 2001 February 15; 154(3): 667-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11257268
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Influence of age, sex and vitamin status on fasting and post-methionine load plasma homocysteine levels. Author(s): Sassi S, Cosmi B, Palareti G, Legnani C, Grossi G, Musolesi S, Coccheri S. Source: Haematologica. 2002 September; 87(9): 957-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12217808
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Interaction between dietary methionine and methyl donor intake on rat liver betainehomocysteine methyltransferase gene expression and organization of the human gene. Author(s): Park EI, Garrow TA. Source: The Journal of Biological Chemistry. 1999 March 19; 274(12): 7816-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10075673
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Investigation of methionine metabolism in peripheral blood mononuclear cells of Irish hyperhomocysteinemic subjects. Author(s): Betts V, Collins PB, Meleady R, Graham I. Source: Biochemical Society Transactions. 1998 February; 26(1): S10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10909768
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Investigation of the metal binding site in methionine aminopeptidase by density functional theory. Author(s): Jorgensen AT, Norrby PO, Liljefors T. Source: Journal of Computer-Aided Molecular Design. 2002 March; 16(3): 167-79. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12363216
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Kinetic and thermodynamic characterization of the common polymorphic variants of human methionine synthase reductase. Author(s): Olteanu H, Wolthers KR, Munro AW, Scrutton NS, Banerjee R. Source: Biochemistry. 2004 February 24; 43(7): 1988-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14967039
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Kinetic evidence for decreased methionine adenosyltransferase activity in erythrocytes from schizophrenics. Author(s): Kelsoe JR Jr, Tolbert LC, Crews EL, Smythies JR. Source: Journal of Neuroscience Research. 1982; 8(1): 99-103. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7175980
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Kinetics of methionine transport and metabolism by Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense. Author(s): Goldberg B, Rattendi D, Lloyd D, Yarlett N, Bacchi CJ. Source: Archives of Biochemistry and Biophysics. 2000 May 1; 377(1): 49-57. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10775440
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Lack of effect of L-methionine ingestion on 14CO2 excretion from L-histidine (imidazole-2-14C) in folic acid and vitamin B12 deficient humans. Author(s): Stahelin HB, Winchell HS, Kusubov N. Source: Blood. 1970 January; 35(1): 86-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5412678
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Large-scale expression, purification and characterization of small fragments of thrombomodulin: the roles of the sixth domain and of methionine 388. Author(s): White CE, Hunter MJ, Meininger DP, White LR, Komives EA. Source: Protein Engineering. 1995 November; 8(11): 1177-87. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8819984
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Leukocyte 12-lipoxygenase: expression, purification, and investigation of the role of methionine residues in turnover-dependent inactivation and 5,8,11,14eicosatetraynoic acid inhibition. Author(s): Richards KM, Marnett LJ. Source: Biochemistry. 1997 June 3; 36(22): 6692-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9184149
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Levels of L-methionine S-adenosyltransferase activity in erythrocytes and concentrations of S-adenosylmethionine and S-adenosylhomocysteine in whole blood of patients with Parkinson's disease. Author(s): Cheng H, Gomes-Trolin C, Aquilonius SM, Steinberg A, Lofberg C, Ekblom J, Oreland L. Source: Experimental Neurology. 1997 June; 145(2 Pt 1): 580-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9217094
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L-methionine uptake by human cerebral cortex: maturation from infancy to old age. Author(s): O'Tuama LA, Phillips PC, Smith QR, Uno Y, Dannals RF, Wilson AA, Ravert HT, Loats S, Loats HA, Wagner HN Jr. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 1991 January; 32(1): 16-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1988624
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Loss of the oncogene from human H-ras-1-transfected NIH/3T3 cells grown in the presence of excess methionine. Author(s): Hillova J, Hill M, Belehradek J Jr, Mariage-Samson R, Brada Z. Source: Journal of the National Cancer Institute. 1986 September; 77(3): 721-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3462412
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Low concentrations of folate in serum and erythrocytes of smokers: methionine loading decreases folate concentrations in serum of smokers and nonsmokers. Author(s): Mansoor MA, Kristensen O, Hervig T, Drablos PA, Stakkestad JA, Woie L, Hetland O, Osland A. Source: Clinical Chemistry. 1997 November; 43(11): 2192-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9365412
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Low diagnostic value of fasting and post-methionine load homocysteine tests. A study in Dutch subjects with homocysteine test indications. Author(s): Fokkema MR, Dijck-Brouwer DA, van Doormaal JJ, Reijngoud DJ, Muskiet FA. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 2003 May; 331(1-2): 153-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12691876
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Low methionine diet treatment of homocystinuria. Author(s): Schimke RN. Source: Annals of Internal Medicine. 1969 March; 70(3): 642-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=5775042
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Lung tumor imaging by positron emission tomography using C-11 L-methionine. Author(s): Kubota K, Matsuzawa T, Ito M, Ito K, Fujiwara T, Abe Y, Yoshioka S, Fukuda H, Hatazawa J, Iwata R, et al. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 1985 January; 26(1): 37-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=2981300
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Maternal methionine adenosyltransferase I/III deficiency: reproductive outcomes in a woman with four pregnancies. Author(s): Mudd SH, Tangerman A, Stabler SP, Allen RH, Wagner C, Zeisel SH, Levy HL. Source: Journal of Inherited Metabolic Disease. 2003; 26(5): 443-58. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14518826
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Methionine adenosyltransferase as a useful molecular systematics tool revealed by phylogenetic and structural analyses. Author(s): Sanchez-Perez GF, Bautista JM, Pajares MA. Source: Journal of Molecular Biology. 2004 January 16; 335(3): 693-706. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14687567
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Methionine catabolism and production of volatile sulphur compounds by OEnococcus oeni. Author(s): Pripis-Nicolau L, de Revel G, Bertrand A, Lonvaud-Funel A. Source: Journal of Applied Microbiology. 2004; 96(5): 1176-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15078536
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Methionine dependency and cancer treatment. Author(s): Cellarier E, Durando X, Vasson MP, Farges MC, Demiden A, Maurizis JC, Madelmont JC, Chollet P. Source: Cancer Treatment Reviews. 2003 December; 29(6): 489-99. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14585259
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Methionine enkephalin suppresses metabolic activity of a leukemic cell line (NALM1) and enhances CD10 expression. Author(s): Martin-Kleiner I, Gabrilovac J, Kusec R, Boranic M. Source: International Immunopharmacology. 2003 May; 3(5): 707-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12757739
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Methionine positron emission tomography of recurrent metastatic brain tumor and radiation necrosis after stereotactic radiosurgery: is a differential diagnosis possible? Author(s): Tsuyuguchi N, Sunada I, Iwai Y, Yamanaka K, Tanaka K, Takami T, Otsuka Y, Sakamoto S, Ohata K, Goto T, Hara M. Source: Journal of Neurosurgery. 2003 May; 98(5): 1056-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12744366
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Methionine restriction selectively targets thymidylate synthase in prostate cancer cells. Author(s): Lu S, Chen GL, Ren C, Kwabi-Addo B, Epner DE. Source: Biochemical Pharmacology. 2003 September 1; 66(5): 791-800. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12948860
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Methionine sulfoxide reductase A is important for lens cell viability and resistance to oxidative stress. Author(s): Kantorow M, Hawse JR, Cowell TL, Benhamed S, Pizarro GO, Reddy VN, Hejtmancik JF. Source: Proceedings of the National Academy of Sciences of the United States of America. 2004 June 29; 101(26): 9654-9. Epub 2004 Jun 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15199188
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Methionine synthase (MTR) 2756 (A --> G) polymorphism, double heterozygosity methionine synthase 2756 AG/methionine synthase reductase (MTRR) 66 AG, and elevated homocysteinemia are three risk factors for having a child with Down syndrome. Author(s): Bosco P, Gueant-Rodriguez RM, Anello G, Barone C, Namour F, Caraci F, Romano A, Romano C, Gueant JL. Source: American Journal of Medical Genetics. 2003 September 1; 121A(3): 219-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12923861
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Methionine synthase D919G polymorphism, folate metabolism, and colorectal adenoma risk. Author(s): Goode EL, Potter JD, Bigler J, Ulrich CM. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2004 January; 13(1): 157-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14744749
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Methionine synthase polymorphism is a risk factor for Alzheimer disease. Author(s): Beyer K, Lao JI, Latorre P, Riutort N, Matute B, Fernandez-Figueras MT, Mate JL, Ariza A. Source: Neuroreport. 2003 July 18; 14(10): 1391-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12876480
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Methylenetetrahydrofolate reductase (MTHFR) 677C>T and methionine synthase reductase (MTRR) 66A>G polymorphisms: association with serum homocysteine and angiographic coronary artery disease in the era of flour products fortified with folic acid. Author(s): Brilakis ES, Berger PB, Ballman KV, Rozen R. Source: Atherosclerosis. 2003 June; 168(2): 315-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12801615
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Monitoring the effect of chemotherapy in a mixed glioma by C-11-methionine PET. Author(s): Herholz K, Kracht LW, Heiss WD. Source: Journal of Neuroimaging : Official Journal of the American Society of Neuroimaging. 2003 July; 13(3): 269-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12889176
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MtaR, a regulator of methionine transport, is critical for survival of group B streptococcus in vivo. Author(s): Shelver D, Rajagopal L, Harris TO, Rubens CE. Source: Journal of Bacteriology. 2003 November; 185(22): 6592-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14594832
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Mutations at the S1 sites of methionine aminopeptidases from Escherichia coli and Homo sapiens reveal the residues critical for substrate specificity. Author(s): Li JY, Cui YM, Chen LL, Gu M, Li J, Nan FJ, Ye QZ. Source: The Journal of Biological Chemistry. 2004 May 14; 279(20): 21128-34. Epub 2004 February 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14976199
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N-Acetylcysteine improves the disturbed thiol redox balance after methionine loading. Author(s): Raijmakers MT, Schilders GW, Roes EM, van Tits LJ, Hak-Lemmers HL, Steegers EA, Peters WH. Source: Clinical Science (London, England : 1979). 2003 August; 105(2): 173-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12708964
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Neuritogenesis induced by vasoactive intestinal peptide, pituitary adenylate cyclaseactivating polypeptide, and peptide histidine methionine in SH-SY5y cells is associated with regulated expression of cytoskeleton mRNAs and proteins. Author(s): Heraud C, Hilairet S, Muller JM, Leterrier JF, Chadeneau C. Source: Journal of Neuroscience Research. 2004 February 1; 75(3): 320-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14743445
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Nitric oxide inhibits methionine synthase activity in vivo and disrupts carbon flow through the folate pathway. Author(s): Danishpajooh IO, Gudi T, Chen Y, Kharitonov VG, Sharma VS, Boss GR. Source: The Journal of Biological Chemistry. 2001 July 20; 276(29): 27296-303. Epub 2001 May 22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11371572
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Non-Invasive assessment of human hepatic mitochondrial function through the 13Cmethionine breath test. Author(s): Armuzzi A, Marcoccia S, Zocco MA, De Lorenzo A, Grieco A, Tondi P, Pola P, Gasbarrini G, Gasbarrini A. Source: Scandinavian Journal of Gastroenterology. 2000 June; 35(6): 650-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10912667
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Normal human lymphocytes exhibit a wide range of methionine-dependency which is related to altered cell division but not micronucleus frequency. Author(s): Crott J, Thomas P, Fenech M. Source: Mutagenesis. 2001 July; 16(4): 317-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11420399
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Normal variants, artefacts and interpretative pitfalls in PET imaging with 18-fluoro-2deoxyglucose and carbon-11 methionine. Author(s): Cook GJ, Maisey MN, Fogelman I. Source: European Journal of Nuclear Medicine. 1999 October; 26(10): 1363-78. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10541839
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N-terminal methionine removal and methionine metabolism in Saccharomyces cerevisiae. Author(s): Dummitt B, Micka WS, Chang YH. Source: Journal of Cellular Biochemistry. 2003 August 1; 89(5): 964-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12874831
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N-terminal RAG1 frameshift mutations in Omenn's syndrome: internal methionine usage leads to partial V(D)J recombination activity and reveals a fundamental role in vivo for the N-terminal domains. Author(s): Santagata S, Gomez CA, Sobacchi C, Bozzi F, Abinun M, Pasic S, Cortes P, Vezzoni P, Villa A. Source: Proceedings of the National Academy of Sciences of the United States of America. 2000 December 19; 97(26): 14572-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11121059
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Nutrient intake and nutritional indexes in adults with metastatic cancer on a phase I clinical trial of dietary methionine restriction. Author(s): Epner DE, Morrow S, Wilcox M, Houghton JL. Source: Nutrition and Cancer. 2002; 42(2): 158-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12416254
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Oral methionine loading as a cause of acute serum folate deficiency: its relevance to parenteral nutrition. Author(s): Connor H, Newton DJ, Preston FE, Woods HF. Source: Postgraduate Medical Journal. 1978 May; 54(631): 318-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=97644
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Oxidation of either methionine 351 or methionine 358 in alpha 1-antitrypsin causes loss of anti-neutrophil elastase activity. Author(s): Taggart C, Cervantes-Laurean D, Kim G, McElvaney NG, Wehr N, Moss J, Levine RL. Source: The Journal of Biological Chemistry. 2000 September 1; 275(35): 27258-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10867014
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Oxidation of Ikappa Balpha at methionine 45 is one cause of taurine chloramineinduced inhibition of NF-kappa B activation. Author(s): Kanayama A, Inoue J, Sugita-Konishi Y, Shimizu M, Miyamoto Y. Source: The Journal of Biological Chemistry. 2002 July 5; 277(27): 24049-56. Epub 2002 April 30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11983684
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Oxidation of methionine 35 attenuates formation of amyloid beta -peptide 1-40 oligomers. Author(s): Palmblad M, Westlind-Danielsson A, Bergquist J. Source: The Journal of Biological Chemistry. 2002 May 31; 277(22): 19506-10. Epub 2002 March 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11912198
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Oxidation of methionine in proteins: roles in antioxidant defense and cellular regulation. Author(s): Levine RL, Moskovitz J, Stadtman ER. Source: Iubmb Life. 2000 October-November; 50(4-5): 301-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11327324
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Oxidation of methionine residues affects the structure and stability of apolipoprotein A-I in reconstituted high density lipoprotein particles. Author(s): Sigalov AB, Stern LJ. Source: Chemistry and Physics of Lipids. 2001 November; 113(1-2): 133-46. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11687233
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Oxidation of methionine residues in antithrombin. Effects on biological activity and heparin binding. Author(s): Van Patten SM, Hanson E, Bernasconi R, Zhang K, Manavalan P, Cole ES, McPherson JM, Edmunds T. Source: The Journal of Biological Chemistry. 1999 April 9; 274(15): 10268-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10187813
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Oxidation of methionine residues of proteins: biological consequences. Author(s): Stadtman ER, Moskovitz J, Levine RL. Source: Antioxidants & Redox Signalling. 2003 October; 5(5): 577-82. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14580313
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Oxidation of methionine residues to methionine sulfoxides does not decrease potential antiatherogenic properties of apolipoprotein A-I. Author(s): Panzenbock U, Kritharides L, Raftery M, Rye KA, Stocker R. Source: The Journal of Biological Chemistry. 2000 June 30; 275(26): 19536-44. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10751387
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Oxidative stress and an altered methionine metabolism in alcoholism. Author(s): Bleich S, Spilker K, Kurth C, Degner D, Quintela-Schneider M, Javaheripour K, Ruther E, Kornhuber J, Wiltfang J. Source: Neuroscience Letters. 2000 November 3; 293(3): 171-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11036188
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Peptide methionine sulfoxide reductase: biochemistry and physiological role. Author(s): Brot N, Weissbach H. Source: Biopolymers. 2000; 55(4): 288-96. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11169920
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Peptidyl hydroxamic acids as methionine aminopeptidase inhibitors. Author(s): Hu X, Zhu J, Srivathsan S, Pei D. Source: Bioorganic & Medicinal Chemistry Letters. 2004 January 5; 14(1): 77-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14684302
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Physiologically relevant metal cofactor for methionine aminopeptidase-2 is manganese. Author(s): Wang J, Sheppard GS, Lou P, Kawai M, Park C, Egan DA, Schneider A, Bouska J, Lesniewski R, Henkin J. Source: Biochemistry. 2003 May 6; 42(17): 5035-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12718546
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Plasma taurine and cysteine levels following an oral methionine load: relationship with coronary heart disease. Author(s): Obeid OA, Johnston K, Emery PW. Source: European Journal of Clinical Nutrition. 2004 January; 58(1): 105-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14679374
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Polymorphism of methionine synthase gene in nuclear families of congenital heart disease. Author(s): Zhu WL, Cheng J, Dao JJ, Zhao RB, Yan LY, Li SQ, Li Y. Source: Biomed Environ Sci. 2004 March; 17(1): 57-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15202865
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Polymorphisms of the 5,10-methylenetetrahydrofolate and the methionine synthase reductase genes as independent risk factors for spina bifida. Author(s): Pietrzyk JJ, Bik-Multanowski M, Sanak M, Twardowska M. Source: Journal of Applied Genetics. 2003; 44(1): 111-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12590188
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Potential role of methionine sulfoxide in the inactivation of the chaperone GroEL by hypochlorous acid (HOCl) and peroxynitrite (ONOO-). Author(s): Khor HK, Fisher MT, Schoneich C. Source: The Journal of Biological Chemistry. 2004 May 7; 279(19): 19486-93. Epub 2004 February 02. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14757771
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Protein N-terminal methionine excision. Author(s): Giglione C, Boularot A, Meinnel T. Source: Cellular and Molecular Life Sciences : Cmls. 2004 June; 61(12): 1455-74. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15197470
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Proteomics-based target identification: bengamides as a new class of methionine aminopeptidase inhibitors. Author(s): Towbin H, Bair KW, DeCaprio JA, Eck MJ, Kim S, Kinder FR, Morollo A, Mueller DR, Schindler P, Song HK, van Oostrum J, Versace RW, Voshol H, Wood J, Zabludoff S, Phillips PE. Source: The Journal of Biological Chemistry. 2003 December 26; 278(52): 52964-71. Epub 2003 October 08. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14534293
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Putrescine or a combination of methionine and arginine restores virulence gene expression in a tRNA modification-deficient mutant of Shigella flexneri: a possible role in adaptation of virulence. Author(s): Durand JM, Bjork GR. Source: Molecular Microbiology. 2003 January; 47(2): 519-27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12519201
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Quantification of erythrocyte S-adenosyl-L-methionine levels and its application in enzyme studies. Author(s): Lagendijk J, Ubbink JB, Vermaak WJ. Source: Journal of Chromatography. 1992 April 15; 576(1): 95-101. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1500462
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Quantitation of total homocysteine, total cysteine, and methionine in normal serum and urine using capillary gas chromatography-mass spectrometry. Author(s): Stabler SP, Marcell PD, Podell ER, Allen RH. Source: Analytical Biochemistry. 1987 April; 162(1): 185-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3605587
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Quantitative analysis of methionine enkephalin and beta-endorphin in the pituitary by liquid secondary ion mass spectrometry and tandem mass spectrometry. Author(s): Desiderio DM, Zhu X. Source: J Chromatogr A. 1998 January 23; 794(1-2): 85-96. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9491558
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Quantitative evaluation of liver function by the methionine and aminopyrine breath tests in the early stages of liver transplantation. Author(s): Di Campli C, Angelini G, Armuzzi A, Nardo B, Zocco MA, Candelli M, Santoliquido A, Cavallari A, Bernardi M, Gasbarrini A. Source: European Journal of Gastroenterology & Hepatology. 2003 July; 15(7): 727-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12811302
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Reaction mechanism, evolutionary analysis, and role of zinc in Drosophila methionine-R-sulfoxide reductase. Author(s): Kumar RA, Koc A, Cerny RL, Gladyshev VN. Source: The Journal of Biological Chemistry. 2002 October 4; 277(40): 37527-35. Epub 2002 July 26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12145281
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Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma. Author(s): Avila MA, Berasain C, Torres L, Martin-Duce A, Corrales FJ, Yang H, Prieto J, Lu SC, Caballeria J, Rodes J, Mato JM. Source: Journal of Hepatology. 2000 December; 33(6): 907-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11131452
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Redundancy in the pathway for redox regulation of mammalian methionine synthase: reductive activation by the dual flavoprotein, novel reductase 1. Author(s): Olteanu H, Banerjee R. Source: The Journal of Biological Chemistry. 2003 October 3; 278(40): 38310-4. Epub 2003 July 18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12871938
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Regulation of the human MAT2A gene encoding the catalytic alpha 2 subunit of methionine adenosyltransferase, MAT II: gene organization, promoter characterization, and identification of a site in the proximal promoter that is essential for its activity. Author(s): Halim AB, LeGros L, Chamberlin ME, Geller A, Kotb M. Source: The Journal of Biological Chemistry. 2001 March 30; 276(13): 9784-91. Epub 2000 December 21. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11124935
