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S-Adenosyl methionine

Huihua Sun, Wan Lin Yeo, Yee Hwee Lim, Xinying Chew, Derek John Smith, Bo Xue, Kok Ping Chan, Robert C Robinson, Edward G Robins, Huimin Zhao, Ee Lui Ang
Fluorinases offer an environmentally friendly alternative for selective fluorination under mild conditions. However, their diversity is limited in nature and they have yet to be engineered through directed evolution. Herein, we report the directed evolution of the fluorinase FlA1 for improved conversion of the non-native substrate 5'-chloro-5'-deoxyadenosine (5'-ClDA) into 5'-fluoro-5'-deoxyadenosine (5'-FDA). The evolved variants, fah2081 (A279Y) and fah2114 (F213Y, A279L), were successfully applied in the radiosynthesis of 5'-[(18) F]FDA, with overall radiochemical conversion (RCC) more than 3-fold higher than wild-type FlA1...
October 14, 2016: Angewandte Chemie
Ilaria Galizia, Lucio Oldani, Karine Macritchie, Erica Amari, Dominic Dougall, Tessa N Jones, Raymond W Lam, Guido Jacopo Massei, Lakshmi N Yatham, Allan H Young
BACKGROUND: Depression is a recurrent illness with high rates of chronicity, treatment-resistance and significant economic impact. There is evidence in the literature that S-adenosyl methionine (SAMe), a naturally occurring compound in the human body, has antidepressant efficacy. This product may be an important addition to the armamentarium of antidepressant agents. OBJECTIVES: To assess the effects of SAMe in comparison with placebo or antidepressants for the treatment of depression in adults...
October 10, 2016: Cochrane Database of Systematic Reviews
Ezhilarasi Krishnamoorthy, Sameer Hassan, Luke Elizabeth Hanna, Indira Padmalayam, Rama Rajaram, Vijay Viswanathan
Lipoic acid synthase (LIAS) is an iron-sulfur cluster mitochondrial enzyme which catalyzes the final step in the de novo pathway for the biosynthesis of lipoic acid, a potent antioxidant. Recently there has been significant interest in its role in metabolic diseases and its deficiency in LIAS expression has been linked to conditions such as diabetes, atherosclerosis and neonatal-onset epilepsy, suggesting a strong inverse correlation between LIAS reduction and disease status. In this study we use a bioinformatics approach to predict its structure, which would be helpful to understanding its role...
October 4, 2016: Journal of Theoretical Biology
Tao Long, Jing Li, Hao Li, Mi Zhou, Xiao-Long Zhou, Ru-Juan Liu, En-Duo Wang
Human NSun6 is an RNA methyltransferase that catalyses the transfer of the methyl group from S-adenosyl-L-methionine (SAM) to C72 of tRNAThr and tRNACys. In the current study, we used mass spectrometry to demonstrate that human NSun6 indeed introduces 5-methylcytosine (m5C) into tRNA, as expected. To further reveal the tRNA recognition mechanism of human NSun6, we measured the methylation activity of human NSun6 and its kinetic parameters for different tRNA substrates and their mutants. We showed that human NSun6 requires a well-folded, full-length tRNA as its substrate...
October 4, 2016: Journal of Biological Chemistry
Takafumi Ogawa, Ryohei Tsubakiyama, Muneyoshi Kanai, Tetsuya Koyama, Tsutomu Fujii, Haruyuki Iefuji, Tomoyoshi Soga, Kazunori Kume, Tokichi Miyakawa, Dai Hirata, Masaki Mizunuma
Dietary restriction (DR), such as calorie restriction (CR) or methionine (Met) restriction, extends the lifespan of diverse model organisms. Although studies have identified several metabolites that contribute to the beneficial effects of DR, the molecular mechanism underlying the key metabolites responsible for DR regimens is not fully understood. Here we show that stimulating S-adenosyl-l-methionine (AdoMet) synthesis extended the lifespan of the budding yeast Saccharomyces cerevisiae The AdoMet synthesis-mediated beneficial metabolic effects, which resulted from consuming both Met and ATP, mimicked CR...
October 3, 2016: Proceedings of the National Academy of Sciences of the United States of America
Benjamin D Horning, Radu M Suciu, Darian A Ghadiri, Olesya A Ulanovskaya, Megan L Matthews, Kenneth M Lum, Keriann M Backus, Steven J Brown, Hugh Rosen, Benjamin F Cravatt
Methylation is a fundamental mechanism used in Nature to modify the structure and function of biomolecules, including proteins, DNA, RNA, and metabolites. Methyl groups are predominantly installed into biomolecules by a large and diverse class of S-adenosyl methionine (SAM)-dependent methyltransferases (MTs), of which there are ∼200 known or putative members in the human proteome. Deregulated MT activity contributes to numerous diseases, including cancer, and several MT inhibitors are in clinical development...
