S Adenosylmethionine Dependent Methyltransferases Structures And Functions
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S Adenosylmethionine Dependent Methyltransferases
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Author : Xiaodong Cheng
language : en
Publisher: World Scientific
Release Date : 1999
S Adenosylmethionine Dependent Methyltransferases written by Xiaodong Cheng and has been published by World Scientific this book supported file pdf, txt, epub, kindle and other format this book has been release on 1999 with Science categories.
This invaluable volume, written by an international group of scientists, presents an overview of the AdoMet-dependent methyltransferases, with special emphasis on structure-function relationships. S-adenosyl-L-methionine (AdoMet) is the second most commonly used enzyme cofactor after ATP. The AdoMet-dependent methyltransferases act on a wide variety of target molecules, including DNA, RNA, protein, polysaccharides, lipids and a range of small molecules. The well-conserved architecture of these enzymes, and the implications of this conservation for their evolutionary history, are major themes of this book. The thirteen chapters describe in detail the structures, enzyme kinetics and biological roles of the AdoMet-dependent methyltransferases from a wide range of cell types: plant, animal, bacterial and archaeal.
Structural Studies Of The S Adenosylmethionine Dependent Methyltransferases
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Author : Yi Peng
language : en
Publisher:
Release Date : 2009
Structural Studies Of The S Adenosylmethionine Dependent Methyltransferases written by Yi Peng and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2009 with Biochemistry categories.
S-adenosylmethionine-dependent methyltransferases (AdoMet-dependent MTases) are a main subfamily of MTases, which play critical roles in diverse methylation reactions in many significant biological processes. AdoMet-dependent MTases catalyze methylation reactions utilizing the methyl donor AdoMet. This thesis describes structure-function studies of several members of this enzyme family which are biomedically important. By combining experimental (X-ray crystallography) and theoretical (molecular dynamics simulation calculations) structural biology techniques with molecular biology and functional studies, the work presented here provides molecular insight into mechanisms of enzyme function and drug response. The first enzyme studied, thiopurine S-methyltransferase (TPMT), modulates the cytotoxic effects of thiopurine prodrugs such as 6-mercaptopurine (6MP) by methylating them in a reaction using AdoMet as the donor. Patients with TPMT variant allozymes exhibit diminished levels of protein and/or enzyme activity and are at risk for thiopurine drug-induced toxicity. We have determined two crystal structures of wild-type murine TPMT, as a binary complex with the product S-adenosyl-L-homocysteine (AdoHcy) and as a ternary complex with AdoHcy and the substrate 6MP, to 1.8 Å and 2.0 Å resolution, respectively. Comparison of the structures reveals that an active site loop becomes ordered upon 6MP binding. The positions of the two ligands are consistent with the expected SN2 reaction mechanism. Arg147 and Arg221, the only polar amino acids near 6MP, are highlighted as possible participants in substrate deprotonation. Structure-based mutagenesis and enzyme activity assays suggest that either Arg152 or Arg226 may participate in some fashion in the TPMT reaction, with one residue compensating when the other is altered, and that Arg152 may interact with substrate more directly than Arg226, consistent with observations in the murine TPMT crystal structure. In addition, we have compared the catalytic activity of wild-type and *5 variant TPMTs, and found that the variant's binding affinity for its methyl acceptor and donor substrates are reduced 10-fold and 2-fold, contributing to decreased enzyme activity of murine TPMT*5. We have determined two crystal structures of murine TPMT*5, as a binary complex with AdoHcy and as a ternary complex with AdoHcy and 6MP, respectively. The TPMT*5 crystal structures together with molecular dynamics simulation calculations reveal that the active site loop is more flexible in TPMT*5, which affects the AdoMet and 6MP substrate affinity and results in loss of the enzyme activity. In addition, these TPMT*5 crystal structures and the computational modeling of other TPMT variants using wild-type murine TPMT structures aid our understanding of the molecular consequences of TPMT polymorphisms. Furthermore, crystal structures of TPMT complexes with benzoic acid inhibitors and thiophenol substrate reveal that TPMT possesses a flexible active site which can accommodate both a smaller acceptor substrate such as thiophenol and larger benzoic acid inhibitors. These structures provide insights into the connection between the subtle variation in binding of different acceptor substrate site ligands to TPMT and the different degree of inhibition by these benzoic acid inhibitors. The structural features of the acceptor binding site characterized by the ensemble of TPMT structures reported here may be useful in identifying new small molecule modulators for optimization of thiopurine-based therapy. Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation of nicotinamide, pyridines and other structural analogs using AdoMet as methyl donor. The crystal structure of human NNMT, which plays a significant role in the regulation of metabolic pathways and cancers, was solved as the ternary complex bound to both AdoHcy and nicotinamide. The structure reveals the structural basis for nicotinamide binding, highlights several residues in the active site, which may play roles in nicotinamide recognition and NNMT catalysis, and provides a structural basis for the design of NNMT mutants to further investigate the enzyme's catalytic mechanism. The structure-based mutagenesis of NNMT is being pursued in ongoing studies. Arsenic methyltransferase (AS3MT) is the third important AdoMet-dependent MTase included in our studies. It is involved in methylation of inorganic arsenic and relevant to public health. To obtain the crystal structure of AS3MT for elucidation of the mechanism of arsenic methylation and to probe the relationship between AS3MT polymorphisms and individual variation in arsenic metabolism, a number of AS3MT constructs have been prepared and characterized, and efforts to crystallize AS3MT are ongoing.