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Relationship of folate, vitamin B-6, vitamin B-12, and methionine intake to incidence of colorectal cancers. Author(s): Harnack L, Jacobs DR Jr, Nicodemus K, Lazovich D, Anderson K, Folsom AR. Source: Nutrition and Cancer. 2002; 43(2): 152-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12588695
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Response to "genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) in ethnic populations in Texas; a report of a novel MTHFR polymorphic site, G1793A". Author(s): Isotalo PA, Donnelly JG. Source: American Journal of Medical Genetics. 2002 June 15; 110(2): 191-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12116261
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Role of abnormal methionine metabolism in alcoholic liver injury. Author(s): Lu SC, Tsukamoto H, Mato JM. Source: Alcohol (Fayetteville, N.Y.). 2002 July; 27(3): 155-62. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12163143
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Role of individual methionines in the fibrillation of methionine-oxidized alphasynuclein. Author(s): Hokenson MJ, Uversky VN, Goers J, Yamin G, Munishkina LA, Fink AL. Source: Biochemistry. 2004 April 20; 43(15): 4621-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15078109
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Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence. Author(s): Mischoulon D, Fava M. Source: The American Journal of Clinical Nutrition. 2002 November; 76(5): 1158S-61S. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12420702
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S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism. Author(s): Baric I, Fumic K, Glenn B, Cuk M, Schulze A, Finkelstein JD, James SJ, Mejaski-Bosnjak V, Pazanin L, Pogribny IP, Rados M, Sarnavka V, Scukanec-Spoljar M, Allen RH, Stabler S, Uzelac L, Vugrek O, Wagner C, Zeisel S, Mudd SH. Source: Proceedings of the National Academy of Sciences of the United States of America. 2004 March 23; 101(12): 4234-9. Epub 2004 Mar 15. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15024124
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S-adenosyl-L-methionine is able to reverse micronucleus formation induced by sodium arsenite and other cytoskeleton disrupting agents in cultured human cells. Author(s): Ramirez T, Garcia-Montalvo V, Wise C, Cea-Olivares R, Poirier LA, Herrera LA. Source: Mutation Research. 2003 July 25; 528(1-2): 61-74. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12873724
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S-Adenosyl-Methionine improves depression in patients with Parkinson's disease in an open-label clinical trial. Author(s): Di Rocco A, Rogers JD, Brown R, Werner P, Bottiglieri T. Source: Movement Disorders : Official Journal of the Movement Disorder Society. 2000 November; 15(6): 1225-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11104210
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S-adenosyl-methionine in depression: a comprehensive review of the literature. Author(s): Papakostas GI, Alpert JE, Fava M. Source: Current Psychiatry Reports. 2003 December; 5(6): 460-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14609501
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Selective solid-phase isolation of methionine-containing peptides and subsequent matrix-assisted laser desorption/ionisation mass spectrometric detection of methionine- and of methionine-sulfoxide-containing peptides. Author(s): Grunert T, Pock K, Buchacher A, Allmaier G. Source: Rapid Communications in Mass Spectrometry : Rcm. 2003; 17(16): 1815-24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12876681
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Severe methylenetetrahydrofolate reductase deficiency, methionine synthase, and nitrous oxide--a cautionary tale. Author(s): Erbe RW, Salis RJ. Source: The New England Journal of Medicine. 2003 July 3; 349(1): 5-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12840086
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Simple plasma work-up for a fast chromatographic analysis of homocysteine, cysteine, methionine and aromatic amino acids. Author(s): Husek P, Matucha P, Vrankova A, Simek P. Source: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2003 June 15; 789(2): 311-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12742122
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Structure of Mycobacterium tuberculosis methionine sulfoxide reductase A in complex with protein-bound methionine. Author(s): Taylor AB, Benglis DM Jr, Dhandayuthapani S, Hart PJ. Source: Journal of Bacteriology. 2003 July; 185(14): 4119-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12837786
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Synthesis of glutathione in response to methionine load in control subjects and in patients with cirrhosis. Author(s): Bianchi G, Brizi M, Rossi B, Ronchi M, Grossi G, Marchesini G. Source: Metabolism: Clinical and Experimental. 2000 November; 49(11): 1434-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11092507
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Targeted disruption of the methionine synthase gene in mice. Author(s): Swanson DA, Liu ML, Baker PJ, Garrett L, Stitzel M, Wu J, Harris M, Banerjee R, Shane B, Brody LC. Source: Molecular and Cellular Biology. 2001 February; 21(4): 1058-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11158293
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The 2756A>G variant in the gene encoding methionine synthase: its relation with plasma homocysteine levels and risk of coronary heart disease in a Dutch case-control study. Author(s): Klerk M, Lievers KJ, Kluijtmans LA, Blom HJ, den Heijer M, Schouten EG, Kok FJ, Verhoef P. Source: Thrombosis Research. 2003 May 1; 110(2-3): 87-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12893022
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The additional methionine residue at the N-terminus of bacterially expressed human interleukin-2 affects the interaction between the N- and C-termini. Author(s): Endo S, Yamamoto Y, Sugawara T, Nishimura O, Fujino M. Source: Biochemistry. 2001 January 30; 40(4): 914-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11170412
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The impact of supplemental dietary methionine sources on volatile compound concentrations in broiler excreta. Author(s): Chavez C, Coufal CD, Carey JB, Lacey RE, Beier RC, Zahn JA. Source: Poultry Science. 2004 June; 83(6): 901-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15206616
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The methionine synthase polymorphism D919G alters susceptibility to primary central nervous system lymphoma. Author(s): Linnebank M, Schmidt S, Kolsch H, Linnebank A, Heun R, Schmidt-Wolf IG, Glasmacher A, Fliessbach K, Klockgether T, Schlegel U, Pels H. Source: British Journal of Cancer. 2004 May 17; 90(10): 1969-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15138479
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The peptide methionine sulfoxide reductases, MsrA and MsrB (hCBS-1), are downregulated during replicative senescence of human WI-38 fibroblasts. Author(s): Picot CR, Perichon M, Cintrat JC, Friguet B, Petropoulos I. Source: Febs Letters. 2004 January 30; 558(1-3): 74-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14759519
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The role of c-Myb in the up-regulation of methionine adenosyltransferase 2A expression in activated Jurkat cells. Author(s): Zeng Z, Yang H, Huang ZZ, Chen C, Wang J, Lu SC. Source: The Biochemical Journal. 2001 January 1; 353(Pt 1): 163-168. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11115410
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The role of methionine in ethylmalonic encephalopathy with petechiae. Author(s): McGowan KA, Nyhan WL, Barshop BA, Naviaux RK, Yu A, Haas RH, Townsend JJ. Source: Archives of Neurology. 2004 April; 61(4): 570-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15096407
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Tumor suppression by a rationally designed reversible inhibitor of methionine aminopeptidase-2. Author(s): Wang J, Sheppard GS, Lou P, Kawai M, BaMaung N, Erickson SA, TuckerGarcia L, Park C, Bouska J, Wang YC, Frost D, Tapang P, Albert DH, Morgan SJ, Morowitz M, Shusterman S, Maris JM, Lesniewski R, Henkin J. Source: Cancer Research. 2003 November 15; 63(22): 7861-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14633714
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Unchecked DNA synthesis and blocked cell division induced by methionine deprivation in a human prostate cancer cell line. Author(s): Guo HY, Hoffman RM, Herrera H. Source: In Vitro Cellular & Developmental Biology. Animal. 1993 May; 29A(5): 359-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8314730
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Understanding the selectivity of fumagillin for the methionine aminopeptidase type II. Author(s): Klein CD, Folkers G. Source: Oncology Research. 2003; 13(12): 513-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12899241
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Up-regulation of integrin alpha5 by a C-terminus four-amino-acid sequence of substance P (phenylalanine-glycine-leucine-methionine- amide) synergistically with insulin-like growth factor-1 in SV-40 transformed human corneal epithelial cells. Author(s): Chikama T, Nakamura M, Nishida T. Source: Biochemical and Biophysical Research Communications. 1999 February 24; 255(3): 692-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10049772
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Uptake of 11C-methionine in breast cancer studied by PET. An association with the size of S-phase fraction. Author(s): Leskinen-Kallio S, Nagren K, Lehikoinen P, Ruotsalainen U, Joensuu H. Source: British Journal of Cancer. 1991 December; 64(6): 1121-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=1662533
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Uptake of positron emission tomography tracers in experimental bacterial infections: a comparative biodistribution study of radiolabeled FDG, thymidine, L-methionine, 67Ga-citrate, and 125I-HSA. Author(s): Sugawara Y, Gutowski TD, Fisher SJ, Brown RS, Wahl RL. Source: European Journal of Nuclear Medicine. 1999 April; 26(4): 333-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10199938
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Uptake of tritiated thymidine, deoxyglucose and methionine in three lung cancer cell lines: deoxyglucose uptake mirrors tritiated thymidine uptake. Author(s): Nerini-Molteni S, Seregni E, Crippa F, Maffioli L, Botti C, Bombardieri E. Source: Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine. 2001 March-April; 22(2): 92-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11125281
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Use of carbon-11 methionine positron emission tomography to assess malignancy grade and predict survival in patients with lymphomas. Author(s): Nuutinen J, Leskinen S, Lindholm P, Soderstrom KO, Nagren K, Huhtala S, Minn H. Source: European Journal of Nuclear Medicine. 1998 July; 25(7): 729-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9662595
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Use of co-registered 11C-methionine PET and computed tomography for the localisation of parathyroid adenomas. Author(s): Beggs AD, Hain SF. Source: European Journal of Nuclear Medicine and Molecular Imaging. 2003 November; 30(11): 1602. Epub 2003 August 23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14579103
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Usefulness of 11C-methionine PET in the evaluation of brain lesions that are hypo- or isometabolic on 18F-FDG PET. Author(s): Chung JK, Kim YK, Kim SK, Lee YJ, Paek S, Yeo JS, Jeong JM, Lee DS, Jung HW, Lee MC. Source: European Journal of Nuclear Medicine and Molecular Imaging. 2002 February; 29(2): 176-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11926379
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Usefulness of PET with 11C-methionine for the detection of hilar and mediastinal lymph node metastasis in lung cancer. Author(s): Yasukawa T, Yoshikawa K, Aoyagi H, Yamamoto N, Tamura K, Suzuki K, Tsujii H, Murata H, Sasaki Y, Fujisawa T. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 2000 February; 41(2): 283-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10688112
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Validation of a method for automatic image fusion (BrainLAB System) of CT data and 11C-methionine-PET data for stereotactic radiotherapy using a LINAC: first clinical experience. Author(s): Grosu AL, Lachner R, Wiedenmann N, Stark S, Thamm R, Kneschaurek P, Schwaiger M, Molls M, Weber WA. Source: International Journal of Radiation Oncology, Biology, Physics. 2003 August 1; 56(5): 1450-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12873691
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Validation of abbreviated oral methionine-loading test. Author(s): Bostom AG, Roubenoff R, Dellaripa P, Nadeau MR, Sutherland P, Wilson PW, Jacques PF, Selhub J, Rosenberg IH. Source: Clinical Chemistry. 1995 June; 41(6 Pt 1): 948-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7768022
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Valine, not methionine, is amino acid 106 in human cytosolic thymidine kinase (TK1). Impact on oligomerization, stability, and kinetic properties. Author(s): Berenstein D, Christensen JF, Kristensen T, Hofbauer R, Munch-Petersen B. Source: The Journal of Biological Chemistry. 2000 October 13; 275(41): 32187-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10924519
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Variability of fasting and post-methionine plasma homocysteine levels in normo- and hyperhomocysteinaemic individuals. Author(s): van den Berg M, de Jong SC, Deville W, Rauwerda JA, Jakobs C, Pals G, Boers GH, Stehouwer CD. Source: The Netherlands Journal of Medicine. 1999 July; 55(1): 29-38. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10431553
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Variability of post-methionine load plasma homocysteine assays. Author(s): Ubbink JB, Becker PJ, Delport R, Bester M, Riezler R, Vermaak WJ. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 2003 April; 330(1-2): 111-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12636929
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Variability of the methionine loading test: no effect of a low protein diet. Author(s): den Heijer M, Bos GM, Brouwer IA, Gerrits WB, Blom HJ. Source: Annals of Clinical Biochemistry. 1996 November; 33 ( Pt 6): 551-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=8937588
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Variation in plasma cystathionine and its relation to changes in plasma concentrations of homocysteine and methionine in healthy subjects during a 24-h observation period. Author(s): Guttormsen AB, Solheim E, Refsum H. Source: The American Journal of Clinical Nutrition. 2004 January; 79(1): 76-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14684400
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Vasoactive intestinal polypeptide and peptide histidine methionine. Presence in human follicular fluid and effects on DNA synthesis and steroid secretion in cultured human granulosa/lutein cells. Author(s): Gras S, Ovesen P, Andersen AN, Sorensen S, Fahrenkrug J, Ottesen B. Source: Human Reproduction (Oxford, England). 1994 June; 9(6): 1053-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7962375
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Vibrational spectroscopic study of DL-methionine dihydrogen phosphate. Author(s): Rajkumar BJ, Ramakrishnan V. Source: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy. 2001 February; 57(2): 247-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11206558
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Whole brain methionine-enkephalin of ethanol-avoiding and ethanol-preferring c57BL mice. Author(s): Blum K, Briggs AH, DeLallo L, Elston SF, Ochoa R. Source: Experientia. 1982 December 15; 38(12): 1469-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=6891340
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Whole-serum assay of L-methionine using a chloramphenicol resistant strain of Pediococcus acidilactici. Author(s): Tennant GB. Source: The Journal of Applied Bacteriology. 1979 December; 47(3): 395-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=541304
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Why not add methionine to paracetamol tablets? Author(s): Neuvonen PJ, Simell O, Tokola O. Source: British Medical Journal (Clinical Research Ed.). 1986 October 11; 293(6552): 958. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=3094739
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X-linked dominant Charcot-Marie-Tooth neuropathy: valine-38-methionine substitution of connexin32. Author(s): Orth U, Fairweather N, Exler MC, Schwinger E, Gal A. Source: Human Molecular Genetics. 1994 September; 3(9): 1699-700. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=7833935
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Young stroke and basal plasma and post-methionine load homocysteine and cysteine levels 1 year after the acute event: do plasma folates make the difference? Author(s): Beccia M, Mele MC, Ferrari M, Ranieri M, Barini A, Rasura M. Source: European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies. 2004 April; 11(4): 269-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15061829
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CHAPTER 2. NUTRITION AND METHIONINE Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and methionine.
Finding Nutrition Studies on Methionine The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements; National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: 301-435-2920, Fax: 301-480-1845, E-mail:
[email protected]). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.7 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “methionine” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.
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Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.
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The following information is typical of that found when using the “Full IBIDS Database” to search for “methionine” (or a synonym): •
Composition and properties of the milk in sheep from newly created dairy breed in Bulgaria. Author(s): Agricultural Institute, Shumen (Bulgaria) Source: Boikovski, S. Stancheva, N. Stefanova, G. Dimitrov, D. Bulgarian-Journal-ofAgricultural-Science. (2002). volume 8(2-3) page 289-293.
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Effect of enzyme lysis on the digestibility of brewer's yeasts included in the diets of chicken broilers. Author(s): Bulgarian Academy of Science, Plovdiv (Bulgaria). Inst. of Microbiology Source: Pavlova, K. Grigorova, D. Czech-Journal-of-Animal-Science-UZPI (Czech Republic). (September 2001). volume 46(9) page 408-412.
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Effect of partial dietary amino acid deductions on growth rate and nitrogen balance in growing chicks. Source: Gruber, K. Roth, F.X. Kirchgessner, M. Archiv-fuer-Gefluegelkunde (Germany). (2000). volume 64(6) page 244-250.
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Reducing the risk of urinary tract infections in breeding sows. Source: Hoehler, D. Lindermeayer, H. Wolffram, S. Kraftfutter (Germany). (2000). (no. 78) page 293-296.
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Requirement of lysine and total sulfur amino acid for force moulted WL layers. Source: Rama Rao, S.V. Praharaj, N.K. Shyam Sunder, G. Raju, M.V.L.N. Reddy, M.R. Panda, A.K. Archiv-fuer-Gefluegelkunde (Germany). (2000). volume 64(5) page 214-218.
Additional physician-oriented references include: •
5-demethylovalicin, as a methionine aminopeptidase-2 inhibitor produced by Chrysosporium. Author(s): Korea Research Institute of Bioscience and Biotechnology, 52-Eundong, Yusong, 305-333, Taejon, Republic of Korea.
[email protected] Source: Son, Kwang Hee Kwon, Ju Young Jeong, Ha Won Kim, Hyae Kyeong Kim, Chang Jin Chang, Yie Hwa Choi, Jung Do Kwon, Byoung Mog Bioorg-Med-Chem. 2002 January; 10(1): 185-8 0968-0896
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A single-nucleotide mutation in a gene encoding S-adenosylmethionine synthetase is associated with methionine over-accumulation phenotype in Arabidopsis thaliana. Author(s): Laboratory of Molecular Biology, Division of Applied Bioscience, Graduate School of Agriculture, Hokkaido University, Japan. Source: Goto, D B Ogi, M Kijima, F Kumagai, T van Werven, F Onouchi, H Naito, S Genes-Genet-Syst. 2002 April; 77(2): 89-95 1341-7568
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Catabolism of methionine and threonine in vitro by mixed ruminal bacteria and protozoa. Author(s): Laboratory of Animal Nutrition and Biochemistry, Division of Animal Science, Faculty of Agriculture, Miyazaki University, Japan.
[email protected] Source: Or Rashid, M M Onodera, R Wadud, S Oshiro, S Okada, T Amino-Acids. 2001 December; 21(4): 383-91 0939-4451
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Cystathionine gamma-synthase and threonine synthase operate in concert to regulate carbon flow towards methionine in plants. Author(s): Plant Science Laboratory, Migal Galilee Technological Center, PO Box 90000, Rosh Pina 12100, Israel.
[email protected] Nutrition
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Source: Amir, Rachel Hacham, Yael Galili, Gad Trends-Plant-Sci. 2002 April; 7(4): 153-6 1360-1385 •
Dihydrolipoic acid as an effective cofactor for peptide methionine sulfoxide reductase in enzymatic repair of oxidative damage to both lipid-free and lipid-bound apolipoprotein a-I. Author(s): Biomedical Department, AMW Biomed, 22-1-11 Tarusskaya Street, Moscow 117588, Russia.
[email protected] Source: Sigalov, A B Stern, L J Antioxid-Redox-Signal. 2002 June; 4(3): 553-7 1523-0864
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Effect of maternal methionine pre-treatment on alcohol-induced exencephaly and axial skeletal dysmorphogenesis in mouse fetuses. Author(s): Department of Anatomy, Faculty of Medicine and Health Sciences, UAE University, PO Box 17666, Al Ain, United Arab Emirates.
[email protected] Source: Padmanabhan, R Ibrahim, Ahmad Bener, Abulbari Drug-Alcohol-Depend. 2002 February 1; 65(3): 263-81 0376-8716
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Effects of dietary methionine and ethanol on acetaminophen hepatotoxicity in mice. Source: Reicks, M M Hathcock, J N Drug-Nutr-Interact. 1984; 3(1): 43-51 0272-3530
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Functional modeling of cobalamine-independent methionine synthase with pyrazolylborate-zinc-thiolate complexes. Author(s): Institut fur Anorganische und Analytische Chemie der Universitat Freiburg, Albertstrasse 21, D-79104 Freiburg, Germany. Source: Brand, U Rombach, M Seebacher, J Vahrenkamp, H Inorg-Chem. 2001 November 19; 40(24): 6151-7 0020-1669
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High dietary folate supplementation: effects on diet utilization and methionine metabolism in aged rats. Author(s): Seccion de Nutricion y Bromatologia, Departamento de Ciencias Biomedicas I, Facultad de Ciencias Experimentales y de la Salud, Universidad San Pablo-CEU, 28668 Boadilla del Monte, Madrid, Spain.
[email protected] Source: Achon, M Alonso Aperts, E Varela Moreiras, G J-Nutr-Health-Aging. 2002; 6(1): 51-4 1279-7707
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Leishmania donovani methionine adenosyltransferase. Role of cysteine residues in the recombinant enzyme. Author(s): Departamento de Farmacologia y Toxicologia (INTOXCAL), Universidad de Leon, Leon, Spain. Source: Perez Pertejo, Y Reguera, R M Villa, H Garcia Estrada, C Balana Fouce, R Pajares, M A Ordonez, D Eur-J-Biochem. 2003 January; 270(1): 28-35 0014-2956
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Microsporidian methionine aminopeptidase type 2. Author(s): Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
[email protected] Source: Weiss, L M Costa, S F Zhang, H J-Eukaryot-Microbiol. 2001; Suppl: 88S-90S 1066-5234
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Mutations in human glycine N-methyltransferase give insights into its role in methionine metabolism. Author(s): Department of Biochemistry, Medical Center Vanderbilt University, 620 Light Hall, Nashville, TN 37232, USA. Source: Luka, Zigmund Cerone, Roberto Phillips, John A 3rd Mudd, Harvey S Wagner, Conrad Hum-Genet. 2002 January; 110(1): 68-74 0340-6717
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Spontaneous oxidative stress and liver tumors in mice lacking methionine adenosyltransferase 1A. Author(s): Division of Hepatology and Gene Therapy, Department of Medicine, School of Medicine, University of Navarra, Pamplona, Spain. Source: Martinez Chantar, Maria L Corrales, Fernando J Martinez Cruz, L Alfonso Garcia Trevijano, Elena R Huang, Zong Zhi Chen, Lixin Kanel, Gary Avila, Matias A Mato, Jose M Lu, Shelly C FASEB-J. 2002 August; 16(10): 1292-4 1530-6860
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Synthesis of optically active homocysteine from methionine and its use in preparing four stereoisomers of cystathionine. Author(s): Unit of Chemistry, Faculty of Engineering and High Technology Research Center, Kansai University, Osaka, Japan.