October 12, 2016: Journal of the American Chemical Society
Christian Lerner, Roland Jakob-Roetne, Bernd Buettelmann, Andreas Ehler, Markus Rudolph, Rosa María Rodríguez Sarmiento
A fragment screening approach designed to target specifically the S-adenosyl-l-methionine pocket of catechol O-methyl transferase allowed the identification of structurally related fragments of high ligand efficiency and with activity on the described orthogonal assays. By use of a reliable enzymatic assay together with X-ray crystallography as guidance, a series of fragment modifications revealed an SAR and, after several expansions, potent lead compounds could be obtained. For the first time nonphenolic and small low nanomolar potent, SAM competitive COMT inhibitors are reported...
October 14, 2016: Journal of Medicinal Chemistry
Chun-Min Shan, Jiyong Wang, Ke Xu, Huijie Chen, Jia-Xing Yue, Stuart Andrews, James J Moresco, John R Yates, Peter L Nagy, Liang Tong, Songtao Jia
Histone lysine-to-methionine (K-to-M) mutations are associated with multiple cancers, and they function in a dominant fashion to block the methylation of corresponding lysines on wild type histones. However, their mechanisms of function are controversial. Here we show that in fission yeast, introducing the K9M mutation into one of the three histone H3 genes dominantly blocks H3K9 methylation on wild type H3 across the genome. In addition, H3K9M enhances the interaction of histone H3 tail with the H3K9 methyltransferase Clr4 in a SAM (S-adenosyl-methionine)-dependent manner, and Clr4 is trapped at nucleation sites to prevent its spreading and the formation of large heterochromatin domains...
2016: ELife
Yao-Yu Hsieh, Hsiang-Ling Lo, Pei-Ming Yang
Enhancer of zeste homolog 2 (EZH2) has been emerged as novel anticancer target. Various EZH2 small-molecule inhibitors have been developed in recent years. A major class of EZH2 inhibitors are S-adenosyl-L-methionine (SAM)-competitive inhibitors, such as EPZ005687, EI1, GSK126, UNC1999 and GSK343. Autophagy, a physiological process of self-digestion, is involved in the turnover of proteins or intracellular organelles. It can serve as cytoprotective or cytotoxic function in cancer. Our previous study has found that UNC1999 and GSK343 are potent autophagy inducers...
2016: American Journal of Cancer Research
Edward A Lilla, Kenichi Yokoyama
Nikkomycins and polyoxins are antifungal peptidylnucleoside antibiotics active against human and plant pathogens. Here we report that during peptidylnucleoside biosynthesis in Streptomyces cacaoi and S. tendae, the C5' extension of the nucleoside essential for downstream structural diversification is catalyzed by a conserved radical S-adenosyl-L-methionine (SAM) enzyme, PolH or NikJ. This is distinct from the nucleophilic mechanism reported for antibacterial nucleosides and represents a new mechanism of nucleoside natural product biosynthesis...
November 2016: Nature Chemical Biology
Caiyan Wang, Qian Jia, Ran Chen, Yuming Wei, Juntao Li, Jie Ma, Wei Xie
tRNA methyltransferase Trm5 catalyses the transfer of a methyl group from S-adenosyl-L-methionine to G37 in eukaryotes and archaea. The N1-methylated guanosine is the product of the initial step of the wyosine hypermodification, which is essential for the maintenance of the reading frame during translation. As a unique member of this enzyme family, Trm5a from Pyrococcus abyssi (PaTrm5a) catalyses not only the methylation of N1, but also the further methylation of C7 on 4-demethylwyosine at position 37 to produce isowyosine, but the mechanism for the double methylation is poorly understood...
2016: Scientific Reports
Feng Yu, Minjun Li, Chunyan Xu, Bo Sun, Huan Zhou, Zhijun Wang, Qin Xu, Muyun Xie, Gang Zuo, Pei Huang, Haojie Guo, Qisheng Wang, Jianhua He
TleD is an S-adenosyl-L-methionine dependent methyltransferase and acts as one of the key enzymes in the teleocidin B biosynthesis pathway. Besides the methyl transferring, TleD also rearranges the geranyl and indole moiety of the precursor to form a six-membered ring. Moreover, it does not show homologies to any known terpenoid cyclases. In order to elucidate how such a remarkable reaction could be achieved, we determined the complex crystal structures of TleD and the cofactor analogue S-adenosyl-L-homocysteine with or without substrate teleocidin A1...
September 9, 2016: Biochemical Journal
Fumitaka Kudo, Takahiro Tokumitsu, Tadashi Eguchi
A radical S-adenosyl-l-methionine dehydratase AprD4 and an NADPH-dependent reductase AprD3 are responsible for the C3'-deoxygenation of pseudodisaccharide paromamine in the biosynthesis of apramycin. These enzymes are involved in the construction of the characteristic structural motif that is not modified by 3'-phosphotransferase in aminoglycoside-resistant bacterial strains. AprD4 catalyzes the C3'-dehydration of paromamine via a radical-mediated reaction mechanism to give 4'-oxolividamine, which is then reduced by AprD3 with NADPH to afford lividamine...
