S Adenosylmethionine Dependent Methyltransferases
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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.
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.
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.
Identifying Unknown Substrates Of S Adenosyl Methionine Dependent Methyltransferases Via In Situ Formation Of Tight Binding Bisubstrate Adducts
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Author : Wanlu Qu
language : en
Publisher:
Release Date : 2015
Identifying Unknown Substrates Of S Adenosyl Methionine Dependent Methyltransferases Via In Situ Formation Of Tight Binding Bisubstrate Adducts written by Wanlu Qu and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2015 with Adenosylmethionine categories.
Identification of enzyme substrates is an essential step toward understanding the physiological functions of enzymes. However, progress in substrate elucidation is hampered by the transient nature of enzyme-substrate interactions. This challenge is exemplified by S-adenosyl-methionine (AdoMet or SAM) dependent methyltransferases (MTases). AdoMet dependent MTases catalyze the methyl-transfer reaction from AdoMet to a wide array of nucleophilic substrates. These nucleophilic substrates, however, are only transiently associated to the enzyme. Inspired by the concept of multisubstrate adduct inhibition, a novel approach of enzyme-catalyzed in situ bisubstrate-adduct formation is presented for capturing substrates of MTases via tight binding MTase-adduct complexes. In our approach, the electrophilic methyl sulfonium in AdoMet is replaced with a vinyl sulfonium in S-adenosyl-vinthionine (AdoVin). AdoVin forms a covalent bisubstrate-adduct with the nucleophilic substrate and the resulting adduct tightly binds the enzyme. Using this strategy, an unknown substrate was readily identified in crude cell lysates, and was found to be a derivative of exogenous substrates. Another significant achievement is the detection of the complex between the bisubstrate-adduct and enzyme using native mass spectrometry directly from the reaction mixture, without prior purification even using crude cell lysates. The subsequent identification of substrates was achieved by employing various tandem mass spectrometric techniques, such as collision induced dissociation (CID) and surface induced dissociation (SID), in a single run. To the best of our knowledge, this is the first example of MTase substrate identification from cell lysates without any separation prior to mass spectrometric analysis. The approaches outlined here should be generally applicable for identifying substrates of other group transferases or enzymes sharing similar mechanisms.
The Approach To Characterizing Three S Adenosyl L Methionine Dependent Methyltransferases From Mycobacterium Tuberculosis
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Author : Gwendal Loarer
language : en
Publisher:
Release Date : 2018
The Approach To Characterizing Three S Adenosyl L Methionine Dependent Methyltransferases From Mycobacterium Tuberculosis written by Gwendal Loarer and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2018 with Adenosylmethionine categories.
Tuberculosis (TB) remains a global health threat, especially due to the emergence and rapid evolution of resistant strains of pathogenic bacteria coupled to the lack of development in treatment. The main treatment requires infected individuals to take multiple drugs over an extended period of time. The treatment for individuals infected with strains of TB that are resistant to classic antibiotics is even heavier. The main drugs have remained the same over the past 50 years and more efficient drugs against TB are yet to be discovered. The development of new and more efficient drugs is therefore becoming increasingly urgent. Mycobacterium tuberculosis, the causative agent of TB, is particularly difficult to kill because of the thick and highly hydrophobic cell wall. 6-O-Methylglucose lipopolysaccharides (MGLP) have a major role in the biosynthesis of fatty acids and mycolic acids. Mycolic acids are one of the main reasons for the hydrophobicity and efficiency of the cell wall in protecting the bacteria. Disrupting the synthesis of MGLP shows significant decrease in growth and bacterial activity of Mtb. Rv3030 is an S-Adenosyl-L-Methionine (SAM)-dependent methyltransferase (MTase) and is a major enzyme in the biosynthetic pathway of MGLP as it is responsible for the essential 6-O- methylation. Unfortunately, the information currently available on this protein is limited as no crystal structure has been published. Therefore, to suppress the production of MGLP through the inhibition of Rv3030, it is necessary to fully characterize Rv3030. In order to achieve this goal, we screened