[email protected] Source: Shiraiwa, T Nakagawa, K Kanemoto, N Kinda, T Yamamoto, H Chem-PharmBull-(Tokyo). 2002 August; 50(8): 1081-5 0009-2363
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Tolerance of point substitution of methionine for isoleucine in hen egg white lysozyme. Author(s): Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan. Source: Ohmura, T Ueda, T Hashimoto, Y Imoto, T Protein-Eng. 2001 June; 14(6): 421-5 0269-2139
Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •
healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0
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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov
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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov
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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/
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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/
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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/
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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/
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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/
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Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •
AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats
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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html
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Google: http://directory.google.com/Top/Health/Nutrition/
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Healthnotes: http://www.healthnotes.com/
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Open Directory Project: http://dmoz.org/Health/Nutrition/
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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/
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WebMDHealth: http://my.webmd.com/nutrition
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
The following is a specific Web list relating to methionine; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •
Vitamins Folic Acid Source: Healthnotes, Inc.; www.healthnotes.com Vitamin B12 Source: Healthnotes, Inc.; www.healthnotes.com Vitamin B12 Source: Prima Communications, Inc.www.personalhealthzone.com
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Minerals Creatine Source: Prima Communications, Inc.www.personalhealthzone.com Gabapentin Source: Healthnotes, Inc.; www.healthnotes.com L-Carnitine Source: Healthnotes, Inc.; www.healthnotes.com Lecithin and Choline Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10040,00.html
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Selenium Source: Healthnotes, Inc.; www.healthnotes.com Selenium Source: Prima Communications, Inc.www.personalhealthzone.com Sulfur Source: Healthnotes, Inc.; www.healthnotes.com Zinc Source: Integrative Medicine Communications; www.drkoop.com Zinc Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10071,00.html •
Food and Diet Betaine (Trimethylglycine) Source: Healthnotes, Inc.; www.healthnotes.com Spinach Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/foods_view/0,1523,35,00.html
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CHAPTER 3. ALTERNATIVE MEDICINE AND METHIONINE Overview In this chapter, we will begin by introducing you to official information sources on complementary and alternative medicine (CAM) relating to methionine. At the conclusion of this chapter, we will provide additional sources.
The Combined Health Information Database The Combined Health Information Database (CHID) is a bibliographic database produced by health-related agencies of the U.S. federal government (mostly from the National Institutes of Health) that can offer concise information for a targeted search. The CHID database is updated four times a year at the end of January, April, July, and October. Check the titles, summaries, and availability of CAM-related information by using the “Simple Search” option at the following Web site: http://chid.nih.gov/simple/simple.html. In the drop box at the top, select “Complementary and Alternative Medicine.” Then type “methionine” (or synonyms) in the second search box. We recommend that you select 100 “documents per page” and to check the “whole records” options. The following was extracted using this technique: •
S-Adenosyl-L-Methionine for Treatment of Depression, Osteoarthritis, and Liver Disease Source: Rockville, MD: Agency for Healthcare Research and Quality. 2002. 6 p. Contact: Available from National Center for Complementary and Alternative Medicine Clearinghouse. P.O. Box 7923, Gaithersburg, MD 20898. (888) 644-6226; INTERNATIONAL PHONE: (301) 519-3153; TTY: (866) 464-3615; FAX: (866) 464-3616; EMAIL:
[email protected]. PRICE: Free. Publication Number: D175. Summary: This evidence report/technology assessment summary from the Agency for Healthcare Research and Quality (AHRQ) provides a review of the published literature on the use of S-adenosyl-L-methionine (SAMe) for the treatment of osteoarthritis, depression, and liver disease (cholestasis of pregnancy). The literature review is used to evaluate evidence for the efficacy of SAMe. The summary includes a description of the methodology, including the search strategy; selection criteria; and data collection and
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analysis. The findings are then discussed followed by an overview of future research on the topic. Information is also given on when and where the full report will be available. 1 reference.
National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov/) has created a link to the National Library of Medicine’s databases to facilitate research for articles that specifically relate to methionine and complementary medicine. To search the database, go to the following Web site: http://www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “methionine” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of complementary and alternative medicine that are related to methionine: •
Abnormal hepatic methionine and glutathione metabolism in patients with alcoholic hepatitis. Author(s): Lee TD, Sadda MR, Mendler MH, Bottiglieri T, Kanel G, Mato JM, Lu SC. Source: Alcoholism, Clinical and Experimental Research. 2004 January; 28(1): 173-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14745316
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Analysis of cell-cycle kinetics and sulfur amino acid metabolism in methioninedependent tumor cell lines; the effect of homocysteine supplementation. Author(s): Pavillard V, Drbal AA, Swaine DJ, Phillips RM, Double JA, Nicolaou A. Source: Biochemical Pharmacology. 2004 April 15; 67(8): 1587-99. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15041476
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Antioxidant effects of alpha tocopherol, ascorbic acid and L-methionine on lead induced oxidative stress to the liver, kidney and brain in rats. Author(s): Patra RC, Swarup D, Dwivedi SK. Source: Toxicology. 2001 May 11; 162(2): 81-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11337108
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Antioxidant properties of S-adenosyl-L-methionine in Fe(2+)-initiated oxidations. Author(s): Caro AA, Cederbaum AI. Source: Free Radical Biology & Medicine. 2004 May 15; 36(10): 1303-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15110395
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Betaine as a determinant of postmethionine load total plasma homocysteine before and after B-vitamin supplementation. Author(s): Holm PI, Bleie O, Ueland PM, Lien EA, Refsum H, Nordrehaug JE, Nygard O.
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Betaine supplementation decreases post-methionine hyperhomocysteinemia in chronic renal failure. Author(s): McGregor DO, Dellow WJ, Robson RA, Lever M, George PM, Chambers ST. Source: Kidney International. 2002 March; 61(3): 1040-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11849459
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Capillary gas chromatography inductively coupled plasma mass spectrometry (CGCICPMS) for the enantiomeric analysis of D,L-selenomethionine in food supplements and urine. Author(s): Devos C, Sandra K, Sandra P. Source: Journal of Pharmaceutical and Biomedical Analysis. 2002 January 15; 27(3-4): 507-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11755752
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cDNA cloning and biochemical characterization of S-adenosyl-L-methionine: 2,7,4'trihydroxyisoflavanone 4'-O-methyltransferase, a critical enzyme of the legume isoflavonoid phytoalexin pathway. Author(s): Akashi T, Sawada Y, Shimada N, Sakurai N, Aoki T, Ayabe S. Source: Plant & Cell Physiology. 2003 February; 44(2): 103-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12610212
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Comparison of the in situ and in vivo intestinal disappearance of ruminally protected methionine. Author(s): Berthiaume R, Lapierre H, Stevenson M, Cote N, McBride BW. Source: Journal of Dairy Science. 2000 September; 83(9): 2049-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11003238
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Complementary responses between feather meal and poultry by-product meal with or without ruminally protected methionine and lysine in growing calves. Author(s): Klemesrud MJ, Klopfenstein TJ, Lewis AJ. Source: Journal of Animal Science. 1998 July; 76(7): 1970-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9690654
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Correlation of carnitine levels to methionine and lysine intake. Author(s): Krajcovicova-Kudlackova M, Simoncic R, Bederova A, Babinska K, Beder I. Source: Physiological Research / Academia Scientiarum Bohemoslovaca. 2000; 49(3): 399-402. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11043928
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C-terminal extension of phaseolin with a short methionine-rich sequence can inhibit trimerisation and result in high instability. Author(s): Nuttall J, Vitale A, Frigerio L. Source: Plant Molecular Biology. 2003 April; 51(6): 885-94. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12777049
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Dietary supplementation of selenomethionine reduces metastasis of melanoma cells in mice. Author(s): Yan L, Yee JA, Li D, McGuire MH, Graef GL. Source: Anticancer Res. 1999 March-April; 19(2A): 1337-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10368696
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Dietary supplementation with L-methionine impairs the utilization of urea-nitrogen and increases 5-L-oxoprolinuria in normal women consuming a low protein diet. Author(s): Meakins TS, Persaud C, Jackson AA. Source: The Journal of Nutrition. 1998 April; 128(4): 720-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9521634
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Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in ApoE-deficient mice. Author(s): Zhou J, Moller J, Danielsen CC, Bentzon J, Ravn HB, Austin RC, Falk E. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2001 September; 21(9): 14706. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11557674
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DL-methionine supplementation of rice-and-bean diets affects gammaglutamyltranspeptidase activity and glutathione content in livers of growing rats. Author(s): De-Oliveira IM, Fujimori E, Pereira VG, De-Castro VD. Source: Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas / Sociedade Brasileira De Biofisica. [et Al.]. 1999 April; 32(4): 483-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10347814
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Doxorubicin and vincristine with methionine depletion contributed to survival in the Yoshida sarcoma bearing rats. Author(s): Nagahama T, Goseki N, Endo M. Source: Anticancer Res. 1998 January-February; 18(1A): 25-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9568051
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Effect of a methionine-supplemented diet on the blood pressure of Sprague-Dawley and deoxycorticosterone acetate-salt hypertensive rats. Author(s): Robin S, Maupoil V, Laurant P, Jacqueson A, Berthelot A.
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Source: The British Journal of Nutrition. 2004 June; 91(6): 857-65. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15182389 •
Effect of a methionine-supplemented diet on the blood pressure of Wistar-Kyoto and spontaneously hypertensive rats. Author(s): Robin S, Maupoil V, Groubatch F, Laurant P, Jacqueson A, Berthelot A. Source: The British Journal of Nutrition. 2003 April; 89(4): 539-48. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12654173
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Effect of dietary chromium-L-methionine on glucose metabolism of beef steers. Author(s): Kegley EB, Galloway DL, Fakler TM. Source: Journal of Animal Science. 2000 December; 78(12): 3177-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11132832
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Effect of methionine supplementation on endothelial function, plasma homocysteine, and lipid peroxidation. Author(s): McAuley DF, Hanratty CG, McGurk C, Nugent AG, Johnston GD. Source: Journal of Toxicology. Clinical Toxicology. 1999; 37(4): 435-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10465239
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Effect of rumen protected methionine supplementation on early lactational responses of dairy cows fed a grass silage and cereals diet. Author(s): Iwanska S, Strusinska D, Pysera B. Source: Acta Vet Hung. 1999; 47(2): 191-206. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10344080
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Effect of supplemental methionine on plasma homocysteine concentrations in healthy men: a preliminary study. Author(s): Ward M, McNulty H, McPartlin J, Strain JJ, Weir DG, Scott JM. Source: Int J Vitam Nutr Res. 2001 January; 71(1): 82-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11276928
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Effect of supplemental methionine, choline and their combinations on the performance and immune response of broilers. Author(s): Swain BK, Johri TS. Source: British Poultry Science. 2000 March; 41(1): 83-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10821528
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Effect of supplementation of dry cat food with D,L-methionine and ammonium chloride on struvite activity product and sediment in urine. Author(s): Funaba M, Yamate T, Narukawa Y, Gotoh K, Iriki T, Hatano Y, Abe M.
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Source: The Journal of Veterinary Medical Science / the Japanese Society of Veterinary Science. 2001 March; 63(3): 337-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11307939 •
Effect of two levels of crude protein and methionine supplementation on performance of dairy cows. Author(s): Leonardi C, Stevenson M, Armentano LE. Source: Journal of Dairy Science. 2003 December; 86(12): 4033-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14740841
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Effect of vitamin A supplementation on rhodopsin mutants threonine-17 --> methionine and proline-347 --> serine in transgenic mice and in cell cultures. Author(s): Li T, Sandberg MA, Pawlyk BS, Rosner B, Hayes KC, Dryja TP, Berson EL. Source: Proceedings of the National Academy of Sciences of the United States of America. 1998 September 29; 95(20): 11933-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9751768
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Effects of dietary supplements of zinc-methionine on milk production, udder health and zinc metabolism in dairy goats. Author(s): Salama AA, Caja G, Albanell E, Such X, Casals R, Plaixats J. Source: The Journal of Dairy Research. 2003 February; 70(1): 9-17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12617388
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Effects of methionine loading on plasma and erythrocyte sulphur amino acids and sulph-hydryls before and after co-factor supplementation in haemodialysis patients. Author(s): Suliman ME, Filho JC, Barany P, Anderstam B, Lindholm B, Bergstrom J. Source: Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. 2001 January; 16(1): 102-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11209001
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Effects of methionine supplement on methionine incorporation in rat embryos cultured in vitro. Author(s): Pugarelli JE, Brent RL, Lloyd JB. Source: Teratology. 1999 July; 60(1): 6-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10413332
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Effects of replacing fish meal with soy protein concentrate and of DL-methionine supplementation in high-energy, extruded diets on the growth and nutrient utilization of rainbow trout, Oncorhynchus mykiss. Author(s): Mambrini M, Roem AJ, Carvedi JP, Lalles JP, Kaushik SJ.
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Source: Journal of Animal Science. 1999 November; 77(11): 2990-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10568469 •
Efficacy of the dietary supplement S-adenosyl-L-methionine. Author(s): Fetrow CW, Avila JR. Source: The Annals of Pharmacotherapy. 2001 November; 35(11): 1414-25. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11724095
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Electrophysiological neuroimaging of the central effects of S-adenosyl-L-methionine by mapping of electroencephalograms and event-related potentials and lowresolution brain electromagnetic tomography. Author(s): Saletu B, Anderer P, Di Padova C, Assandri A, Saletu-Zyhlarz GM. Source: The American Journal of Clinical Nutrition. 2002 November; 76(5): 1162S-71S. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12418497
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Elucidation of solvent exposure, side-chain reactivity, and steric demands of the trifluoromethionine residue in a recombinant protein. Author(s): Duewel HS, Daub E, Robinson V, Honek JF. Source: Biochemistry. 2001 November 6; 40(44): 13167-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11683625
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Excess dietary methionine markedly increases the vitamin B-6 requirement of young chicks. Author(s): Scherer CS, Baker DH. Source: The Journal of Nutrition. 2000 December; 130(12): 3055-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11110868
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Free methionine supplementation limits alcohol-induced liver damage in rats. Author(s): Parlesak A, Bode C, Bode JC. Source: Alcoholism, Clinical and Experimental Research. 1998 April; 22(2): 352-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9581640
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Functional proteomics of nonalcoholic steatohepatitis: mitochondrial proteins as targets of S-adenosylmethionine. Author(s): Santamaria E, Avila MA, Latasa MU, Rubio A, Martin-Duce A, Lu SC, Mato JM, Corrales FJ. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 March 18; 100(6): 3065-70. Epub 2003 Mar 11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12631701
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Genetic engineering for high methionine grain legumes. Author(s): Muntz K, Christov V, Saalbach G, Saalbach I, Waddell D, Pickardt T, Schieder O, Wustenhagen T.
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Source: Die Nahrung. 1998 August; 42(3-4): 125-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9739551 •
Growth stimulation of intestinal tumours in Apc(Min/+) mice by dietary Lmethionine supplementation. Author(s): Paulsen JE, Alexander J. Source: Anticancer Res. 2001 September-October; 21(5): 3281-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11848484
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High dietary folate supplementation: effects on diet utilization and methionine metabolism in aged rats. Author(s): Achon M, Alonso-Aperts E, Varela-Moreiras G. Source: J Nutr Health Aging. 2002; 6(1): 51-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11813082
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High-dose folic acid supplementation in rats: effects on gestation and the methionine cycle. Author(s): Achon M, Alonso-Aperte E, Reyes L, Ubeda N, Varela-Moreiras G. Source: The British Journal of Nutrition. 2000 February; 83(2): 177-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10743497
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Identification of limiting amino acids in methionine- and lysine-supplemented lowprotein diets for turkeys. Author(s): Waibel PE, Carlson CW, Brannon JA, Noll SL. Source: Poultry Science. 2000 September; 79(9): 1299-305. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11020075
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Induction of human methionine adenosyltransferase 2A expression by tumor necrosis factor alpha. Role of NF-kappa B and AP-1. Author(s): Yang H, Sadda MR, Yu V, Zeng Y, Lee TD, Ou X, Chen L, Lu SC. Source: The Journal of Biological Chemistry. 2003 December 19; 278(51): 50887-96. Epub 2003 October 06. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14530285
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Influence of dietary protein level on the broiler chicken's response to methionine and betaine supplements. Author(s): Garcia Neto M, Pesti GM, Bakalli RI. Source: Poultry Science. 2000 October; 79(10): 1478-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11055856
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Influence of postruminal supplementation of methionine and lysine, isoleucine, or all three amino acids on intake and chewing behavior, ruminal fermentation, and milk and milk component production.
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Author(s): Robinson PH, Chalupa W, Sniffen CJ, Julien WE, Sato H, Fujieda T, Watanabe K, Suzuki H. Source: Journal of Animal Science. 1999 October; 77(10): 2781-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10521041 •
Interaction between genotype and dietary concentrations of methionine for immune function in commercial broilers. Author(s): Rama Rao SV, Praharaj NK, Ramasubba Reddy V, Panda AK. Source: British Poultry Science. 2003 March; 44(1): 104-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12737232
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L- and D- methionine provide equivalent long term protection against CDDPinduced ototoxicity in vivo, with partial in vitro and in vivo retention of antineoplastic activity. Author(s): Reser D, Rho M, Dewan D, Herbst L, Li G, Stupak H, Zur K, Romaine J, Frenz D, Goldbloom L, Kopke R, Arezzo J, Van De Water T. Source: Neurotoxicology. 1999 October; 20(5): 731-48. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10591510
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Limiting amino acids after methionine and lysine with growing turkeys fed lowprotein diets. Author(s): Waibel PE, Carlson CW, Brannon JA, Noll SL. Source: Poultry Science. 2000 September; 79(9): 1290-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11020074
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Liquid chromatographic determination of S-adenosyl-L-methionine in dietary supplement tablets. Author(s): Zhou JZ, Waszkuc T, Garbis S, Mohammed F. Source: J Aoac Int. 2002 July-August; 85(4): 901-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12180685
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L-methionine availability regulates expression of the methionine adenosyltransferase 2A gene in human hepatocarcinoma cells: role of S-adenosylmethionine. Author(s): Martinez-Chantar ML, Latasa MU, Varela-Rey M, Lu SC, Garcia-Trevijano ER, Mato JM, Avila MA. Source: The Journal of Biological Chemistry. 2003 May 30; 278(22): 19885-90. Epub 2003 March 26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12660248
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L-methionine supplementation accelerates tumour growth and shifts the phospholipid derivative pattern in a murine model of malignant melanoma. A proton HRMAS NMR spectroscopy study. Author(s): Demidem A, Morvan D, Papon J, Madelmont JC.
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Low-dose folic acid supplementation does not influence plasma methionine concentrations in young non-pregnant women. Author(s): Brouwer IA, van Dusseldorp M, Duran M, Thomas CM, Hautvast JG, Eskes TK, Steegers-Theunissen RP. Source: The British Journal of Nutrition. 1999 August; 82(2): 85-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10743479
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Lymphocyte proliferation response of lactating dairy cows fed varying concentrations of rumen-protected methionine. Author(s): Soder KJ, Holden LA. Source: Journal of Dairy Science. 1999 September; 82(9): 1935-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10509252
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Methionine and somatotropin supplementation in growing beef cattle. Author(s): Tripp MW, Hoagland TA, Dahl GE, Kimrey AS, Zinn SA. Source: Journal of Animal Science. 1998 April; 76(4): 1197-203. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9581945
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Methionine depletion enhances the antitumoral efficacy of cytotoxic agents in drugresistant human tumor xenografts. Author(s): Poirson-Bichat F, Goncalves RA, Miccoli L, Dutrillaux B, Poupon MF. Source: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. 2000 February; 6(2): 643-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10690550
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Methionine supplementation of soya products: effects on nitrogen balance parameters. Author(s): de Oliveira JE, de Souza N, Jordao Junior AA, Marchin JS. Source: Arch Latinoam Nutr. 1998 March; 48(1): 35-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9754403
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Methionine-induced hyperhomocysteinemia promotes superoxide anion generation and NFkappaB activation in peritoneal macrophages of C57BL/6 mice. Author(s): Song YS, Rosenfeld ME. Source: Journal of Medicinal Food. 2004 Summer; 7(2): 229-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15298772
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Methionine-induced phytoalexin production in rice leaves. Author(s): Nakazato Y, Tamogami S, Kawai H, Hasegawa M, Kodama O.