S Adenosylmethionine Dependent Methyltransferases Structures And Functions
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Author : Robert M Blumenthal
language : en
Publisher: World Scientific
Release Date : 1999-07-23
S Adenosylmethionine Dependent Methyltransferases Structures And Functions written by Robert M Blumenthal and has been published by World Scientific this book supported file pdf, txt, epub, kindle and other format this book has been release on 1999-07-23 with Science categories.
This invaluable volume, written by an international group of scientists, presents an overview of the AdoMet-dependent methyltransferases, with special emphasis on structure-function relationships.S-adenosyl-L-methionine (AdoMet) is the second most commonly used enzyme cofactor after ATP. The AdoMet-dependent methyltransferases act on a wide variety of target molecules, including DNA, RNA, protein, polysaccharides, lipids and a range of small molecules.The well-conserved architecture of these enzymes, and the implications of this conservation for their evolutionary history, are major themes of this book. The thirteen chapters describe in detail the structures, enzyme kinetics and biological roles of the AdoMet-dependent methyltransferases from a wide range of cell types: plant, animal, bacterial and archaeal.
S Adenosylmethiionine Dependent Methyltransferases
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Author : Robert M. Blumenthal
language : en
Publisher:
Release Date : 1999
S Adenosylmethiionine Dependent Methyltransferases written by Robert M. Blumenthal and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 1999 with categories.
Homocysteine In Health And Disease
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Author : Ralph Carmel
language : en
Publisher: Cambridge University Press
Release Date : 2001-07-19
Homocysteine In Health And Disease written by Ralph Carmel and has been published by Cambridge University Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2001-07-19 with Medical categories.
This is an unusually comprehensive 2001 account of the broad range of medical implications of homocysteine.
Radical Sam Enzymes
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Author :
language : en
Publisher: Academic Press
Release Date : 2018-08-09
Radical Sam Enzymes written by and has been published by Academic Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2018-08-09 with Science categories.
Radical SAM Enzymes, Volume 606, the latest release in the Methods in Enzymology series, highlights new advances in the field, with this new volume presenting interesting chapters on the Characterization of the glycyl radical enzyme choline trimethylamine-lyase and its radical S-adenosylmethionine activating enzyme, Diphathimide biosynthesis, Radical SAM glycyl radical activating enzymes, Radical SAM enzyme BioB in the biosynthesis of biotin, Biogenesis of the PQQ cofactor, Role of MoaAC in the biogenesis of the molybdenum cofactor, Biosynthesis of the nitrogenase cofactor, Bioinformatics of the radical SAM superfamily, The involvement of SAM radical enzymes in the biosynthesis of methanogenic coenzymes, methanopterin and coenzyme F420, and more.
Regulatory Roles Of S Adenosylmethionine Dependent O Methyltransferases
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Author : Kelley L. Banfield
language : en
Publisher:
Release Date : 2004
Regulatory Roles Of S Adenosylmethionine Dependent O Methyltransferases written by Kelley L. Banfield and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2004 with categories.
The Enzymes
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Author : Fuyuhiko Tamanoi
language : en
Publisher: Academic Press
Release Date : 2011-09-21
The Enzymes written by Fuyuhiko Tamanoi and has been published by Academic Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2011-09-21 with Science categories.
Protein methylation has recently emerged as one of the most exciting areas of study on posttranslational modification. A large family of protein methyltransferases has been identified and their structural properties have been characterized. These studies have provided novel insights into how methylation regulates a variety of biological functions including DNA and RNA metabolism, protein synthesis and signal transduction. Methylation also plays important roles in aging. This volume is intended to capture these recent developments concerning protein methyltransferases.
Practical Bioinformatics
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Author : Janusz M. Bujnicki
language : en
Publisher: Springer Science & Business Media
Release Date : 2004-03-03
Practical Bioinformatics written by Janusz M. Bujnicki and has been published by Springer Science & Business Media this book supported file pdf, txt, epub, kindle and other format this book has been release on 2004-03-03 with Computers categories.
Bridges the gap between bioinformaticists and molecular biologists, i.e. the developers and the users of computational methods for biological data analysis and in that it presents examples of practical applications of the bioinformatics tools in the "daily practice" of an experimental research scientist.
Advances In Virus Research
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Author :
language : en
Publisher: Academic Press
Release Date : 2009-08-19
Advances In Virus Research written by and has been published by Academic Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2009-08-19 with Science categories.
Published since 1953, Advances in Virus Research covers a diverse range of in-depth reviews providing a valuable overview of the current field of virology. The impact factor for 2008 is 4.886, placing it 4th in the highly competitive category of virology. Contributions from leading authorities Informs and updates on all the latest developments in the field