September 7, 2016: Journal of Antibiotics
Nataša Karas Kuželički
Preclinical Research S-adenosyl methionine (SAM) is a major methyl donor and as such exerts its influence on CNS function through methylation reactions, such as methylation of several catecholamine moiety-containing neurotransmitters, epigenetic changes through methylation of DNA, RNA, RNA-binding proteins and histones, and phospholipid methylation. Based on available evidence, SAM is currently recommended as a next-step (second-line) treatment option following inadequate treatment response to a first-line antidepressant...
September 4, 2016: Drug Development Research
Mingxing Wang, Yuwei Zhu, Chongyuan Wang, Xiaojiao Fan, Xuguang Jiang, Mohammad Ebrahimi, Zhi Qiao, Liwen Niu, Maikun Teng, Xu Li
The N(1) methylation of adenine at position 58 (m(1)A58) of tRNA is an important post-transcriptional modification, which is vital for maintaining the stability of the initiator methionine tRNAi(Met). In eukaryotes, this modification is performed by the TRM6-TRM61 holoenzyme. To understand the molecular mechanism that underlies the cooperation of TRM6 and TRM61 in the methyl transfer reaction, we determined the crystal structure of TRM6-TRM61 holoenzyme from Saccharomyces cerevisiae in the presence and absence of its methyl donor S-Adenosyl-L-methionine (SAM)...
2016: Scientific Reports
Xinjian Ji, Yongzhen Li, Liqi Xie, Haojie Lu, Wei Ding, Qi Zhang
Radical S-adenosyl-l-methionine (SAM) enzymes utilize a [4Fe-4S] cluster to bind SAM and reductively cleave its carbon-sulfur bond to produce a highly reactive 5'-deoxyadenosyl (dAdo) radical. In almost all cases, the dAdo radical abstracts a hydrogen atom from the substrates or from enzymes, thereby initiating a highly diverse array of reactions. Herein, we report a change of the dAdo radical-based chemistry from hydrogen abstraction to radical addition in the reaction of the radical SAM enzyme NosL. This change was achieved by using a substrate analogue containing an olefin moiety...
September 19, 2016: Angewandte Chemie
Thomas Christian, Reiko Sakaguchi, Agata P Perlinska, Georges Lahoud, Takuhiro Ito, Erika A Taylor, Shigeyuki Yokoyama, Joanna I Sulkowska, Ya-Ming Hou
Proteins with knotted configurations, in comparison with unknotted proteins, are restricted in conformational space. Little is known regarding whether knotted proteins have sufficient dynamics to communicate between spatially separated substrate-binding sites. TrmD is a bacterial methyltransferase that uses a knotted protein fold to catalyze methyl transfer from S-adenosyl methionine (AdoMet) to G37-tRNA. The product, m(1)G37-tRNA, is essential for life and maintains protein-synthesis reading frames. Using an integrated approach of structural, kinetic, and computational analysis, we show that the structurally constrained TrmD knot is required for its catalytic activity...
October 2016: Nature Structural & Molecular Biology
Matthijs J van Haren, Javier Sastre Toraño, Davide Sartini, Monica Emanuelli, Richard B Parsons, Nathaniel I Martin
Nicotinamide N-methyltransferase (NNMT) is one of the most abundant small molecule methyltransferases in the human body and is primarily responsible for the N-methylation of the nicotinamide (vitamin B3). Employing the cofactor S-adenosyl-l-methionine, NNMT transfers a methyl group to the pyridine nitrogen of nicotinamide to generate N-methylnicotinamide. Interestingly, NNMT is also able to N-methylate a variety of other pyridine-containing small molecules, suggesting a secondary role for the enzyme in the detoxification of xenobiotics...
September 20, 2016: Biochemistry
Kilmer S McCully
Hyperhomocysteinemia is a risk factor for development of dementia and Alzheimer's disease (AD), and low blood levels of folate and cobalamin are associated with hyperhomocysteinemia and AD. In elderly subjects with cognitive decline, supplementation with folate, cobalamin, and pyridoxal demonstrated reduction of cerebral atrophy in gray matter regions vulnerable to the AD process. Multiple pathogenic microbes are implicated as pathogenic factors in AD and atherosclerosis, and the deposition of amyloid-β (Aβ), phosphorylation of tau protein, neuronal injury, and apoptosis in AD are secondary to microbial infection...
August 10, 2016: Journal of Alzheimer's Disease: JAD
Madeline C Weiss, Filipa L Sousa, Natalia Mrnjavac, Sinje Neukirchen, Mayo Roettger, Shijulal Nelson-Sathi, William F Martin
The concept of a last universal common ancestor of all cells (LUCA, or the progenote) is central to the study of early evolution and life's origin, yet information about how and where LUCA lived is lacking. We investigated all clusters and phylogenetic trees for 6.1 million protein coding genes from sequenced prokaryotic genomes in order to reconstruct the microbial ecology of LUCA. Among 286,514 protein clusters, we identified 355 protein families (∼0.1%) that trace to LUCA by phylogenetic criteria. Because these proteins are not universally distributed, they can shed light on LUCA's physiology...
2016: Nature Microbiology
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