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Source: Bioscience, Biotechnology, and Biochemistry. 2000 March; 64(3): 577-83. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10803956 •
Nitrogen metabolism of beef steers fed endophyte-free tall fescue hay: effects of ruminally protected methionine supplementation. Author(s): Archibeque SL, Burns JC, Huntington GB. Source: Journal of Animal Science. 2002 May; 80(5): 1344-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12019624
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NMR regulatory analysis: determination and characterization of S-adenosyl-Lmethionine in dietary supplements. Author(s): Hanna GM. Source: Pharmazie. 2004 April; 59(4): 251-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15125566
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Nutritional and technological evaluation of an enzymatically methionine-enriched soy protein for infant enteral formulas. Author(s): de Regil LM, de la Barca AM. Source: International Journal of Food Sciences and Nutrition. 2004 March; 55(2): 91-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14985181
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Part II: surface-enhanced Raman spectroscopy investigation of methionine containing heterodipeptides adsorbed on colloidal silver. Author(s): Podstawka E, Ozaki Y, Proniewicz LM. Source: Applied Spectroscopy. 2004 May; 58(5): 581-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15165335
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Production of hydrogen peroxide and methionine sulfoxide by epigallocatechin gallate and antioxidants. Author(s): Sakagami H, Arakawa H, Maeda M, Satoh K, Kadofuku T, Fukuchi K, Gomi K. Source: Anticancer Res. 2001 July-August; 21(4A): 2633-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11724332
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Protective effect of methionine supplementation on arsenic-induced alteration of glucose homeostasis. Author(s): Pal S, Chatterjee AK. Source: Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association. 2004 May; 42(5): 737-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15046819
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Purification and properties of a new S-adenosyl-L-methionine:flavonoid 4'-Omethyltransferase from carnation (Dianthus caryophyllus L.). Author(s): Curir P, Lanzotti V, Dolci M, Dolci P, Pasini C, Tollin G. Source: European Journal of Biochemistry / Febs. 2003 August; 270(16): 3422-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12899699
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Radical production from free and peptide-bound methionine sulfoxide oxidation by peroxynitrite and hydrogen peroxide/iron(II). Author(s): Nakao LS, Iwai LK, Kalil J, Augusto O. Source: Febs Letters. 2003 July 17; 547(1-3): 87-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12860391
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Response of nitrogen metabolism in preparturient dairy cows to methionine supplementation. Author(s): Bach A, Huntington GB, Stern MD. Source: Journal of Animal Science. 2000 March; 78(3): 742-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10764083
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Role of S-adenosyl-L-methionine in the treatment of alcoholic liver disease: introduction and summary of the symposium. Author(s): Purohit V, Russo D. Source: Alcohol (Fayetteville, N.Y.). 2002 July; 27(3): 151-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12163142
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Rumen degradation and availability of various amounts of liquid methionine hydroxy analog in lactating dairy cows. Author(s): Koenig KM, Rode LM, Knight CD, Vazquez-Anon M. Source: Journal of Dairy Science. 2002 April; 85(4): 930-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12018438
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Rumen-protected methionine or lysine supplementation of Comisana ewes' diets: effects on milk fatty acid composition. Author(s): Sevi A, Rotunno T, Di Caterina R, Muscio A. Source: The Journal of Dairy Research. 1998 August; 65(3): 413-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9718494
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Ruminal escape, gastrointestinal absorption, and response of serum methionine to supplementation of liquid methionine hydroxy analog in dairy cows. Author(s): Koenig KM, Rode LM, Knight CD, McCullough PR. Source: Journal of Dairy Science. 1999 February; 82(2): 355-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10068957
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S-adenosyl-L-methionine: effects on brain bioenergetic status and transverse relaxation time in healthy subjects. Author(s): Silveri MM, Parow AM, Villafuerte RA, Damico KE, Goren J, Stoll AL, Cohen BM, Renshaw PF. Source: Biological Psychiatry. 2003 October 15; 54(8): 833-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14550683
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S-adenosylmethionine (AdoMet) supplementation for treatment of chemotherapyinduced liver injury. Author(s): Santini D, Vincenzi B, Massacesi C, Picardi A, Gentilucci UV, Esposito V, Liuzzi G, La Cesa A, Rocci L, Marcucci F, Montesarchio V, Groeger AM, Bonsignori M, Tonini G. Source: Anticancer Res. 2003 November-December; 23(6D): 5173-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14981985
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S-adenosylmethionine and its metabolite induce apoptosis in HepG2 cells: Role of protein phosphatase 1 and Bcl-x(S). Author(s): Yang H, Sadda MR, Li M, Zeng Y, Chen L, Bae W, Ou X, Runnegar MT, Mato JM, Lu SC. Source: Hepatology (Baltimore, Md.). 2004 July; 40(1): 221-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=15239106
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Safety and efficacy of S-adenosylmethionine (SAMe) for osteoarthritis. Author(s): Soeken KL, Lee WL, Bausell RB, Agelli M, Berman BM. Source: The Journal of Family Practice. 2002 May; 51(5): 425-30. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12019049
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Selenomethionine content of candidate reference materials. Author(s): Wolf WR, Zainal H, Yager B. Source: Fresenius' Journal of Analytical Chemistry. 2001 June; 370(2-3): 286-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11451253
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Site-directed mutagenesis of Glu-297 from the alpha-polypeptide of Phaseolus vulgaris glutamine synthetase alters kinetic and structural properties and confers resistance to L-methionine sulfoximine. Author(s): Clemente MT, Marquez AJ. Source: Plant Molecular Biology. 1999 July; 40(5): 835-45. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10487218
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S-methylmethionine plays a major role in phloem sulfur transport and is synthesized by a novel type of methyltransferase. Author(s): Bourgis F, Roje S, Nuccio ML, Fisher DB, Tarczynski MC, Li C, Herschbach C, Rennenberg H, Pimenta MJ, Shen TL, Gage DA, Hanson AD.
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Source: The Plant Cell. 1999 August; 11(8): 1485-98. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10449582 •
Structure and function of the methionine aminopeptidases. Author(s): Lowther WT, Matthews BW. Source: Biochimica Et Biophysica Acta. 2000 March 7; 1477(1-2): 157-67. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10708856
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Supplemental protein plus ruminally protected methionine and lysine for primiparous beef cattle consuming annual rye hay. Author(s): Hess BW, Scholljegerdes EJ, Coleman SA, Williams JE. Source: Journal of Animal Science. 1998 July; 76(7): 1767-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9690631
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Supplementation of methionine and selection of highly digestible rumen undegradable protein to improve nitrogen efficiency for milk production. Author(s): Noftsger S, St-Pierre NR. Source: Journal of Dairy Science. 2003 March; 86(3): 958-69. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12703633
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Supplementation of milk replacers containing soy protein with threonine, methionine, and lysine in the diets of calves. Author(s): Kanjanapruthipong J. Source: Journal of Dairy Science. 1998 November; 81(11): 2912-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9839234
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Suppression of rat hepatic cytochrome P450s by protein-calorie malnutrition: complete or partial restoration by cysteine or methionine supplementation. Author(s): Cho MK, Kim YG, Lee MG, Kim SG. Source: Archives of Biochemistry and Biophysics. 1999 December 1; 372(1): 150-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10562428
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The canonical methionine 392 of matrix metalloproteinase 2 (gelatinase A) is not required for catalytic efficiency or structural integrity: probing the role of the methionine-turn in the metzincin metalloprotease superfamily. Author(s): Butler GS, Tam EM, Overall CM. Source: The Journal of Biological Chemistry. 2004 April 9; 279(15): 15615-20. Epub 2004 January 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14732714
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The effect of graded levels of dietary casein, with or without methionine supplementation, on glutathione concentration in unstressed and endotoxin-treated
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rats. Author(s): Alhamdan AA, Grimble RF. Source: Int J Vitam Nutr Res. 2003 November; 73(6): 468-77. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14743552 •
The effect of tryptophan plus methionine, 5-azacytidine, and methotrexate on adjuvant arthritis of rat. Author(s): Kroger H, Dietrich A, Gratz R, Wild A, Ehrlich W. Source: General Pharmacology. 1999 August; 33(2): 195-201. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10461858
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The effects of dietary selenomethionine on polyamines and azoxymethane-induced aberrant crypts. Author(s): Baines AT, Holubec H, Basye JL, Thorne P, Bhattacharyya AK, Spallholz J, Shriver B, Cui H, Roe D, Clark LC, Earnest DL, Nelson MA. Source: Cancer Letters. 2000 November 28; 160(2): 193-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11053649
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The metal-catalyzed oxidation of methionine in peptides by Fenton systems involves two consecutive one-electron oxidation processes. Author(s): Hong J, Schoneich C. Source: Free Radical Biology & Medicine. 2001 December 1; 31(11): 1432-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11728815
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The methionine-homocysteine cycle and its effects on cognitive diseases. Author(s): Miller AL. Source: Alternative Medicine Review : a Journal of Clinical Therapeutic. 2003 February; 8(1): 7-19. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12611557
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The nutritional significance, metabolism and toxicology of selenomethionine. Author(s): Schrauzer GN. Source: Adv Food Nutr Res. 2003; 47: 73-112. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14639782
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The Pneumocystis carinii drug target S-adenosyl-L-methionine:sterol C-24 methyl transferase has a unique substrate preference. Author(s): Kaneshiro ES, Rosenfeld JA, Basselin-Eiweida M, Stringer JR, Keely SP, Smulian AG, Giner JL. Source: Molecular Microbiology. 2002 May; 44(4): 989-99. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12010494
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The purification and characterization of a Bacillus stearothermophilus methionine aminopeptidase (MetAP). Author(s): Chung JM, Chung IY, Lee YS. Source: J Biochem Mol Biol. 2002 March 31; 35(2): 228-35. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12297034
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The Rhizobium etli metZ gene is essential for methionine biosynthesis and nodulation of Phaseolus vulgaris. Author(s): Tate R, Riccio A, Caputo E, Iaccarino M, Patriarca EJ. Source: Mol Plant Microbe Interact. 1999 January; 12(1): 24-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=9885190
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Thymoquinone and Nigella sativa oil protection against methionine-induced hyperhomocysteinemia in rats. Author(s): El-Saleh SC, Al-Sagair OA, Al-Khalaf MI. Source: International Journal of Cardiology. 2004 January; 93(1): 19-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14729430
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Visualizing central effects of S-adenosyl-L-methionine (SAMe), a natural molecule with antidepressant properties, by pharmaco-EEG mapping. Author(s): Saletu-Zyhlarz GM, Anderer P, Linzmayer L, Semlitsch HV, Assandri A, Prause W, Hassan Abu-Bakr M, Lindeck-Pozza E, Saletu B. Source: The International Journal of Neuropsychopharmacology / Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum (Cinp). 2002 September; 5(3): 199-215. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12366873
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What is SAMe? S-Adenosylmethionine. Author(s): Cowley G, Underwood A. Source: Newsweek. 1999 July 5; 134(1): 46-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10538206
Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •
Alternative Medicine Foundation, Inc.: http://www.herbmed.org/
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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats
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Chinese Medicine: http://www.newcenturynutrition.com/
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drkoop.com: http://www.drkoop.com/InteractiveMedicine/IndexC.html
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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm
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Google: http://directory.google.com/Top/Health/Alternative/
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Healthnotes: http://www.healthnotes.com/
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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine
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Open Directory Project: http://dmoz.org/Health/Alternative/
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HealthGate: http://www.tnp.com/
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WebMDHealth: http://my.webmd.com/drugs_and_herbs
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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html
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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/
The following is a specific Web list relating to methionine; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •
General Overview Alzheimer's Disease Source: Integrative Medicine Communications; www.drkoop.com Arthritis Source: Integrative Medicine Communications; www.drkoop.com Bipolar Disorder Source: Healthnotes, Inc.; www.healthnotes.com Bladder Infection Alternative names: Urinary Tract Infection [UTI] Source: Prima Communications, Inc.www.personalhealthzone.com Brain Cancer Source: Integrative Medicine Communications; www.drkoop.com Cancer Prevention (Reducing the Risk) Source: Prima Communications, Inc.www.personalhealthzone.com Cirrhosis Source: Integrative Medicine Communications; www.drkoop.com Colon Cancer Source: Healthnotes, Inc.; www.healthnotes.com Congestive Heart Failure Source: Healthnotes, Inc.; www.healthnotes.com Dementia Source: Integrative Medicine Communications; www.drkoop.com
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Depression Source: Healthnotes, Inc.; www.healthnotes.com Depression Source: Integrative Medicine Communications; www.drkoop.com Depression (Mild to Moderate) Source: Prima Communications, Inc.www.personalhealthzone.com Fibromyalgia Source: Healthnotes, Inc.; www.healthnotes.com Fibromyalgia Source: Integrative Medicine Communications; www.drkoop.com Hepatitis Source: Healthnotes, Inc.; www.healthnotes.com High Cholesterol Source: Integrative Medicine Communications; www.drkoop.com High Homocysteine Source: Healthnotes, Inc.; www.healthnotes.com HIV and AIDS Support Source: Healthnotes, Inc.; www.healthnotes.com Hypercholesterolemia Source: Integrative Medicine Communications; www.drkoop.com Liver Cirrhosis Source: Healthnotes, Inc.; www.healthnotes.com Liver Disease Source: Integrative Medicine Communications; www.drkoop.com Liver Disorders Source: Integrative Medicine Communications; www.drkoop.com Male Infertility Source: Healthnotes, Inc.; www.healthnotes.com Memory Loss Source: Integrative Medicine Communications; www.drkoop.com Migraine Headaches Source: Healthnotes, Inc.; www.healthnotes.com Miscarriage Source: Integrative Medicine Communications; www.drkoop.com
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Osteoarthritis Source: Healthnotes, Inc.; www.healthnotes.com Osteoarthritis Source: Integrative Medicine Communications; www.drkoop.com Osteoarthritis Source: Prima Communications, Inc.www.personalhealthzone.com Pancreatic Insufficiency Source: Healthnotes, Inc.; www.healthnotes.com Pancreatitis Source: Integrative Medicine Communications; www.drkoop.com Parkinson's Disease Source: Healthnotes, Inc.; www.healthnotes.com Phenylketonuria Source: Healthnotes, Inc.; www.healthnotes.com Pregnancy and Postpartum Support Source: Healthnotes, Inc.; www.healthnotes.com Psychological Conditions and Disorders Source: Integrative Medicine Communications; www.drkoop.com Serum Sickness Source: Integrative Medicine Communications; www.drkoop.com Skin Cancer Source: Integrative Medicine Communications; www.drkoop.com Spontaneous Abortion Source: Integrative Medicine Communications; www.drkoop.com •
Herbs and Supplements Acetaminophen Alternative names: Acephen, Aceta, Amaphen, Anoquan, Apacet, Arthritis Foundation Aspirin Free, Arthritis Foundation Nighttime, Aspirin Free Anacin, Aspirin Free Excedrin, Bayer Select, Dapacin, Dynafed, Endolor, Esgic, Excedrin P.M., Fem-Etts, Femcet, Feverall, Fioricet, Fiorpap, Genapap, Genebs, Halenol, Isocet, Liquiprin, Mapap, Maranox, Meda, Medigesic, Midol, Multi-Symptom Pamprin, Neopap, Nighttime Pamprin, Oraphen-PD, Panadol, Phrenilin, Repan, Ridenol, Sedapap, Silapap, Sominex Pain Relief, Tapanol, Tempra, Tylenol, Uni-Ace, Unisom with Pain Relief Source: Prima Communications, Inc.www.personalhealthzone.com Amino Acids Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com
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Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10003,00.html Amino Acids Overview Source: Healthnotes, Inc.; www.healthnotes.com Anticonvulsants Source: Healthnotes, Inc.; www.healthnotes.com Astragalus Sp Alternative names: Vetch, Rattlepod, Locoweed; Astragalus sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Betaine Alternative names: Trimethylglycine Source: Integrative Medicine Communications; www.drkoop.com Calendula Alternative names: Calendula officinalis L. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Cysteine Source: Healthnotes, Inc.; www.healthnotes.com Dandelion Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10021,00.html Dryopteris Alternative names: Male Fern; Dryopteris sp. Source: Alternative Medicine Foundation, Inc.; www.amfoundation.org Glucosamine Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,790,00.html Glutathione Source: Healthnotes, Inc.; www.healthnotes.com Lecithin Source: Prima Communications, Inc.www.personalhealthzone.com Levodopa/Carbidopa Alternative names: Sinemet Source: Prima Communications, Inc.www.personalhealthzone.com Lipotropic Combination Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,861,00.html
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MAO Inhibitors Source: Prima Communications, Inc.www.personalhealthzone.com Methionine Source: Healthnotes, Inc.; www.healthnotes.com Methionine Source: Prima Communications, Inc.www.personalhealthzone.com Methionine Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10084,00.html Milk Thistle Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,10044,00.html Phosphatidylserine (PS) Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,813,00.html S-Adenosylmethionine (SAMe) Alternative names: SAMe Source: Integrative Medicine Communications; www.drkoop.com SAMe Source: Healthnotes, Inc.; www.healthnotes.com SAMe Alternative names: S-Adenosylmethionine (SAMe) Source: Integrative Medicine Communications; www.drkoop.com SAMe (S-Adenosylmethionine) Source: Prima Communications, Inc.www.personalhealthzone.com SAMe (S-Adenosylmethionine) Source: WholeHealthMD.com, LLC.; www.wholehealthmd.com Hyperlink: http://www.wholehealthmd.com/refshelf/substances_view/0,1525,818,00.html Taurine Source: Prima Communications, Inc.www.personalhealthzone.com Tmg (trimethylglycine) Source: Prima Communications, Inc.www.personalhealthzone.com Tramadol Alternative names: Ultram Source: Prima Communications, Inc.www.personalhealthzone.com
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Tricyclic Antidepressants Source: Healthnotes, Inc.; www.healthnotes.com Tricyclic Antidepressants Source: Prima Communications, Inc.www.personalhealthzone.com Trimethylglycine Source: Integrative Medicine Communications; www.drkoop.com Valproic Acid Source: Healthnotes, Inc.; www.healthnotes.com
General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.
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CHAPTER 4. DISSERTATIONS ON METHIONINE Overview In this chapter, we will give you a bibliography on recent dissertations relating to methionine. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “methionine” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on methionine, we have not necessarily excluded nonmedical dissertations in this bibliography.
Dissertations on Methionine ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to methionine. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •
Biochemical studies of human methionine synthase reductase by Olteanu, Horatiu, PhD from THE UNIVERSITY OF NEBRASKA - LINCOLN, 2003, 126 pages http://wwwlib.umi.com/dissertations/fullcit/3092583
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Effects of dietary supplemental methionine sources on odor volatiles in broiler excreta by Chavez, Cesar, PhD from TEXAS A&M UNIVERSITY, 2003, 124 pages http://wwwlib.umi.com/dissertations/fullcit/3115023
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Mapping the interactions between Escherichia coli flavodoxin and its physiological partners, flavodoxin reductase and cobalamin-dependent methionine synthase by Hall, Diane Anita, PhD from UNIVERSITY OF MICHIGAN, 2003, 134 pages http://wwwlib.umi.com/dissertations/fullcit/3079454
•
Part I. Enantioselectivity of hydroxy methionine (HMB) incorporation in short chain peptides. Part II. Development of an enzymatic process for isolation of enantio enriched HMB on a preparative scale. Part III. Synthesis and characterization of
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tailored s by Roy, Arindam, PhD from UNIVERSITY OF MISSOURI - ROLLA, 2003, 156 pages http://wwwlib.umi.com/dissertations/fullcit/3115170 •
Structures of two zinc-dependent homocysteine S-methyltransferases: Betainehomocysteine methyltransferase and cobalamin-dependent methionine synthase by Evans, John Charles, PhD from UNIVERSITY OF MICHIGAN, 2004, 191 pages http://wwwlib.umi.com/dissertations/fullcit/3121925
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Studies of methionine oxidation in abductin, a rubber-like protein by Xu, Jihong , MS from THE TEXAS A&M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER, 2003, 52 pages http://wwwlib.umi.com/dissertations/fullcit/1416265
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The effects of age and folate intake on the activities of four methionine cycle enzymes and plasma homocysteine levels in the rat by Keith, Roger Howard, MS from UNIVERSITY OF NEVADA, RENO, 2003, 78 pages http://wwwlib.umi.com/dissertations/fullcit/1414488
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The role of homoserine kinase and substrate availability on the regulation of methionine biosynthesis in Arabidopsis thaliana by Lee, Minsang, PhD from RUTGERS THE STATE UNIVERSITY OF NEW JERSEY - NEW BRUNSWICK, 2003, 176 pages http://wwwlib.umi.com/dissertations/fullcit/3092959
Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.
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CHAPTER 5. PATENTS ON METHIONINE Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.8 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “methionine” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on methionine, we have not necessarily excluded nonmedical patents in this bibliography.
Patents on Methionine By performing a patent search focusing on methionine, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. The following is an 8Adapted
from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.