compounds against Rv3030 using Differential Scanning Fluorimetry (DSF) to obtain information on chemotypes that could potentially be used as a basis for the development of Rv3030 inhibitors. Additionally, we used a competitive fluorescence polarization (FP) assay to measure in vitro activity of Rv3030, which would allow for inhibitor validation studies. In parallel, Rv3030 was crystallized in an initial screen and will provide valuable information leading crystal structure determination. The second part of this thesis focuses on the characterization of an enzyme essential for the survival of Mtb within the host. Rv1405 is an uncharacterized putative SAM- dependent MTase for which the function remains at the stage of hypothesis. This part describes the steps we have taken to obtain information on this enzyme screening multiple libraries of compounds using a DSF assay and optimizing a competitive FP assay to carry out inhibitory studies. In an attempt to gain invaluable structural knowledge of Rv1405, we obtained preliminary crystals of Rv1405 establishing a basis for further improvement of crystallization. The last part of this thesis describes the work and experiments carried out to characterize Rv0893 and confirm that it is a SAM-dependent MTase. Knowledge about this enzyme is extremely limited, making the study of Rv0893 to be challenging. We have used DSF and competitive FP assays with the intention to identify the biological methyl acceptor of this enzyme. In parallel, we crystallized and attempted to optimize crystallization in an attempt to gain valuable structural knowledge about Rv0893.
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.
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.
S Adenosylmethionine Dependent Methylation Of Proteins And Lipids
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Author : Kevin McBride
language : en
Publisher:
Release Date : 1988
S Adenosylmethionine Dependent Methylation Of Proteins And Lipids written by Kevin McBride and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 1988 with categories.
I Damaged Proteins In Aging Caenorhabditis Elegans
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Author : Agnieszka Niewmierzycka
language : en
Publisher:
Release Date : 1998
I Damaged Proteins In Aging Caenorhabditis Elegans written by Agnieszka Niewmierzycka and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 1998 with categories.
Epigenetics Of Aging
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Author : Trygve O. Tollefsbol
language : en
Publisher: Springer Science & Business Media
Release Date : 2009-11-11
Epigenetics Of Aging written by Trygve O. Tollefsbol 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 2009-11-11 with Medical categories.
Recent studies have indicated that epigenetic processes may play a major role in both cellular and organismal aging. These epigenetic processes include not only DNA methylation and histone modifications, but also extend to many other epigenetic mediators such as the polycomb group proteins, chromosomal position effects, and noncoding RNA. The topics of this book range from fundamental changes in DNA methylation in aging to the most recent research on intervention into epigenetic modifications to modulate the aging process. The major topics of epigenetics and aging covered in this book are: 1) DNA methylation and histone modifications in aging; 2) Other epigenetic processes and aging; 3) Impact of epigenetics on aging; 4) Epigenetics of age-related diseases; 5) Epigenetic interventions and aging: and 6) Future directions in epigenetic aging research. The most studied of epigenetic processes, DNA methylation, has been associated with cellular aging and aging of organisms for many years. It is now apparent that both global and gene-specific alterations occur not only in DNA methylation during aging, but also in several histone alterations. Many epigenetic alterations can have an impact on aging processes such as stem cell aging, control of telomerase, modifications of telomeres, and epigenetic drift can impact the aging process as evident in the recent studies of aging monozygotic twins. Numerous age-related diseases are affected by epigenetic mechanisms. For example, recent studies have shown that DNA methylation is altered in Alzheimer’s disease and autoimmunity. Other prevalent diseases that have been associated with age-related epigenetic changes include cancer and diabetes. Paternal age and epigenetic changes appear to have an effect on schizophrenia and epigenetic silencing has been associated with several of the progeroid syndromes of premature aging. Moreover, the impact of dietary or drug intervention into epigenetic processes as they affect normal aging or age-related diseases is becoming increasingly feasible.