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example of the type of information that you can expect to obtain from a patent search on methionine: •
Amidase Inventor(s): Murphy; Dennis (Paoli, PA), Reid; John (Bryn Mawr, PA), Robertson; Dan (Haddonfield, NJ) Assignee(s): Diversa Corporation (San Diego, CA) Patent Number: 6,465,204 Date filed: June 30, 2000 Abstract: A purified thermostable enzyme is derived from the archael bacterium Thermococcus GU5L5. The enzyme has a molecular weight of about 68.5 kilodaltons and has cellulase activity. The enzyme can be produced from native or recombinant host cells and can be used for the removal of arginine, phenylalanine, or methionine amino acids from the N-terminal end of peptides in peptide or peptidomimetic synthesis. The enzyme is selective for the L, or `natural` enantiomer of the amino acid derivatives and is therefore useful for the production of optically active compounds. These reactions can be performed in the presence of the chemically more reactive ester functionally, a step which is very difficult to achieve with nonenzymatic methods. Excerpt(s): This invention relates to newly identified polynucleotides, polypeptides encoded by such polynucleotides, the use of such polynucleotides and polypeptides, as well as the production and isolation of such polynucleotides and polypeptides. More particularly, the polypeptide of the present invention has been identified as an amidase and in particular an enzyme having activity in the removal of arginine, phenylalanine or methionine from the N-terminal end of peptides in peptide or peptidomimetic synthesis. Thermophilic bacteria have received considerable attention as sources of highly active and thermostable enzymes (Bronneomeier, K. and Staudenbauer, W. L., D. R. Woods (Ed.), The Clostridia and Biotechnology, Butterworth Publishers, Stoneham, Mass. (1993). Recently, the most extremely thermophilic organotrophic eubacteria presently known have been isolated and characterized. These bacteria, which belong to the genus Thermotoga, are fermentative microorganisms metabolizing a variety of carbohydrates (Huber, R. and Stetter, K. O., in Ballows, et al., (Ed.), The Procaryotes, 2nd Ed., Springer-Verlaz, New York, pgs. 3809-3819 (1992)). Because to date most organisms identified from the archaeal domain are thermophiles or hyperthermophiles, archaeal bacteria are also considered a fertile source of thermophilic enzymes. Web site: http://www.delphion.com/details?pn=US06465204__
•
Chelated feed additive and method of preparation Inventor(s): Ciribolla; Antonio (Reggio Emilia, IT) Assignee(s): Agristudio S. r. L. (Reggio Emilia, IT) Patent Number: 6,461,664 Date filed: April 26, 2001 Abstract: Feed additive for agro-zootechnical use, in particular for alimentary use in the zootechnical sector, consisting of a chelate obtained by the reaction of methionine hydroxy analogue with the carbonate of a bivalent metal. The reaction is free from
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undesirable by-products, and the product is stable and effective in improving the main growth factors of the animal. Excerpt(s): The present invention relates to a chelated additive for agro-zootechnical use in the broad sense, and in particular for alimentary use in the zootechnical sector, and the associated method for obtaining said additive. A chelate is a compound which is obtained from an organic molecule (in the case in question an amino acid or a peptide chain) and a metal ion by means of strong co-ordination bonds. These compounds are widely used both in the agronomic field and in the zootechnical field since their usefulness is derived from the biological action of the metal involved, which acts as activator in a great number of enzymatic reactions and as regulator in various metabolic functions in all living organisms. The presence of the bond with an amino acid material favours the absorption, availability and use of the metal since it is transported by the organic component to all areas of the organism. Web site: http://www.delphion.com/details?pn=US06461664__ •
Compositions for protecting a plant from a disease and using method thereof Inventor(s): Kase; Rieko (9-1, Koishikawa 3-chome, Bunkyo-ku, Tokyo 112-0002, JP), Kawai; Hiroshi (409-5, Yabata Chigasaki-shi, Kanagawa 253-0085, JP) Assignee(s): none reported Patent Number: 6,492,303 Date filed: April 9, 2001 Abstract: An object of the present invention is to provide a composition for protecting a plant from a disease that is safe, at low cost, environment friendly, and improves the natural resistance of plant itself by inducing production of a phytoalexin, an antibacterial substance inherent to plant, and a using method thereof. For the above purpose the present invention employs said composition for protecting a plant from a disease comprised of at least one sulfur-containing amino acid selected from the group comprising methionine, cysteine, and cystine, and D-glucose in a mixed form. In a preferred embodiment of the present invention, it is sprayed on the aboveground part of a plant either undiluted or after dilution with water by 100,000 times, directly mixed with soil, or irrigated on a plant after dilution with water by 1-1,000,000 times. Excerpt(s): This invention relates to a composition for protecting a plant from a disease and a using method thereof. More particularly, it relates to a composition for protecting a plant from a disease that induces production of a phytoalexin by application to a plant and suppresses pathogenic plant bacteria, and further a method of applying said composition to a plant in order to induce production of a phytoalexin and suppress various pathogenic plant bacteria resulting in protection of a disease of plant. The present inventors have already found out that treatment of methionine to a rice plant is capable of inducing production of a phytoalexin that donates resistance to various diseases (Japanese Patent Application H09-44206). Treatment of methionine to a rice plant induces accumulation of phytoalexins such as Sakuranetin and Momilactone, and resultantly donates resistance to rice blight (Pyricularia oryzae) that is a representative disease of rice plants. However, the effect of using methionine alone has proved to be insufficient and occasionally led to an inability to exhibit a desired effect. The primary object of the present invention is to provide a composition for protecting a plant from a disease that induces production of a phytoalexin by application to a plant and suppresses plant bacteria more effectively than using methionine alone, and can be
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used throughout the year. The secondary object of the present invention is to provide a method of applying said protecting composition to a plant in order to induce production of a phytoalexin, suppress plant bacteria, and resultantly protect a plant from plant diseases. Web site: http://www.delphion.com/details?pn=US06492303__ •
Compositions for the protection of plants against the stress of oxidation Inventor(s): De Mil; Christophe (7, Rue Mechain, 75014 Paris, FR), Lauzanne; Eliane (57, Avenue de la Republique, 75011 Paris, FR), Morelle; Jean (170, Avenue Parmentier, 75010 Paris, FR), Rothfuss; Jacqueline (14, Rue du Faubourg, 67630 Lauterbourg, FR) Assignee(s): none reported Patent Number: 6,492,302 Date filed: June 20, 2001 Abstract: This invention concerns making compounds destined for the protection of plants against oxidative stress, characterized by lipo-amino acids enriched with methionine during a process of acylation with hydrolysates of proteins or of amino acids taken individually or combined; or after acylation and lipo-amino acids partially or totally salified by basic amino acids which gives them antioxidant and anti-free radical properties. This invention extends to the total or partial salification of this type of lipo-amino acids with oligoelements. Excerpt(s): It is well-known that many plants are sensitive to drops in temperature, even above the freezing point. This is the case for most fruit-bearing trees. It has been determined that frost and other fluctuations in temperature, including dryness and excessive heat, are aggressive to plant life, generating a phenomenon defined as "oxidative stress", defined as an accelerated and excessive generation of free radicals: alkoxy, peroxy, and oxygen singlets. These free radicals are produced by the interaction of lipooxygenase with the lipids of cell membranes. In the case of excessive dryness, the formation of super-oxidated anions (O.sub.2.degree.) among the plant chloroplasts has been observed. Web site: http://www.delphion.com/details?pn=US06492302__
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DAX-1 protein, methods for production and use thereof Inventor(s): Burris; Thomas P. (Woodland Hills, CA), Guo; Weiwen (Los Angeles, CA), McCabe; Edward R. B. (Pacific Palisades, CA), Vilain; Eric (Los Angeles, CA) Assignee(s): The Regents of the University of California (Oakland, CA) Patent Number: 6,465,627 Date filed: July 26, 1996 Abstract: The invention provides a DAX-1 protein molecule having the amino acid sequence beginning with methionine at position 1 and ending with isoleucine at position 470 as shown in FIG. 12. The invention further provides the genomic nucleic acid sequence for DAX-1, including intron, exons and a promoter region. Additionally, the invention provides methods for using and making the DAX-1 protein and DAX-1 nucleic acid molecules.
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Excerpt(s): Throughout this application, various publications are referenced within parentheses. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein. Presently, there are no commercially effective tests to provide a rapid diagnostic approach to individuals with adrenocortical disorders of metabolism and development such as the X-linked cytomegalic form of adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HH) due to mutations in DAX-1, a new member of the nuclear hormone receptor gene superfamily. Left untreated, the results of these disorders include failure to achieve pubertal growth, sexual maturity, and eventually death. Clinical signs and symptoms of infants with adrenal hypoplasia include poor feeding, failure to gain weight, hyperpigmentation, vomiting, diarrhea, vascular collapse, and sudden death. Dehydration, hyponatremia, hyperkalemia, acidosis, and hypoglycemia are common biochemical findings characteristic of combined glucocorticoid and mineralocorticoid deficiency. Web site: http://www.delphion.com/details?pn=US06465627__ •
Fluorogenic or fluorescent reporter molecules and their applications for whole-cell fluorescence screening assays for caspases and other enzymes and the use thereof Inventor(s): Cai; Sui Xiong (San Diego, CA), Drewe; John A. (Carlsbad, CA), Keana; John F. W. (Eugene, OR), Weber; Eckard (San Diego, CA), Zhang; Han-Zhong (Irvine, CA) Assignee(s): Cytovia, Inc. (San Diego, CA) Patent Number: 6,759,207 Date filed: September 7, 2001 Abstract: The present invention relates to novel fluorescent dyes, novel fluorogenic and fluorescent reporter molecules and new enzyme assay processes that can be used to detect the activity of caspases and other enzymes involved in apoptosis in whole cells, cell lines and tissue samples derived from any living organism or organ. The reporter molecules and assay processes can be used in drug screening procedures to identify compounds which act as inhibitors or inducers of the caspase cascade in whole cells or tissues. The reagents and assays described herein are also useful for determining the chemosensitivity of human cancer cells to treatment with chemotherapeutic drugs. The present invention also relates to novel fluorogenic and fluorescent reporter molecules and new enzyme assay processes that can be used to detect the activity of type 2 methionine aminopeptidase, dipeptidyl peptidase IV, calpain, aminopeptidase, HIV protease, adenovirus protease, HSV-1 protease, HCMV protease and HCV protease. Excerpt(s): This invention is in the field of intracellular detection of enzymes using fluorogenic or fluorescent probes. The invention relates to novel fluorescent dyes and application of these dyes for the preparation of novel fluorogenic or fluorescent peptide or amino acid derivatives which are substrates of proteases and peptidases. In particular, the invention relates to novel fluorogenic or fluorescent peptide derivatives which are substrates of enzymes involved in apoptosis, such as caspases and the lymphocyte-derived serine protease Granzyme B. The invention also relates to a process for measuring the activity of caspases and other enzymes involved in apoptosis in living or dead whole cells, cell lines or tissue samples derived from any healthy, diseased, infected or cancerous organ or tissue. The invention also relates to the use of the
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fluorogenic or fluorescent substrates in a novel assay system for discovering or detecting inhibitors or inducers of apoptosis in compound collections or compound libraries. Furthermore, the invention relates to the use of the fluorogenic or fluorescent substrates in determining the sensitivity of cancer cells to treatment with chemotherapeutic drugs. The invention also relates to novel fluorogenic or fluorescent peptide derivatives which are substrates of exopeptidases such as aminopeptidase A and N, methionine aminopeptidase and dipeptidyl-peptidase IV, endopetidases such as calpain, proteases such as HIV proteases, HCMV protease, HSV protease, HCV protease and adenovirus protease. Organisms eliminate unwanted cells by a process variously known as regulated cell death, programmed cell death or apoptosis. Such cell death occurs as a normal aspect of animal development as well as in tissue homeostasis and aging (Glucksmann, A., Biol. Rev. Cambridge Philos. Soc. 26:59-86 (1951); Glucksmann, A., Archives de Biologie 76:419-437 (1965); Ellis et al., Dev. 112:591-603 (1991); Vaux et al., Cell 76:777-779 (1994)). Apoptosis regulates cell number, facilitates morphogenesis, removes harmful or otherwise abnormal cells and eliminates cells that have already performed their function. Additionally, apoptosis occurs in response to various physiological stresses, such as hypoxia or ischemia (PCT published application WO96/20721). There are a number of morphological changes shared by cells experiencing regulated cell death, including plasma and nuclear membrane blebbing, cell shrinkage (condensation of nucleoplasm and cytoplasm), organelle relocalization and compaction, chromatin condensation and production of apoptotic bodies (membrane enclosed particles containing intracellular material) (Orrenius, S., J. Internal Medicine 23 7:529-536 (1995)). Web site: http://www.delphion.com/details?pn=US06759207__ •
Materials and methods for controlling pests Inventor(s): Cuda; James S. (Gainesville, FL), Long; Lewis S. (Gainesville, FL), Stevens; Bruce Russell (Gainesville, FL) Assignee(s): University of Florida Research Foundation, Inc. (Gainesville, FL) Patent Number: 6,766,613 Date filed: November 16, 2001 Abstract: The present invention provides materials and methods for pest control. The subject invention provides pesticidal compositions that contain one or more compounds that interact with organic solute transporter/ligand-gated ion channel multifunction polypeptides in the pest. Upon exposure to a target pest, these compositions either compromise pest growth and/or cause the death of the pest. In a preferred embodiment, the compositions of the subject invention contain one or more amino acids and/or amino acid analogs. In a particularly preferred embodiment, the methods of the subject invention involve exposing a pest to a composition that comprises methionine or leucine, or an analog thereof. Excerpt(s): A longstanding worldwide demand exists for new, effective, environmentally friendly, and safe means to control pests that damage agriculture or serve as disease vectors. Agriculture costs incurred by pests exceed billions of dollars annually in decreased crop yields, reduced crop quality, increased harvesting costs, pesticide application costs, and negative ecological impact. In addition to agriculture pests, many blood-feeding insects are vectors for pathogenic microorganisms that threaten human and animal health, or are annoying at the least. As in the case of agriculture pests, direct and intangible costs incurred by blood-feeding pests concern
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pesticide safety hazards to humans and animals, bioaccumulation and environmental incompatibility, and synthesis and application costs. Almost all field crops, nursery and horticulture plants, and commercial farming areas are susceptible to attack by one or more pests. Particularly problematic are Coleopteran and Lepidopteran pests. An example of a Lepidopteran pest is the hornworm larva of Manduca sexta, and an example of a Coleopteran pest is the Colorado potato beetle, Leptinotarsa decemlineata. Vegetable and cole crops, lentils, leafy vegetables, melons, peppers, potatoes and related tubers, tomatoes, cucumbers and related vine crops, as well as a variety of spices are sensitive to infestation by one or more pests including loopers, armyworms, moth larvae, budworms, webworms, earworms, leafeaters, borers, cloverworms, melonworms, leafrollers, various caterpillars, fruitworms, hornworms, and pinworms. Likewise, pasture and hay crops such as alfalfa, pasture and forage grasses and silage are often attacked by a variety of pests including armyworms, alfalfa caterpillars, European skipper, a variety of loopers and webworms, as well as yellowstriped armyworms. Fruit (including citrus), nut, and vine crops are susceptible to attack by a variety of pests, including sphinx moth larvae, cutworms, skippers, fireworms, leafrollers, cankerworms, fruitworms, girdlers, webworms, leaffolders, skeletonizers, shuckworms, hornworms, loopers, orangeworms, tortrix, twig borers, casebearers, spanworms, budworms, budmoths, and a variety of caterpillars and armyworms. Web site: http://www.delphion.com/details?pn=US06766613__ •
Methioninase gene therapy for tumor treatment Inventor(s): Tan; Yuying (San Diego, CA), Xu; Mingxu (San Diego, CA) Assignee(s): AntiCancer, Inc. (San Diego, CA) Patent Number: 6,524,571 Date filed: November 18, 1998 Abstract: A depletion method to inhibit tumor growth includes introducing a viral expression system capable of expressing methioninase or a fusion protein containing methioninase into a tumor contained in a vertebrate subject or cells thereof. The fusion protein may contain a fluorescent protein to permit monitoring of the completeness of the depletion method. The fusion protein can be used in vivo as well as in vitro screening protocols which employ the viral expression system. The expression system includes control sequences and means to integrate the nucleotide sequence into the genome of a host cell for expression. The method may also include treating the cells with isolated methioninase and/or with a therapeutic cell. The depletion method can be with other known therapies, such as maintaining the animal having the tumor on a methionine depleted diet. Excerpt(s): The invention relates to protocols for the treatment of tumors. More specifically, the invention concerns insertion of a methioninase gene into tumor cells, optionally in combination with administration of methioninase, methionine deprivation or administration of a chemotherapeutic agent. Various approaches to tumor treatment using gene replacement or other genetic therapy protocols have been suggested and verified in animal models. For example, since it is known that the p53 gene is a tumor suppressor (Harris, C. C., JNCI (1996) 88:1442-1445), the antitumor effects of p53 gene transfer have been explored. Successful results for tumors which contain defective p53 genes have been shown by Roth, J. A., et al., Nat Med (1996) 2:985-991 using retrovirusmediated gene transfer in patients with lung cancer. Adenoviral vectors encoding p53 for gene therapy have been described by Wills, K. N., et al., Hum Gene Ther (1994)
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5:1079-1088. An animal model of malignant human breast cancer in nude mice was shown to respond to adenoviral-mediated delivery of p53 by Lesoon-Wood, L. A., et al., Hum Gene Ther (1995) 6:395-405. Alternatively, the Herpes simplex virus thymidine kinase gene (HSV-tk) in combination with gancyclovir has been shown to inhibit tumor growth in melanoma mode by Vile, R., et al. Cancer Res Dec. 1 (1994); 54(23):6228-34. However, surrounding cells may also be killed using such protocols in a "bystander" effect. Web site: http://www.delphion.com/details?pn=US06524571__ •
Method of preparing ultrathin light-sensitive tabular grain emulsions rich in silver bromide Inventor(s): Elst; Kathy (Kessel, BE), Mans; Ilse (Herenthout, BE) Assignee(s): Agfa-Gevaert (Mortsel, BE) Patent Number: 6,558,892 Date filed: July 11, 2001 Abstract: A method has been described for preparing an ultrathin tabular grain emulsion rich in silver bromide, having {111} major faces, wherein tabular grains having a thickness of less than 0.08.mu.m exhibit an average aspect ratio of more than 5:1 and account for at least 75% by number of hexagonal grains and a coefficient of variation on average equivalent surface area of less than 0.50. The process is characterized in that during formation, (a) pH is maintained from 0.8 to 10; (b) a gelatino-peptizer is present in a concentration of 0 to 50 g per liter of dispersing medium, and (c) pBr having a value of at least 1.8 is maintained during grain nucleation and pBr is maintained at less than 2.4 during growth provided that a gelatin peptizer which is free from calcium ions and has a methionine content of less than 30 micromoles per gram of gelatino-peptizer is present. Excerpt(s): The present invention relates to a method of preparing light-sensitive ultrathin tabular grains rich in silver bromide, having {111} major faces. High aspect ratio tabular grains exhibit several pronounced photographic advantages as is wellknown since their introduction into photographic applications in the eighties. Thanks to their particular morphology greater amounts of spectral sensitizers can be adsorbed per mole of silver halide if compared with classical globular (e.g. cubic or octahedral) grains. As a consequence such spectrally sensitized tabular grains show an improved speedgranularity relationship and a wide separation between their blue speed and minus blue speed. Sharpness of photographic images can be improved using tabular grains thanks to their lower light scattering properties, again if compared with conventionally known globular emulsion grains. In color negative materials e.g. the conventional sequence of the light-sensitive layers can be altered and the yellow filter layer can be omitted. In developed black-and-white images high covering power is obtained even at high hardening levels. Alternatively reduced silver halide coverages can be achieved if desired, which again results in improved sharpness. In duplitized radiographic materials the presence of tabular grains reduces the so-called cross-over which is the main factor for sharpness in such materials. Moreover coating amounts of silver can be reduced, further in favor of production cost and ecology. An emulsion is generally understood to be a "tabular grain emulsion" when tabular grains account for at least 50 percent of total grain projected area. A grain is generally considered to be a tabular grain when the ratio of its equivalent circular diameter to its thickness is at least 2. The
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equivalent circular diameter of a grain is the diameter of a circle having an area equal to the projected area of the grain. Web site: http://www.delphion.com/details?pn=US06558892__ •
Method of producing biologically active human acidic fibroblast growth factor and its use in promoting angiogenesis Inventor(s): Chernykh; Svitlana I. (Kiev, UA), Kordyum; Vitaliy A. (Kiev, UA), Slavchenko; Iryna Yu. (Kiev, UA), Stegmann; Thomas J. (Petersberg, DE), Vozianov; Oleksandr F. (Kiev, UA) Assignee(s): Phage Biotechnology Corporation (Tustin, CA) Patent Number: 6,642,026 Date filed: August 15, 2001 Abstract: The gene of human acidic fibroblast growth factor 155 (haFGF 155) has been obtained by chemical synthesis. The nucleotide sequence of haFGF 155 gene has been deduced on the basis of haFGF 155 amino acid sequence as described in the literature. The amino acid sequence of the synthesized haFGF 155 does not differ from those described in the literature. The nucleotide sequence of haFGF gene differs from those described previously. For chemical synthesis of haFGF 155 gene, codons were used which are the ones most often used by E. coli in highly expressed E. coli proteins. A plasmid with haPGF 155 (phaFGF 155) gene was obtained and was used to transform E. coli. Production of haFGF 154 protein was achieved by cultivation of the producer strain under conditions which slow down the lytic development of lambda phage. The haFGF 154 protein accumulated in culture medium in a soluble condition as a result of the producer strain cells lysis by the lambda phage. The haFGF 154 protein constituted 20% of the soluble protein accumulated in the culture medium and its biological activity was demonstrated by its ability to generate new vessels (angiogenesis). The initiator methionine residue at position 1 of the FGF 155 protein was completely removed during protein synthesis resulting in an FGF 154 amino acid product. The use of the phage-dependent method to produce other forms of the haFGF protein is also disclosed. Excerpt(s): The field of the invention relates to methods of producing a recombinant fibroblast growth factor protein and its use in promoting angiogenesis. Fibroblast growth factors (FGF) are nine structurally related polypeptides, which are potent regulators of cell proliferation, differentiation and normal development. They also take part in pathological processes of tumorogenesis and metastasis (Galzie, et al. Biochem. Cell Biol. (1997) 75: 669-685). They are potent mitogens and differentiation factors for a broad range of mesoderm and neuroectoderm derived cells, including endothelial cells. The heparin proteoglycans, heparin or heparin sulfate, bind several FGF molecules together as a complex which are presented to the FGF receptors. FGF proteins bind to their receptors resulting in the activation of protein tyrosine kinases. The phosphorylation of these tyrosine kinases initiates multiple signals including the transcription of new mRNA's. Web site: http://www.delphion.com/details?pn=US06642026__
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Methods and compositions for a gender specific diet for puppies Inventor(s): Bebiak; David M. (Villa Ridge, MO), Kealy; Richard D. (Waterloo, IL) Assignee(s): Nestec, LTD (Vevey, CH) Patent Number: 6,582,752 Date filed: November 2, 2001 Abstract: A gender specific food for puppies is disclosed where the food includes at least about 0.25% methionine by weight and at least about 0.45% total sulfur amino acids. The food further includes a total dietary lipid level based on gender, and for maximizing body weight and length gains, lipid levels and the amounts of methionine are adjusted based upon the gender of the puppy. Excerpt(s): This invention relates generally to food products for pets, and, more particularly, to compositions relating to a gender specific diet for puppies. While pet care product customers presently have a host of suppliers and products to choose from, it may take significant time, effort, and investigation to determine a product that best suits a particular pet's needs among the available alternatives. This is particularly true in the case of pet foods. While veterinarians and other professionals may assist in recommending a given brand of pet food for a particular pet, pet foods are typically mass manufactured to meet the needs of an average pet within a selected range of pets that is typically based on pet age and/or size. Nutritional needs, however, vary from pet to pet, and an optimal regimen of appropriate nutrients for a particular pet or breed of pet would be beneficial. Nutritional requirements for young pets, such as puppies are especially important as the nutritional intake of a puppy will determine such things as health, size, and appearance as the puppy becomes an adult dog and matures into an older dog. In one aspect, a gender specific food for puppies is provided which comprises at least about 0.25% methionine, at least about 0.45% total sulfur amino acids, and a total dietary lipid level based on gender. Web site: http://www.delphion.com/details?pn=US06582752__
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Methods for identifying inhibitors of methionine aminopeptidases Inventor(s): Chang; Yie-Hwa (St. Louis, MO) Assignee(s): Saint Louis University (Saint Louis, MO) Patent Number: 6,593,454 Date filed: May 24, 2001 Abstract: Methods are provided for detecting methionine aminopeptidase (MAP) activity and for detecting inhibitors of MAP. The methods utilize a peptide comprising an N-terminal methionine which can be cleaved from the peptide by MAP, and a Cterminal detection moiety which is released by a second peptidase only if the N-terminal methionine has been cleaved from the peptide. When the peptide is combined with MAP and the second peptidase, the detection moiety is released, while the addition of a MAP inhibitor will inhibit the release of the detection moiety. Reaction mixes, peptides, and kits which are useful for practicing the methods are also provided. Excerpt(s): The present invention generally relates to assays for enzyme activity and for enzyme inhibitors. More specifically, the invention relates to assays for detecting methionine aminopeptidases and inhibitors of methionine aminopeptidases. In all living cells, protein synthesis is initiated with an AUG codon, specifying methionine as
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the N-terminal amino acid in nascent proteins. In both prokaryotes and eukaryotes, this N-terminal methionine will be removed by a methionine aminopeptidase (MAP) (EC 3.4.11.18) if the penultimate amino acid residue is small and uncharged, e.g., Gly, Ala, Ser, Cys, Thr, Pro, and Val, although methionine cleavage activity by MA is reduced when the N-terminal three amino acids are Met-Thr-Pro or Met-Val-Pro (Moerschell et al., 1990, J. Biol. Chem. 265, 19638-19643; Tsunasawa et al., 1985, J. Biol. Chem. 260, 53825391). Removal of the N-terminal methionine is essential for certain proteins to function normally in vivo. For example, the removal of the initiator methionine is often required for subsequent N-terminal modifications, such as N-myristoylation, which is essential for the normal function of various signal transduction proteins, cancer cells, protein targeting moieties, and enzymes (Gordon et al., 1991, J. Biol. Chem. 266, 8647-8650; Duronio et al., 1989, Science 243, 796-800). Methionine aminopeptidases have been isolated and cloned from several organisms, including E. coli and several other eubacteria, yeast, rat, and various archaea. Currently discovered MAPs have been categorized into two types, type 1 MAP and type 2 MAP, based on structural and sequence similarities. Eubacteria have type 1, archaea have type 2, and eukaryotes have both types. In eukaryotes, null mutants in either type are viable but slow growing, but null mutants of both MAP types are nonviable (Li and Chang, 1995, Proc. Natl. Acad. Sci. USA 92, 12357-12361; Li and Chang, 1996, Biochem. Biophys. Res. Commun. 227, 152-159; Bradshaw et al., 1998, Trends Biochem. Sci. 21, 285-286). Similarly, knockouts of the bacterial MAP1 gene are lethal (Ben-Bassat et al., 1987, H. Bacteriol. 169, 751-757). Thus, MAP activity is essential for normal functioning of prokaryotic and eukaryotic cells. Web site: http://www.delphion.com/details?pn=US06593454__ •
Methods of treating asthma with interleukin-9 receptor antibodies Inventor(s): Kari; U. Prasad (Hatfield, PA), Levitt; Roy Clifford (Ambler, PA), Maloy; W. Lee (Lansdale, PA), Nicolaides; Nicholas C. (Media, PA) Assignee(s): Genaera Corporation (Plymouth Meeting, PA) Patent Number: 6,645,492 Date filed: May 4, 2001 Abstract: A C to T DNA variation at position 3365 in exon 5 of the human Asthma Associated Factor 1 (AAF1) produces the predicted amino acid substitution of a methionine for a threonine at codon 117 of AAF1. When this substitution occurs in both alleles in one individual, it is associated with less evidence of atopic allergy including asthma, fewer abnormal skin test responses, and a lower serum total IgE. Thus, applicant has identified the existence of a non-asthmatic, non-atopic phenotype characterized by methionine at codon 117 when it occurs in both AAF1 gene products in one individual. Excerpt(s): This invention relates to regulating IL-9 activity and treating atopic allergies and related disorders like asthma, based upon the relationship between IL-9 and its receptor. Inflammation is a complex process in which the body's defense system combats foreign entities. While the battle against foreign entities may be necessary for the body's survival, some defense systems improperly respond to foreign entities, even innocuous ones, as dangerous and thereby damage surrounding tissue in the ensuing battle. Atopic allergy is an ecogenetic disorder, where genetic background dictates the response to environmental stimuli. The disorder is generally characterized by an increased ability of lymphocytes to produce IgE antibodies in response to ubiquitous
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antigens. Activation of the immune system by these antigens leads to allergic inflammation and may occur after ingestion, penetration through the skin, or after inhalation. When this immune activation occurs and pulmonary inflammation ensues this disorder is broadly characterized as asthma. Certain cells are critical to this inflammatory reaction and they include T cells and antigen presenting cells, B cells that produce IgE, and mast cells/basophils and eosinophils that bind IgE. These inflammatory cells accumulate at the site of allergic inflammation and the toxic products they release contribute to the tissue destruction related to the disorder. Web site: http://www.delphion.com/details?pn=US06645492__ •
Modulators of methylation for control of bacterial virulence Inventor(s): Han; Quinghong (San Diego, CA), Tan; Yuying (San Diego, CA), Xu; Mingxu (San Diego, CA) Assignee(s): AntiCancer, Inc. (San Diego, CA) Patent Number: 6,632,430 Date filed: December 30, 2002 Abstract: Compositions and methods which ameliorate the virulence of bacterial infection are described wherein the active ingredient modulates transmethylation reactions in bacterial cells. Particularly useful compounds are inhibitors of S-adenosyl methionine synthetase (SAMS), of S-adenosyl homocysteine hydrolase (SAHH) and of transmethylases. Excerpt(s): The invention relates to the control of bacterial infection in animals. More particularly, it relates to the use of inhibitors of bacterial transmethylation pathways to control such infection. The importance of transmethylation reactions in metabolism in general has gained considerable recognition. PCT application WO96/20010 and U.S. Pat. No. 5,872,104, incorporated herein by reference, describe the use of methylation inhibitors to reduce the resistance of microorganisms to antibiotics. Heithoff, D. M., et al,. Science (1999) 284:967-970 report the results of a study showing that Salmonella typhimurium which lacks DNA adenine methylase (Dam) were essentially avirulent and therefore could be used as live vaccines against murine typhoid fever. The authors concluded that Dam regulated the expression of at least 20 genes known to be induced during infection and noted that inhibitors of Dam were likely to be antimicrobials. It was earlier shown by Braaten, B. A., et al,. Cell (1994) 76:577-588 that the methylation patterns associated with pyelonephritis-associated pili (Pap) DNA controlled gene expression in E. coli. Thus, it is clear that in bacteria, methylation status is significant in controlling metabolism, and thus infectivity in general. The importance of S-adenosyl-Lmethionine (SAM) dependent transmethylation in viral infection has also been studied by Liu, S., et al., Antiviral Research (1992) 19:247-265. S-adenosyl-homocysteine hydrolase (SAHH) is significantly related to transmethylation by virtue of its ability to regulate the ratio of SAM to S-adenosylhomocysteine (SAH). SAHH catalyzes the equilibrium between SAH and its lysis products, adenosine and homocysteine. It is significant in regulating the levels of adenosine as well. SAHH has been used as a target for antiparasitic and antiviral chemotherapy as described by Minatto, et al,. Experimental Parasitol (1998) 175-180. SAM is the source of methyl groups for all transmethylation reactions and SAH constitutes a methylation inhibitor. Thus, if SAHH which controls the ratio of SAM to SAH is inhibited, this will result in modulating the transmethylation metabolism of the bacterium, and consequently, the virulence of the bacterium. Methylation processes are also affected by methionine levels, and agents
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that deplete methionine, such as methionine-.alpha.,.gamma.-lyase (methioninase) are effective to modulate methylation status as well. Web site: http://www.delphion.com/details?pn=US06632430__ •
Mutant.alpha.-amylases Inventor(s): Araki; Hiroyuki (Tochigi, JP), Hagihara; Hiroshi (Tochigi, JP), Hatada; Yuji (Tochigi, JP), Hayashi; Yasuhiro (Tochigi, JP), Igarashi; Kazuaki (Tochigi, JP), Ikawa; Kaori (Tochigi, JP), Ito; Susumu (Tochigi, JP), Ozaki; Katsuya (Tochigi, JP) Assignee(s): Kao Corporation (Tokyo, JP) Patent Number: 6,486,113 Date filed: September 23, 1999 Abstract: The invention relates to a mutant.alpha.-amylase having an amino acid sequence obtained by making deletion or replacement by another arbitrary amino acid residue of at least a methionine residue at the 202-position or a position homologous thereto among amino acid residues set forth in SEQ ID NO:1, which constitute a liquefying alkaline.alpha.-amylase, a gene thereof, and a detergent composition comprising the mutant.alpha.-amylase. The mutant.alpha.-amylase has the optimum pH in an alkaline range, an excellent.alpha.-amylase activity, and high and lasting resistance to oxidizing agents, and is hence particularly useful as a component of detergent compositions containing a bleaching agent and an oxidizing agent. Excerpt(s): The present invention relates to mutant liquefying.alpha.-amylases which have the optimum pH in an alkaline range and excellent resistance to oxidizing agents and are particularly useful as enzymes for detergents comprising an oxidizing agent, and genes thereof. Various enzymes are incorporated into detergents for the purpose of enhancing detergency, and it is considered to incorporate an.alpha.-amylase against, for example, starch smears. However, the.alpha.-amylase incorporated into a detergent must be an alkaline.alpha.-amylase, since the detergent comprises a surfactant, and the pH of a detergent solution is in an alkaline range. By the way, detergents, in which an oxidation bleaching component is incorporated to expect not only detergency against dirt, but also a bleaching action, have been recently marketed. It is considered that the.alpha.-amylase is also incorporated into such an oxidation bleaching agentcontaining detergent. However, the usual.alpha.-amylase is easy to inactivate in the presence of an oxidizing agent and has hence been unable to be incorporated into the oxidation bleaching agent-containing detergent. Web site: http://www.delphion.com/details?pn=US06486113__
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Mutant form of a cytotoxic ribonucleolytic protein which allows production by recombinant methods Inventor(s): Ardelt; Wojciech (New City, NY), Boix; Ester (Barcelona, ES), Vasandani; Veena M. (Rockville, MD), Wu; Yon-Neng (Bethesda, MD), Youle; Richard J. (Bethesda, MD) Assignee(s): The United States of America as represented by the Department of Health and (Washington, DC) Patent Number: 6,649,392 Date filed: April 4, 1996 Abstract: The present invention provides recombinant Onc (rOnc) compositions and methods. Recombinant Onc proteins of the invention have an amino terminal methionine and comprise an Onc polypeptide. The amino terminal methionine of the protein allows for recombinant production in a bacterial host cell. Cleaving the amino terminal methionine exposes the amino terminal glutamine of the polypeptide. The Onc polypeptide has an amino terminal glutamine. Cyclization of the amino terminal glutamine of the polypeptide to a pyroglutamyl residue provides rOnc polypeptides and proteins have anti-cancer and anti-viral activity. Excerpt(s): The invention relates to methods and compositions for the recombinant production of Onc, a cytotoxic ribonucleolytic protein having anti-tumor and anti-viral properties. In particular, the invention relates to a recombinant Onc protein having an amino terminal methionine and comprising an Onc polypeptide. Unfortunately, since Onc is isolated from oocytes, procurement of an adequate supply is uncertain. Recent concerns regarding the availability of the anti-cancer compound taxol illustrate some of the problems of obtaining natural products for use as pharmaceuticals. Similarly, availability of Onc is increasingly problematic in light of the declining population of R. pipiens and the seasonal variation in the supply of its oocytes. Accordingly, what is needed in the art is a means to produce Onc by recombinant methods so as to meet demand for this therapeutic and alleviate the impact on its native source. Further, what is needed is a means to derivatize and alter the sequence of Onc to provide more efficacious compounds. Quite surprisingly, the present invention provides these and other advantages. Web site: http://www.delphion.com/details?pn=US06649392__
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Nutritional composition containing methionine Inventor(s): Hageman; Robert Johan Joseph (Waddinxveen, NL) Assignee(s): N. V. Nutricia (Zoetermeer, NL) Patent Number: 6,544,547 Date filed: January 31, 2000 Abstract: An enteral food composition for clinical or dietary use, comprises, in addition to carbohydrates and proteins or their hydrolysates the following components or their nutritional equivalents, per daily dosage: methionine (0.6-7 g), cysteine (0.5-2.5 g), folic acid (0.4-8 mg), pyridoxal (vitamin B.sub.6) (3-20 mg), zinc (18-120 mg) and at least 400 kcal energy in the form of carbohydrates. These amounts are well above the Recommended Daily Allowance (RDA) values. Further preferred components include
Patents 167
lecithin, cyanocobalamine, betaine and magnesium, as well as transsulfuration metabolites, ATP enhancers and antioxidants. Excerpt(s): The present invention relates to a module of nutritional components which supports total methionine metabolism in man, for use in a universal medicinal food. The invention also relates to food products containing this module and to a method of producing food products by using selected amounts of the module. Methionine is metabolised in man via a multi-step pathway, the transsulfuration pathway. Several intermediate products are formed in this pathway, which play a dominant role in other biochemical pathways as well. For example, the reaction product S-adenosyl methionine is extensively used in many methylation reactions; homocysteine is the main methyl acceptor in folate metabolism and also the conversion of betaine to dimethylglycine (via methylation of homocysteine) strongly influences folate metabolism. Another intermediate in the transsulfuration pathway is cystathionine generated by reaction between homocysteine and serine, that may split into cysteine and 2-oxy-butyrate. The latter is involved in the metabolism of several other compounds (e.g. threonine). Cysteine is metabolised to various useful products such as taurine and sulphates. It is also an important precursor for glutathione in the liver and some other tissues. Glutathione that is produced in the liver has to be transported to cell compartments in some peripheral organs in order to exhibit its activity. Intracellular glutathione levels are in turn strongly influenced by the presence of reducing equivalents and amino acids in the cell. Web site: http://www.delphion.com/details?pn=US06544547__ •
Plant amino acid biosynthetic enzymes Inventor(s): Allen; Stephen M. (West Chester, PA), Falco; Saverio Carl (Arden, DE) Assignee(s): E. I. du Pont de Nemours and Company (Wilmington, DE) Patent Number: 6,664,445 Date filed: December 2, 1999 Abstract: This invention relates to an isolated nucleic acid fragment encoding a plant enzyme that catalyze steps in the biosynthesis of lysine, threonine, methionine, cysteine and isoleucine from aspartate, the enzyme a member selected from the group consisting of: dihydrodipicolinate reductase, diaminopimelate epimerase, threonine synthase, threonine deaminase and S-adenosylmethionine synthetase. The invention also relates to the construction of a chimeric gene encoding all or a portion of the enzyme, in sense or antisense orientation, wherein expression of the chimeric gene results in production of altered levels of the enzyme in a transformed host cell. Excerpt(s): This invention is in the field of plant molecular biology. More specifically, this invention pertains to nucleic acid fragments encoding enzymes involved in amino acid biosynthesis in plants and seeds. Many vertebrates, including man, lack the ability to manufacture a number of amino acids and therefore require these amino acids preformed in the diet. These are called essential amino acids. Human food and animal feed, derived from many grains, are deficient in essential amino acids, such as lysine, the sulfur amino acids methionine and cysteine, threonine and tryptophan. For example, in corn (Zea mays L.) lysine is the most limiting amino acid for the dietary requirements of many animals. Soybean (Glycine max L.) meal is used as an additive to com-based animal feeds primarily as a lysine supplement. Thus, an increase in the lysine content of either corn or soybean would reduce or eliminate the need to supplement mixed grain
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feeds with lysine produced via fermentation of microbes. Furthermore, in corn the sulfur amino acids are the third most limiting amino acids, after lysine and tryptophan, for the dietary requirements of many animals. The use of soybean meal, which is rich in lysine and tryptophan, to supplement corn in animal feed is limited by the low sulfur amino acid content of the legume. Thus. an increase in the sulfur amino acid content of either corn or soybean would improve the nutritional quality of the mixtures and reduce the need for further supplementation through addition of more expensive methionine. The organization of the pathway leading to biosynthesis of lysine, threonine, methionine, cysteine and isoleucine indicates that over-expression or reduction of expression of genes encoding, inter alia, threonine synthase, dihydrodipicolinate reductase, diaminopimelate epimerase, threonine deaminase and S-adenosylmethionine synthetase in corn, soybean, wheat and other crop plants could be used to alter levels of these amino acids in human food and animal feed. Accordingly, availability of nucleic acid sequences encoding all or a portion of these enzymes would facilitate development of nutritionally improved crop plants. Web site: http://www.delphion.com/details?pn=US06664445__ •
Process for eliminating N-terminal methionine Inventor(s): Asano; Tsuneo (Hyogo, JP), Nishimura; Osamu (Ibaraki, JP), Ohmae; Hiroaki (Nara, JP), Okutani; Norio (Hyogo, JP), Suenaga; Masato (Hyogo, JP) Assignee(s): Takeda Chemical Industries, Ltd. (Osaka, JP) Patent Number: 6,774,221 Date filed: May 7, 2001 Abstract: A method for removing from a peptide the diketone of the methionine residue, and a method for manufacturing a peptide or salt thereof which does not possess an N-terminal methionine residue, characterized by having a peptide or salt thereof which possesses a diketone of the optionally oxidized N-terminal methionine residue react with 3,4-diaminobenzoic acid or a salt thereof in the presence of acetic acid and sodium formate, formic acid and sodium formate, or formic acid and sodium acetate. Excerpt(s): This invention relates to a method for the efficient removal, from peptides (including proteins) or salts thereof which possess an optionally oxidized N-terminal methionine residue or diketone of said methionine residue, of the N-terminal methionine residue or the diketone of said methionine residue, in the presence of acetic acid and sodium formate, formic acid and sodium formate, or formic acid and sodium acetate; and to a method for manufacturing peptides or salts thereof which do not possess an optionally oxidized N-terminal methionine residue or diketone of said methionine residue. When protein is biosynthesized within a cell, its N-terminal is known to start with methionine, which corresponds to the initiation codon AUG of the mRNA. However, as this methionine is removed by subsequent processing, it is usually no longer present in the completed mature protein molecule. With advancements in recombinant DNA techniques, it has become possible to produce useful proteins using microorganisms and/or animal cells, for example Escherichia coli. There have been instances wherein protein produced via this type of method was found to retain a residue comprised of the aforementioned methionine. For example, the retention rate of methionine was as high as approximately 100% in human growth hormone expressed in E. coli [Nature, 293, 408 (1981)], and 50% in interferon-.alpha. [J. Interferon Res., 1, 381 (1981)], while in nonglycosylated human interleukin-2 the presence of a molecular
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species with methionine retention on the amino-terminal (N-terminal methionine residue) (Met-rIL-2) has been noted in addition to the molecular species rIL-2 which, like naturally-occurring human interleukin-2, is initiated with alanine. Web site: http://www.delphion.com/details?pn=US06774221__ •
Process for the production of methionine Inventor(s): Gros; Georges (Antony, FR), Laval; Phillippe (Paris, FR), Ponceblanc; Herve (Villerubanne, FR), Rossi; Jean-Christophe (Villeneuve les Maguelone, FR) Assignee(s): Aventis Animal Nutrition, SA (Antony, FR) Patent Number: 6,545,179 Date filed: February 13, 2001 Abstract: A process for the production of methionine which comprises (a) hydrolysing the methionine amide in the presence of a catalyst comprising titanium to produce ammonium methioninate, said catalyst having a porosity of from 5 to 1000 nm, a total pore volume of from 0.2 to 0.55 cm.sup.3 /g and a surface area of from 30 to 150 m.sup.2 /g, and (b) a second step of recuperating methionine from the ammonium methioninate salt by removing ammonia. Also claimed is an industrial process for the production of methionine incorporating the aforementioned hydrolysis. Excerpt(s): The hydrolysis of the methionine amide to produce the methionine is a known process. In particular, European Patent Application No228938 discloses a process for the production of methionine by the hydrolysis of the methionine amide using a strong base. A problem with this process is that the acidification step uses a strong acid which results in the co-production of mineral salts such as carbonates, chlorides or sulphates. An additional purification step is generally required to remove the salt. French Patent Application No. 9814000 attempts to overcome the aforementioned problem through the use of a titanium catalyst in the hydrolysis reaction. The use of a titanium based catalyst is also disclosed in Japanese patent applications 03093753, 03093754, 03093755, 03093756. We have now found that methionine can be produced in high yields using a specific titanium catalyst. Accordingly, the present invention provides a process for the production of methionine which comprises (a) hydrolysing methionine amide in the presence of a catalyst comprising titanium to produce ammonium methioninate, said catalyst having a porosity of from 5 to 1000 nm, a total pore volume of from 0.2 to 0.55 cm.sup.3 /g and a surface area of from 30 to 150 m.sup.2 /g, and (b) a second step of recuperating methionine from the ammonium methioninate salt by removing ammonia. Web site: http://www.delphion.com/details?pn=US06545179__
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S-adenosyl methionine regulation of metabolic pathways and its use in diagnosis and therapy Inventor(s): O'Day; Christine L. (Mountlake Terrace, WA), Schwartz; Dennis E. (Redmond, WA), Vermeulen; Nicolaas M. J. (Woodinville, WA) Assignee(s): MediQuest Therapeutics, Inc. (Seattle, WA) Patent Number: 6,596,701 Date filed: March 16, 1998
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Abstract: A new paradigm of disease centers around the metabolic pathways of Sadenosyl-L-methionine (SAM), the intermediates of these pathways and other metabolic pathways influenced by the SAM pathways. Methods are provided to analyze and modulate SAM pathways associated with a disease or condition. Such methods permit identification and utilization of diagnostic and therapeutic protocols and agents for such disease states and conditions. Excerpt(s): The invention relates to a new paradigm of disease centering around the metabolic pathways of S-adenosyl-L-methionine (SAM), the intermediates of these pathways and other metabolic pathways influenced by the SAM pathways. Specifically, the invention relates to analyzing and regulating SAM pathways that exist in association with a disease or condition including cancer and a number of diseases or conditions connected with degeneration and aging. More specifically, the invention concerns designing analytical, diagnostic and therapeutic protocols and agents for such disease states and conditions through recognition of the central role of SAM and its metabolic pathways in controlling cell metabolism, cell growth and intercellular communication. It is commonly believed that an understanding of cellular metabolism and function, as well as the nature of biological degeneration and the creation of disease conditions, can be achieved by ascertaining the genetic information contained in eukaryotic cells and understanding how this genetic information is transcribed and translated into proteins which then control chemical conversions within the cell. The present conceptual frame work considers DNA as the core of life. Within this framework, the function of proteins is commonly assumed to be regulated in large part by phosphorylation and dephosphorylation of relevant proteins at appropriate times. The present invention was made in response to the absence of a greater unifying relationship between small molecule biochemistry and the macromolecules RNA, DNA and protein. Present-day molecular biology is focused completely on macromolecules and has provided essentially no connection with the small molecules which carry out the chemical reactions of life. In fact, the study of small molecules in the biological and biochemical sciences has not been in vogue for the last 20 years. Web site: http://www.delphion.com/details?pn=US06596701__ •
Type 2 methionine aminopeptidase (MetAP2) inhibitors and uses thereof Inventor(s): Griffith; Eric C. (Somerville, MA), Liu; Jun O. (Cambridge, MA), Su; Zhuang (Cambridge, MA) Assignee(s): Massachusetts Institute of Technology (Cambridge, MA) Patent Number: 6,566,541 Date filed: March 21, 2001 Abstract: Novel compounds that are anti-angiogenic or immunosuppressive are described. Also described are methods for determining if an animal is at risk for a disease involving abnormal angiogenesis or an immune reaction resulting in pathology comprising evaluating an aspect of MetAP2 metabolism or structure; methods for identifying agents that are anti-angiogenic or immunosuppressive comprising evaluating the effect of the agent on an aspect of MetAP2 metabolism; methods for treating a cell having an abnormality in metabolism or structure of MetAP2; and methods for treating abnormal angiogenesis or an immune reaction which results in pathology in an animal. Pharmaceutical compositions are also provided.
Patents 171
Excerpt(s): This invention relates to agents which inhibit type 2 methionine aminopeptidase (MetAP2), including novel ovalicin and fumagillin derivatives, and to the identification and use of such agents for treating and diagnosing diseases involving abnormal angiogenesis or immune reactions which result in pathology. Angiogenesis is the process of new blood vessel formation. It has been shown to play a pivotal role in certain normal physiological reactions, e.g., wound healing, corpus luteum formation and embryonic development. It has also been reported to play a pivotal role in a variety of pathological conditions, e.g., tumors, diabetic retinopathy, inflammatory diseases and arteriosclerosis. For example, it has been reported that without access to sufficient vasculature, tumor growth is restrained as a result of widespread cell death. Further, while immune reactions are required to protect animals from deleterious foreign antigens, certain immune reactions can result in pathological conditions, e.g., autoimmune diseases, allergies or tissue graft rejection. Web site: http://www.delphion.com/details?pn=US06566541__
Patent Applications on Methionine As of December 2000, U.S. patent applications are open to public viewing.9 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to methionine: •
Anti-microbial agents derived from methionine sulfoximine analogues Inventor(s): Griffith, Owen W.; (Milwaukee, WI), Harth, Gunter; (Los Angeles, CA), Horwitz, Marcus; (Los Angeles, CA) Correspondence: Stradling Yocco Carlson & Rauth; Suite 1600; 660 Newport Center Drive; P.O. Box 7680; Newport Beach; CA; 92660; US Patent Application Number: 20040157802 Date filed: November 17, 2003 Abstract: Novel antimicrobial compositions containing analogues of L-methionine-SRsulfoximine (MSO) that are effective in treating intracellular pathogen infections are provided. Specifically, the compostions provided are MSO analogues having superior antimicrobial activity with significantly less toxicity as compared to MSO. These MSO analogues are suitable for use in treating infection in animals including primates, cows, pigs, horses, rabbits, mice, rats, cats, and dogs. Moreover, the MSO analogues are ideally suited for treating infections caused by the genus Mycobacterium. Additionally, methods for using the novel MSO analogues are also provided. Excerpt(s): The present application claims priority to U.S. provisional patent application serial No. 60/426,502 filed Nov. 15, 2002, now abandoned and 60/430,407 filed Dec. 2, 2002, now abandoned both of which are incorporated herein in their entirety by reference. The present invention relates to anti-microbial agents useful in treating intracellular pathogen infections in animals. Specifically, the present invention relates to methionine sulfoximine (MSO) analogues and structurally similar compounds useful in treating intracellular pathogen infections. More specifically, the present invention relates to MSO analogues and structurally similar compounds useful in treating infections in
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This has been a common practice outside the United States prior to December 2000.
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animals caused by the genus Mycobacterium. Reference to numerous articles and publications are made through the text. For convenience, each reference is cited using numerical notations enclosed in parentheses. These numerical notations correspond to the complete citation found in the Literature Cited list immediately preceding the Claims. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Assay for nitrous oxide neurologic syndrome Inventor(s): Hogan, Kirk J.; (Madison, WI), Selzer, Rebecca M.R.; (Verona, WI) Correspondence: Quarles & Brady Llp; 411 E. Wisconsin Avenue, Suite 2040; Milwaukee; WI; 53202-4497; US Patent Application Number: 20030198985 Date filed: February 24, 2003 Abstract: A method for detection of susceptibility to nitrous oxide neurologic syndrome in a subject is disclosed. In one embodiment, the method comprises: (a) providing a sample from a subject, wherein said subject is a candidate for nitrous oxide anesthesia; and (b) detecting the presence or absence of folate, cobalamin, methionine and homocysteine pathway genetic polymorphisms in said sample, wherein the presence of a polymorphism indicates that the subject is susceptible to nitrous oxide neurologic syndrome. Excerpt(s): The present invention claims priority to U.S. Serial No. 60/358,781, incorporated by reference herein. 5,10-methylene tetrahydrofolate reductase (MTHFR) regulates the synthesis of 5-methyl tetrahydrofolate, the primary circulatory form of folate which acts as the methyl donor to methionine. Homocysteine is a sulphur amino acid formed by demethylation of the essential amino acid methionine. A methyltransferase enzyme known as methionine synthase (MTR) is responsible for converting homocysteine back to methionine, the body's sole methyl donor. Among many other reactions, methyl moieties are crucial for the synthesis of neurotransmitters, assembly of the myelin sheath, and DNA synthesis in proliferating tissues such as bone marrow and the developing brain. Genetic defects that cause deficiencies in either MTR or MTHFR are associated with high serum homocysteine levels and homocystinurea. Nitrous oxide irreversibly oxidizes the cobalt atom of vitamin B.sub.12, and thus inhibits the activity of the cobalamin-dependent enzyme MTR. Over twenty-four rare mutations in MTHFR have been described as associated with pronounced enzymatic deficiency and homocystinuria. In addition, two common single nucleotide polymorphisms have been identified that affect folate and homocysteine metabolism, both of which are implicated in the pathogenesis of cardiovascular disease, neural tube defects and developmental delay. One polymorphism is a missense mutation consisting of a C.fwdarw.T transition at position 677, which produces an alanine to valine amino acid substitution within the catalytic domain of MTHFR. The resulting enzyme has reduced catalytic activity. The second mutation is found at position 1298, an A.fwdarw.C transition which results in a glutamate to alanine substitution located in the presumed regulatory domain of MTHFR. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Asthma associated factors as targets for treating atopic allergies including asthma and related disorders Inventor(s): Kari, U. Prasad; (Hatfield, PA), Levitt, Roy Clifford; (Ambler, PA), Maloy, W. Lee; (Lansdale, PA), Nicolaides, Nicholas C.; (Media, PA) Correspondence: Morgan Lewis & Bockius Llp; 1111 Pennsylvania Avenue NW; Washington; DC; 20004; US Patent Application Number: 20040076607 Date filed: August 18, 2003 Abstract: A C to T DNA variation at position 3365 in exon 5 of the human Asthma Associated Factor 1 (AAF1) produces the predicted amino acid substitution of a methionine for a threonine at codon 117 of AAF1. When this substitution occurs in both alleles in one individual, it is associated with less evidence of atopic allergy including asthma, fewer abnormal skin test responses, and a lower serum total IgE. Thus, applicant has identified the existence of a non-asthmatic, non-atopic phenotype characterized by methionine at codon 117 when it occurs in both AAF1 gene products in one individual. Excerpt(s): This application is related to U.S. Provisional Application Serial No. 60/002,765 which was filed Aug. 24, 1995. This invention relates to regulating IL-9 activity and treating atopic allergies and related disorders like asthma, based upon the relationship between IL-9 and its receptor. Inflammation is a complex process in which the body's defense system combats foreign entities. While the battle against foreign entities may be necessary for the body's survival, some defense systems improperly respond to foreign entities, even innocuous ones, as dangerous and thereby damage surrounding tissue in the ensuing battle. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Catalytic antioxidants and methods of use Inventor(s): Brot, Nathan; (West Orange, NJ), Weissbach, Herbert; (Boynton Beach, FL) Correspondence: Stanley A. Kim, PH.D., ESQ.; Akerman Senterfitt; Suite 400; 222 Lakeview Avenue; West Palm Beach; FL; 33401-6183; US Patent Application Number: 20040143016 Date filed: November 26, 2003 Abstract: The invention provides small molecules that act as catalytic antioxidants and methods of use thereof. The compounds can repeatedly bind and destroy reactive oxygen species by serving as substates for enzymes of the methionine sulfoxide reductase (Msr) class. Some embodiments of the catalytic antioxidant compounds are derived from drugs with anti-inflammatory activity due to inhibition of cyclooxygenase enzymes. Excerpt(s): The present application claims the priority of U.S. provisional patent application No. 60/429,269 filed on Nov. 26, 2002. Not applicable. The invention relates to the fields of biochemistry, pharmacology, and medicine. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Compounds and methods Inventor(s): Kallander, Lara S.; (King of Prussia, PA), Thompson, Scott; (King of Prussia, PA) Correspondence: Smithkline Beecham Corporation; Corporate Intellectual Property-Us, Uw2220; P. O. Box 1539; King OF Prussia; PA; 19406-0939; US Patent Application Number: 20030220371 Date filed: October 10, 2002 Abstract: Compounds of this invention are non-peptide, reversible inhibitors of type 2 methionine aminopeptidase, useful in treating conditions mediated by angiogenesis, such as cancer, haemangioma, proliferative retinophathy, rheumatoid arthritis, atherosclerotic neovascularization, psoriasis, ocular neovascularization and obesity. Excerpt(s): Compounds of this invention are non-peptide, reversible inhibitors of type 2 methionine aminopeptidase, useful in treating conditions mediated by angiogenesis, such as cancer, haemangioma, proliferative retinopathy, rheumatoid arthritis, atherosclerotic neovascularization, psoriasis, ocular neovascularization and obesity. In 1974, Folkman proposed that for tumors to grow beyond a critical size and to spread to form metastases, they must recruit endothelial cells from the surrounding stroma to form their own endogenous microcirculation in a process termed angiogenesis (Folkman J. (1974) Adv Cancer Res. 19; 331). The new blood vessels induced by tumor cells as their life-line of oxygen and nutrients also provide exits for cancer cells to spread to other parts of the body. Inhibition of this process has been shown to effectively stop the proliferation and metastasis of solid tumors. A drug that specifically inhibits this process is known as an angiogenesis inhibitor. Having emerged as a promising new strategy for the treatment of cancer, the anti-angiogenesis therapy ("indirect attack") has several advantages over the "direct attack" strategies. All the "direct attack" approaches such as using DNA damaging drugs, antimetabolites, attacking the RAS pathway, restoring p53, activating death programs, using aggressive T-cells, injecting monoclonal antibodies and inhibiting telomerase, etc., inevitably result in the selection of resistant tumor cells. Targeting the endothelial compartment of tumors as in the "indirect attack", however, should avoid the resistance problem because endothelial cells do not exhibit the same degree of genomic instability as tumor cells. Moreover, anti-angiogenic therapy generally has low toxicity due to the fact that normal endothelial cells are relatively quiescent in the body and exhibit an extremely long turnover. Finally since the "indirect attack" and "direct attack" target different cell types, there is a great potential for a more effective combination therapy. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Expression and secretion vector for human interferon alpha and process for producing human interferon alpha by employing same Inventor(s): Bae, Sung-Min; (Seoul, KR), Choi, Ki-Doo; (Seoul, KR), Jung, Sung-Youb; (Seoul, KR), Kim, Cha-Soon; (Yongin-Shi, Gyonggi-do, KR), Kwon, Se-Chang Chang; (Seoul, KR), Lee, Gwan-Sun; (Seoul, KR) Correspondence: Anderson Kill & Olick; 1251 Avenue OF The Americas; New York; NY; 10020-1182; US Patent Application Number: 20040151695 Date filed: July 18, 2002
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Abstract: Disclosed in this invention are: an expression vector for the secretive production of human interferon alpha (hIFN.alpha.) comprising a polynucleotide encoding a modified E. coli thermostable enterotoxin II signal sequence and a polynucleotide encoding hIFN.alpha.) ligated to the 3'-end thereof; a microorganism transformed with the expression vector, and a process for secretively producing human interferon by culturing the microorganism, said process being capable of secreting a soluble form of active hIFN.alpha.), which does not contain an additional methionine residue at its N-terminal, into the periplasm of an E coli cell. Excerpt(s): The present invention relates to an expression vector for the secretive production of human interferon alpha (hIFN.alpha.) comprising a polynucleotide encoding a modified E.coli thermostable enterotoxin II signal sequence and a polynucleotide encoding hIFN.alpha. ligated to the 3'-end thereof; a microorganism transformed with the expression vector; and a process for secretively producing hIFN.alpha. having no methionine residue added at its N-terminal in the periplasm of E.coli cell. Isaacs and Lindenmann reported in 1957 that when chicken is infected with influenza virus A, a viral replication inhibitory factor designated interferon is produced (Isaacs, K and Lindenmann, J. Proc. R. Soc. Lond., B147:258-267, 1957). Human interferons are cytokine proteins which inhibit in vivo immune response or viral replication and they are classified as interferon alpha (IFN.alpha.), interferon beta (IFN.beta.) and interferon gamma (IFN.gamma.) according to cell types producing them (Kirchner, H. et al., Tex. Rep. Biol. Med., 41:89-93, 1981; Stanton, G. J. et al., Tex. Rep. Biol. Med., 41:84-88, 1981). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Genetic sequences encoding dominant-negative chalcone synthase and uses therefore Inventor(s): Choi, Giltsu; (Kwangju, KR), Choi, Goh; (Kwangju, KR), Hanummappa, Mamatha; (Kwangju, KR) Correspondence: Jacobson Holman Pllc; 400 Seventh Street N.W.; Suite 600; Washington; DC; 20004; US Patent Application Number: 20040038407 Date filed: August 21, 2002 Abstract: The invention includes modified Mazus chalcone synthase (CHS) nucleic acids, which encode a modified chalcone synthase that has alanine instead of cysteine at the 165.sup.th amino acid of Mazus CHS and either glycine or lysine instead of methionine at the 138.sup.th amino acid of Mazus CHS. The property of the encoded modified Mazus CHS is characterized by its dominant-negative inhibition of CHS. The invention also includes plants having at least one cell expressing the modified Mazus CHS. Such plants are characterized by the decreased content of anthocyanins. The invention also includes vectors comprising at least a portion of the modified Mazus CHS nucleic acids. The invention also includes methods using such vectors for producing plants having the decreased content of anthocyanins. Excerpt(s): The invention relates to modified Mazus CHS nucleic acids that encode modified CHS enzymes that inhibit CHS dominant-negatively and their uses for genetically altering plants to decrease the content of anthocyanins in the plants. Flower color is an important horticultural trait and is mainly produced by the flavonoid pigments, anthocyanins. Primarily produced to attract pollinators, flavonoids also protect the plant and its reproductive organs from UV damage, pests and pathogen
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(Brouillard and Cheminat, 1988; Gronquist et al., 2001). Classical breeding methods have been extensively used to develop cultivars with flowers varying in both the color and its intensity. The recent advance of knowledge on flower coloration at the biochemical and molecular level has made it possible to achieve this by genetic engineering (Tanaka et al., 1998). Genetic engineering to alter flower color has been attempted using various genes. Some species lack a particular color due to the absence of a biosynthetic gene or the substrate specificity of an enzyme in the pathway. For example, carnation lacks blue/purple colored flowers due to the absence of F3'5'H, while petunia lacks orange and brick-red flowers due to the inability of its DFR to reduce DHK (Gerats et al., 1982; Forkmann and Ruhnau, 1987). Genetic engineering of blue/purple colored carnation was achieved by introducing petunia F3'5'H gene and orange-colored petunia was developed by introducing DFR from other species (Meyer et al., 1987; Brugliera et al., 2000; Johnson et al., 2001). The modulation of color intensity has been another target for genetic engineering. Expression of biosynthetic genes such as CHS, F3H, and DFR in sense or antisense directions has been the most exploited method (van der Krol et al., 1990; Courtney-Gutterson et al., 1994; Jorgensen et al., 1996; Tanaka et al., 1998). The resulting sense suppression or antisense inhibition is collectively called posttranscriptional gene silencing (PTGS). Though these approaches have been fairly successful in the down-regulation of pigment synthesis, the necessity of cloning the gene of interest from a specific species or closely related species is the major drawback. Further, it is difficult to limit the PTGS to specific tissues (Palauqui et al., 1997; Voinnet and Baulcombe, 1997; Voinnet et al., 1998; Fagard and Vaucheret, 2000; Crete et al., 2001; Vaucheret et al., 2001). Alternatively, transcription factors that can either activate or repress the transcription of anthocyanin biosynthetic genes have been shown to be useful in regulating color intensity in model plants such as Arabidopsis, tobacco, and Petunia (Lloyd et al., 1992; Mol et al., 1998; Borevitz et al., 2000; Aharoni et al., 2001). The overexpression of transcription factors, however, generally alters the expression of many genes, thus the commercial viability of such transgenic flowers has yet to be determined (Lloyd et al., 1994; Bruce et al., 2000). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Human methionine aminopeptidase type 3 Inventor(s): Aurora, Rajeev; (Glencoe, MO), Dotson, Stanton B.; (Chesterfield, MO), Frazier, Ronald B.; (Lake St. Louis, MO), Sympson, Carolyn J.; (Ballwin, MO), Woods, Cynthia L.; (St. Peters, MO), Zakeri, Hamideh; (Chesterfield, MO), Zhou, Xianzhi; (Chesterfield, MO) Correspondence: Pharmacia Corporation; Global Patent Department; Post Office Box 1027; ST. Louis; MO; 63006; US Patent Application Number: 20030203406 Date filed: November 19, 2002 Excerpt(s): The present application is a continuation-in-part of U.S. application Ser. No. 09/523,263, filed Mar. 10, 2000, pending, which claims priority under Title 35, United States Code.sctn.119, to U.S. Provisional Application Serial No. 60/125,139, filed Mar. 11, 1999. Methionine aminopeptidases catalyse the co-translational removal of amino terminal methionine residues from nascent polypeptide chains. A newly-discovered enzyme, designated methionine aminopeptidase type-3 (MetAP-3), has a substrate specificity which is similar to MetAP-1 and MetAP-2, although it is not inhibited by fumagillin, an irreversible inhibitor of MetAP-2. MetAP-3 also preferentially localizes to
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mitochondria, unlike MetAP-1 and MetAP-2, which accumulate in the cytoplasm. One embodiment of the present invention relates to human cDNAs encoding polypeptides comprising MetAP-3. Other embodiments of the invention relate to nucleic acid molecules derived from these cDNAs, including complements, homologues, and fragments thereof, and methods of using these nucleic acid molecules, to generate polypeptides and fragments thereof. Other embodiments of the invention relate to antibodies directed against polypeptides comprising MetAP-3, and methods to screen for compounds or compositions that preferentially or specifically effect the activity of polypeptides comprising MetAP-3. Angiogenesis, the process of new blood vessel formation, is essential for the exponential growth of solid tumors and tumor metastasis. Radiological and cytocidal treatments, combined with regimens involving selective inhibitors of angiogenesis should lead to dramatic reductions in tumor growth. One well-known angiogenesis inhibitor was first discovered as fungal contaminant in bovine endothelial cell cultures that inhibited cell proliferation (Ingber et al. Nature 348:555-557, 1990). The responsible organism was subsequently identified as A. fumagatus, and the product identified as fumagillin, a widely recognized amebicide and antibiotic (McCowen et al., Science 113:202-203 (1951)). Fumagillin was found to be a potent inhibitor of endothelial cell proliferation, but its therapeutic window was insufficient for further clinical advancement. TNP-470, a fumagillin-like derivative with 50-fold higher potency, was subsequently developed from a directed chemical approach (Ingber et al., Nature 348:555-557 (1990), Kusaka et al., Biochem. Biophys. Res. Commun. 174:10701076 (1991)). This compound's therapeutic use is limited, however, by its lack of oral availability and dose-limiting neurotoxicity. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Human methionine synthase: cloning, and methods for evaluating risk of neural tube defects, cardiovascular disease, and cancer Inventor(s): Campeau, Eric; (Montreal, CA), Goyette, Philippe; (Montreal, CA), Gravel, Roy A.; (Westmont, CA), LeClerc, Daniel; (Montreal, CA), Rozen, Rima; (Montreal West, CA) Correspondence: Clark & Elbing Llp; 101 Federal Street; Boston; MA; 02110; US Patent Application Number: 20040073018 Date filed: June 27, 2003 Abstract: The invention features a method for detecting an increased likelihood of hyperhomocysteinemia and, in turn, an increased or decreased likelihood of neural tube defects or cardiovascular disease. The invention also features therapeutic methods for reducing the risk of neural tube defects, colon cancers and related cancers. Also provided are the sequences of the human methionine synthase gene and protein and compounds and kits for performing the methods of the invention. Excerpt(s): This invention claims priority from U.S. Provisional Applications Serial Nos. 60/031,964 and 60/050,310, filed Nov. 27, 1996 and Jun. 20, 1997, respectively. The invention relates to the diagnosis and treatment of patients at risk for methionine synthase deficiency and associated altered risk for diseases such as neural tube defects, cardiovascular disease, and cancer. Methionine synthase (EC 2.1.1.13, 5methyltetrahydrofolate-homocyst- eine methyltransferase) catalyses the remethylation of homocysteine to methionine in a reaction in which methylcobalamin serves as an intermediate methyl carrier. This occurs by transfer of the methyl group of 5methyltetrahydrofolate to the enzyme-bound cob(I)alamin to form methylcobalamin
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with subsequent transfer of the methyl group to homocysteine to form methionine. Over time, cob(I)alamin may become oxidized to cob(II)alamin rendering the enzyme inactive. Regeneration of the functional enzyme occurs through the methionine synthase-mediated methylation of the cob(II)alamin in which S-adenosylmethionine is utilized as methyl donor. In E. coli, two flavodoxins have been implicated in the reductive activation of methionine synthase (Fujii, K. and Huennekens, F. M. (1974) J. Biol. Chem., 249, 6745-6753). A methionine synthase-linked reducing system has yet to be identified in mammalian cells. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Hydrazide and alkoxyamide angiogenesis inhibitors Inventor(s): Ba-Maung, Nwe; (Niles, IL), Craig, Richard A.; (Racine, WI), Kawai, Megumi; (Libertyville, IL), Lynch, Linda M.; (Pleasant Prairie, WI), Patel, Jyoti R.; (Libertyville, IL), Searle, Xenia Beebe; (Grayslake, IL), Sheppard, George S.; (Wilmette, IL), Wang, Jieyi; (Lake Bluff, IL), Yang, Fan; (Highwood, IL) Correspondence: Steven F. Weinstock; Abbott Laboratories; 100 Abbott Park Road; DEPT. 377/ap6a; Abbott Park; IL; 60064-6008; US Patent Application Number: 20040167126 Date filed: February 19, 2004 Abstract: Compounds having the formula 1are methionine aminopeptidase type 2 (MetAP2) inhibitors and are useful for inhibiting angiogenesis. Also disclosed are MetAP2-inhibiting compositions and methods of inhibiting angiogenesis in a mammal. Excerpt(s): This application is a continuation of U.S. patent application Ser. No. 09/833,917, filed Apr. 12, 2001, which claims priority to U.S. provisional patent application 60/197,262, filed Apr. 14, 2000. The present invention relates to substituted hydrazides and N-alkoxyamides which are useful for preventing angiogenesis, methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds. Angiogenesis, the fundamental process by which new blood vessels are formed, is essential to a variety of normal body activities (such as reproduction, development and wound repair). Although the process is not completely understood, it is believed to involve a complex interplay of molecules which both stimulate and inhibit the growth of endothelial cells, the primary cells of the capillary blood vessels. Under normal conditions, these molecules appear to maintain the microvasculature in a quiescent state (i.e., one of no capillary growth) for prolonged periods which may last for as long as weeks or in some cases, decades. When necessary, however, (such as during wound repair), these same cells undergo rapid proliferation and turnover within a 5 day period. (The Journal of biological Chemistry, 267: 1093110934 (1987), Science, 235: 442-447 (1987)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Methionine salvage pathway in bacillus Inventor(s): Danchin, Antoine; (Pokfulam, HK), Sekowska, Agnieszka; (Pokfulam, HK) Correspondence: Oblon, Spivak, Mcclelland, Maier & Neustadt, P.C.; 1940 Duke Street; Alexandria; VA; 22314; US Patent Application Number: 20040019066 Date filed: May 6, 2003 Excerpt(s): This application claims benefit under 35 U.S.C.sctn.119(a) to Provisional Application Serial No. 60/377,622, filed on May 6, 2002, and incorporated herein by reference. The present invention relates to pathways for the synthesis and recycling of methylthioribose (MTR), applications in the fight against plant and vertebrate pathogens (including parasites and their vectors), application for the production of fine chemicals, and in fermentation industry. The present invention also relates to the identification of new drug targets in previously unknown metabolic pathways in living organisms, in particular in bacteria, yeasts, mold, parasites and plants. Polyamine synthesis produces methylthioadenosine, which has to be disposed of. The cell recycles it into methionine through methylthioribose (MTR). Very little was known about MTR recycling for methionine salvage in Bacilli, particularly Bacillus subtilis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Method for supplying bioavailable methionine to a cow Inventor(s): Bennett, Robert; (Antony, FR), Gros, Georges; (Antony, FR), Robert, JeanClaude; (Antony, FR) Correspondence: Connolly Bove Lodge & Hutz, Llp; P O Box 2207; Wilmington; DE; 19899; US Patent Application Number: 20040154549 Date filed: January 16, 2004 Abstract: The present invention relates to a method for supplying bioavailable methionine to a cow which comprises supplying to the cow an ester of methionine or methionine amide and/or an ester of the hydroxy analogue of methionine or a salt thereof. Excerpt(s): This application claims the benefit of foreign priority to French patent application no. 98 14249, filed Nov. 13, 1998, and French patent application no. 99 10050, filed Jul. 29, 1999. Both of these foreign priority documents are incorporated by reference herein. The present invention relates to a method for supplying bioavailable methionine to a cow which comprises administering to the cow an ester of methionine or methionine amide and/or an ester of the hydroxy analogue of methionine or a salt thereof. The present invention also relates to a method of improving milk obtained from dairy cows and in particular to a method which comprises supplying to the dairy cow an ester of methionine or methionine amide and/or an ester of the hydroxy analogue of methionine or a salt thereof. Protein is one of the major nutrients in the diets of lactating cows. The cows however do not actually require proteins but instead they require the specific amino acids, which are the building blocks that make up their own protein. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Novel fluorescence dyes and their applications for whole-cell fluorescence screening assays for caspases, peptidases, proteases and other enzymes and the use thereof Inventor(s): Cai, Sui Xiong; (San Diego, CA), Drewe, John A.; (Carlsbad, CA), Yang, Wu; (Irvine, CA), Zhang, Han-Zhong; (San Diego, CA) Correspondence: Sterne, Kessler, Goldstein & Fox Pllc; 1100 New York Avenue, N.W.; Washington; DC; 20005; US Patent Application Number: 20030208037 Date filed: May 6, 2002 Abstract: The present invention relates to novel fluorescent dyes, novel fluorogenic and fluorescent reporter molecules and new enzyme assay processes that can be used to detect the activity of caspases and other enzymes involved in apoptosis in whole cells, cell lines and tissue samples derived from any living organism or organ. The reporter molecules and assay processes can be used in drug screening procedures to identify compounds which act as inhibitors or inducers of the caspase cascade in whole cells or tissues. The reagents and assays described herein are also useful for determining the chemosensitivity of human cancer cells to treatment with chemotherapeutic drugs. The present invention also relates to novel fluorogenic and fluorescent reporter molecules and new enzyme assay processes that can be used to detect the activity of type 2 methionine aminopeptidase, HIV protease, adenovirus protease, HSV-1 protease, HCMV protease and HCV protease. Excerpt(s): This invention is in the field of intracellular detection of enzymes using fluorogenic or fluorescent probes. The invention relates to novel fluorescent dyes and application of these dyes for the preparation of novel fluorogenic or fluorescent peptide or amino acid derivatives which are substrates of proteases and peptidases. In particular, the invention relates to novel fluorogenic or fluorescent peptide derivatives which are substrates of enzymes involved in apoptosis, such as caspases and the lymphocyte-derived serine protease Granzyme B. The invention also relates to a process for measuring the activity of caspases and other enzymes involved in apoptosis in living or dead whole cells, cell lines or tissue samples derived from any healthy, diseased, infected or cancerous organ or tissue. The invention also relates to the use of the fluorogenic or fluorescent substrates in a novel assay system for discovering or detecting inhibitors or inducers of apoptosis in compound collections or compound libraries. Furthermore, the invention relates to the use of the fluorogenic or fluorescent substrates in determining the sensitivity of cancer cells to treatment with chemotherapeutic drugs. The invention also relates to novel fluorogenic or fluorescent peptide derivatives which are substrates of exopeptidases such as aminopeptidase A and N, methionine aminopeptidase and dipeptidyl-peptidase IV, endopetidases such as calpain, proteases such as HIV proteases, HCMV protease, HSV protease, HCV protease and adenovirus protease. Organisms eliminate unwanted cells by a process variously known as regulated cell death, programmed cell death or apoptosis. Such cell death occurs as a normal aspect of animal development as well as in tissue homeostasis and aging (Glucksmann, A., Biol. Rev. Cambridge Philos. Soc. 26:59-86 (1951); Glucksmann, A., Archives de Biologie 76:419-437 (1965); Ellis et al., Dev. 112:591-603 (1991); Vaux et al., Cell 76:777-779 (1994)). Apoptosis regulates cell number, facilitates morphogenesis, removes harmful or otherwise abnormal cells and eliminates cells that have already performed their function. Additionally, apoptosis occurs in response to various physiological stresses, such as hypoxia or ischemia (PCT published application WO96/20721). There are a number of morphological changes shared by cells
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experiencing regulated cell death, including plasma and nuclear membrane blebbing, cell shrinkage (condensation of nucleoplasm and cytoplasm), organelle relocalization and compaction, chromatin condensation and production of apoptotic bodies (membrane enclosed particles containing intracellular material) (Orrenius, S., J. Internal Medicine 237:529-536 (1995)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Novel gene controlling disease resistance reactions and use thereof Inventor(s): Hirochika, Hirohiko; (Ibaraki, JP), Miyao, Akio; (Ibaraki, JP), Onosato, Katsura; (Tokyo, JP) Correspondence: Perkins Coie Llp; P.O. Box 2168; Menlo Park; CA; 94026; US Patent Application Number: 20040003428 Date filed: November 26, 2002 Abstract: A polynucleotide encoding a plant gene capable of controlling disease resistance reactions in plants is provided which includes a polynucleotide having a nucleotide sequence encoding amino acid sequence from methionine at position 1 to Serine at position 361 of SEQ ID NO: 2 in the sequence listing, or having the amino acid sequence having one or several amino acid deletions, substitutions and/or additions, and being capable of controlling disease resistance reactions. Excerpt(s): The present invention relates to a novel gene. More particularly, the present invention relates to a novel gene encoding a protein capable of controlling disease resistance reactions in plants. A number of gene disruption strains of rice have been produced by the property of rice retrotransposon Tos17 that it is activated by cell/tissue culture to undergo transposition. Transposons are mutagenic genes which are ubiquitous in the genomes of animals, yeast, bacteria, and plants. Transposons are classified into two categories according to their transposition mechanism. Transposons of class II undergo transposition in the form of DNA without replication. Examples of class II transposons include Ac/Ds, Spm/dSpm and Mu elements of maize (Zea mays) (Fedoroff, 1989, Cell 56, 181-191; Fedoroff et al., 1983, Cell 35, 235-242; Schiefelbein et al., 1985, Proc. Natl. Acad. Sci. USA 82, 4783-4787), and Tam element of Antirrhinum (Antirrhinum majus) (Bonas et al., 1984, EMBO J, 3, 1015-1019). Class II transposons are widely used for gene isolation by means of transposon tagging. Such a technique utilizes a property of transposons, that is, a transposon transposes within a genome and enters a certain gene and, as a result, such a gene is physiologically and morphologically modified, whereby the phenotype controlled by the gene is changed. If such a phenotype change can be detected, the affected gene may be isolated (Bancroft et al., 1993, The Plant Cell, 5, 631-638; Colasanti et al., 1998, Cell, 93, 593-603; Gray et al., 1997, Cell, 89, 25-31; Keddie et al., 1998, The Plant Cell, 10, 877-887; and Whitham et al., 1994, Cell, 78, 1101-1115). Transposons of class I are also called retrotransposons. Retrotransposons undergo replicative transposition through RNA as an intermediate. A class I transposon was originally identified and characterized in Drosophila and yeast. A recent study has revealed that retrotransposons are ubiquitous and dominant in plant genomes (Bennetzen, 1996, Trends Microbiolo., 4, 347-353; Voytas, 1996, Science, 274, 737-738). It appears that most retrotransposons are an integratable but non-transposable unit. Recently, it has been reported that some retrotransposons of such a type are activated under stress conditions, such as injury, pathogen attack, and cell culture (Grandbastien, 1998, Trends in Plant Science, 3, 181-187; Wessler, 1996, Curr. Biol., 6, 959-961;Wessler et al., 1995, Curr. Opin. Genet. Devel., 5, 814-821). For example, such
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activation under stress conditions was found in retrotransposons of tobacco, Tnt1A and Tto1 (Pouteau et al., 1994, Plant J., 5, 535-542; Takeda et al., 1988, Plant Mol. Biol., 36, 365-376), and a retrotransposon of rice, Tos17 (Hirochika et al., 1996, Proc. Natl. Acad. Sci. USA, 93, 7783-7788). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •
Novel methionine aminopeptidase-2 and uses thereof Inventor(s): Henkin, Jack; (Highland Park, IL), Lou, PingPing; (Gurnee, IL), Sheppard, George S.; (Wilmette, IL), Wang, Jieyi; (Lake Bluff, IL) Correspondence: Steven F. Weinstock; Abbott Laboratories; 100 Abbott Park Road; DEPT. 377/ap6a; Abbott Park; IL; 60064-6008; US Patent Application Number: 20040077031 Date filed: October 17, 2002 Abstract: The present invention uses the manganese-dependent physiological form of the enzyme methionine aminopeptidase type 2 to assess inhibition by agents that might be used in the treatment of angiogenesis, cancer, malaria and leishmaniasis. This method has the advantage of using the manganese form of the enzyme and therefore, the advantage of identifying potent inhibitors that might not show activity in cellular systems because the wrong metal cofactor is used. Therefore it is a new tool for the development of agents useful in the therapy of cancer and other angiogenesis-related diseases and, several infectious diseases including malaria, leishmaniais and microsporidiosis. Excerpt(s): The present invention relates to a novel, methionine aminopeptidase-2 that uses manganese as the necessary stimulating divalent cation. Methionine aminopeptidase-2 inactivation is linked to anti-angiogenic, anti-tumor, anti-parasitic, anti-bacterial and anti-microsporidian effects. The novel manganese form of the enzyme represents a useful in vitro tool, for example in the discovery of inhibitory compounds that can be used in the treatment of cancer, angiogenesis, malaria and leishmaniasis. Methionine aminopeptidases (MetAPs) are cellular metalloproteases capable of removing the N-terminal initiator methionine residue of nascent proteins. The removal of the N-terminal methionine is a critical step for protein modifications that are important in controlling protein subcellular localization and/or protein degradation. Inhibition of MetAPs therefore affects regulation of cellular signal transduction and cell cycle progression. MetAP enzymes have a conserved C-terminal catalytic domain with a protease fold, termed the "pita bread" fold, that appears to be highly conserved in all MetAP enzymes and other related enzymes (Bazan et al., Proc. Nat'l Acad. Sci. USA, 91(7): 2473-77, 1993). The C-terminus of the human MetAP2 contains the catalytic domain showing high amino acid identity with MetAP sequences from prokaryotes and yeast, while the N-terminal region has two basic poly-lysine blocks and an acidic aspartic acid block. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Novel rice gene controlling tolerance to salt stress Inventor(s): Abe, Kiyomi; (Saitama, JP), Hirochika, Hirohiko; (Ibaraki, JP), Miyao, Akio; (Ibaraki, JP), Takeda, Makoto; (Saitama, JP) Correspondence: Richard M Klein; Fay Sharpe Fagan Minnich & Mckee; Seventh Floor; 1100 Superior Avenue; Cleveland; OH; 44114; US Patent Application Number: 20040016027 Date filed: May 16, 2003 Abstract: A gene encoding a protein capable of controlling salt stress tolerance is provided. A polynucleotide encoding a plant gene capable of controlling salt stress tolerance is provided. The polynucleotide includes a polynucleotide which has a nucleotide sequence encoding an amino acid sequence from methionine at position 1 to asparagine at position 243 of SEQ ID NO: 2 in the sequence listing, or which has a nucleotide sequence encoding the amino acid sequence having one or several amino acid deletions, substitutions and/or additions and is capable of controlling salt stress tolerance. Excerpt(s): The present invention relates to a novel gene. More particularly, the present invention relates to a novel gene encoding a protein having a function of controlling salt stress tolerance in plants. Plants constantly suffer from stresses even in a normal growth environment. Such stresses variously include salt, drying, high temperature, low temperature, intense light, air pollution, and the like. Salt stress has received attention in terms of agricultural production. When soils and stones are decomposed, salts are generated, and the generation of salts is constantly continued. When it rains, the salts may flow into the river or the sea. In desert areas of low rainfall, a lesser amount of salts flow out, so that the salt concentration is considerably higher in soil water. Plants draw salts (nutrients) along with water osmotically through roots. When the salt concentration is high, plants cannot draw water. Moreover, the growth of the plants is inhibited due to physiological actions specific to ions. It is known that responses of plants to a salt stress overlap responses to environmental stresses, such as drying, high osmotic pressure, low temperature, and the like. These stresses lead to considerably severe damage to agriculture. Recently, due to use of fertilizers in bulk or long-term sequential cropping, it is often observed that a high concentration of salt is accumulated in soil. Especially in greenhouse soil, detrimental salt accumulation frequently occurs. In areas near seashores, sea water or sea breeze causes damage. In arid or semiarid regions, salts are accumulated in the surface layer of soil due to excessive evaporation. These problems limit use of agricultural lands. In order to solve such problems, generally, the affected soil is exchanged or salts are removed by irrigation. However, these methods require huge expense or effort. The removal of salts by irrigation causes a large volume of salt water to flow into surrounding regions, leading to environmental pollution. Restriction of irrigation is now under consideration. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html
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Nucleic acids encoding ranpirnase variants and methods of making them Inventor(s): Saxena, Shailendra K.; (West Orange, NJ) Correspondence: Mark H Jay; Post Office Box E; Short Hills; NJ; 07078 Patent Application Number: 20040126865 Date filed: December 30, 2002
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Abstract: Ribonuclease DNA coding for an amino acid sequence beginning with a residue of glutamine is introduced into a vector of pET22b(+) plasmid to form recombinant plasmid DNA that begins with a Pel B leader sequence. The recombinant plasmid DNA is used to transform an E.coli BL21(DE3) host. Signal peptidase enzyme present in the host cell cleaves the pelB leader sequence during signal processing and thereby allows the glutamine residue to autocyclize to pyroglutamic acid. In this way, the Ribonuclease can be produced directly, i.e. without a separate step of cleaving the initial N-terminal methionine residue. Excerpt(s): The invention relates to Ribonucleases (RNases), and more particularly relates to ranpirnase. In its most immediate sense, the invention relates to nucleic acids that encode proteins that produce ranpirnase and proteins closely related to ranpirnase (such closely related proteins being herein referred to as "variants" and "ranpirnase variants"). Ranpirnase is the generic name of an RNase that is produced by Alfacell Corporation (assignee herein) under the registered trademark ONCONASE. Ranpirnase is a protein 104 residues long, with a blocked N-terminal of pyroglutamic acid (
