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[PMID]: 29307522 [Au] Autor: Riberio DF; Cella PS; da Silva LECM; Jordao AA; Deminice R [Ad] Endereço: Department of Physical Education, State University of Londrina, Londrina, PR, Brazil. [Ti] Título: Acute exercise alters homocysteine plasma concentration in an intensity-dependent manner due increased methyl flux in liver of rats. [So] Source: Life Sci;196:63-68, 2018 Mar 01. [Is] ISSN: 1879-0631 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: PURPOSE: We aimed to determine the effects of different intensities of acute exercise on Hcy plasma levels, and the exercise-induced changes in Hcy liver metabolism. METHOD: First, thirty-two Wistar rats were randomly submitted to an acute bout of swimming exercise carrying a load of 2% (n=8), 4% (n=8) and 6% (n=8) of their total body weight attached in their tail. Control rats remained rested (n=8). Blood samples were taken from tail vein for plasma S-containing amino acids determination before (Rest) and post, 1, 2, 3, 4, 6, and 10h after acute swimming exercise. Second, 56 exercised rats (4% loads) were euthanized before (Rest) and1, 2, 3, 4, 6, and 10h after acute swimming exercise. Blood and liver samples were collected for amino acids and keys genes involved in the Hcy metabolism assay. RESULTS: Acute exercise increases (P<0.05) plasma Hcy concentration in an intensity-dependent manner (rest 7.7±0.8; 6% load 13.8±3.6; 4% load 12.2±2.9±and 2% load 10.1±2.6, µmol/L); this increase is transient and does not promote hyperhomocysteinemia (<15µmol/L).Exercise-induced increased plasma Hcywas accompanied by the decreased liver S-adenosylmethionine/S-adenosylhomocysteine ratio and elevated MAT1a mRNA content. Acute exercise also caused elevated mRNA of key enzymes of transsulfuration (CBS) and remethylation (BHMT and the MTRR). CONCLUSION: Our data provided evidence that acute exercise increases plasma Hcy concentration due to the augmented requirement for methylated compounds that increases liver SAM consumption. Also, Hcy remethylation and transsulfuration are coordinately regulated to maintain methyl balance. [Mh] Termos MeSH primário: Homocisteína/sangue Fígado/metabolismo Condicionamento Físico Animal/fisiologia [Mh] Termos MeSH secundário: Animais Peso Corporal/efeitos dos fármacos Hiper-Homocisteinemia/metabolismo Masculino Metionina Adenosiltransferase/metabolismo Metilação Ratos Ratos Wistar S-Adenosil-Homocisteína/metabolismo S-Adenosilmetionina/metabolismo Natação/fisiologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0LVT1QZ0BA (Homocysteine); 7LP2MPO46S (S-Adenosylmethionine); 979-92-0 (S-Adenosylhomocysteine); EC 2.5.1.6 (Mat1a protein, rat); EC 2.5.1.6 (Methionine Adenosyltransferase) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180226 [Lr] Data última revisão: 180226 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180109 [St] Status: MEDLINE

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[PMID]: 29372684 [Au] Autor: Murín R; Vidomanová E; Kowtharapu BS; Hatok J; Dobrota D [Ad] Endereço: Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia. murin@jfmed.uniba.sk. [Ti] Título: Role of S-adenosylmethionine cycle in carcinogenesis. [So] Source: Gen Physiol Biophys;36(5):513-520, 2017 Dec. [Is] ISSN: 0231-5882 [Cp] País de publicação: Slovakia [La] Idioma: eng [Ab] Resumo: Alterations in enzymatic activities underlying the cellular capacity to maintain functional S-adenosylmethionine (SAM) cycle are associated with modified levels of its constituents. Since SAM is the most prominent donor of methyl group for sustaining the methylation pattern of macromolecules by methyltransferases, its availability is an essential prerequisite for sustaining the methylation pattern of nucleic acids and proteins. In addition, increased intracellular concentrations of S-adenosylhomocysteine and homocysteine, another two constituents of SAM cycle, exerts an inhibitory effect on the enzymatic activity of methyltranferases. While methylation pattern of DNA and histones is considered as an important regulatory hallmark in epigenetically regulated gene expression, amended methylation of several cellular proteins, including transcription factors, affects their activity and stability. Indeed, varied DNA methylome is a common consequence of disturbed SAM cycle and is linked with molecular changes underlying the transformation of the cells that may underlay the carcinogenesis. Here we summarize the recent evidences about the impact of disturbed SAM cycle on carcinogenesis. [Mh] Termos MeSH primário: Carcinogênese/genética Carcinogênese/metabolismo DNA de Neoplasias/genética Epigênese Genética/genética Neoplasias/genética Neoplasias/metabolismo S-Adenosilmetionina/metabolismo [Mh] Termos MeSH secundário: Animais Metilação de DNA/genética Regulação Neoplásica da Expressão Gênica/genética Seres Humanos Modelos Genéticos Transdução de Sinais/genética [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (DNA, Neoplasm); 7LP2MPO46S (S-Adenosylmethionine) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180223 [Lr] Data última revisão: 180223 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180127 [St] Status: MEDLINE [do] DOI: 10.4149/gpb_2017031

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[PMID]: 29305263 [Au] Autor: Cao D; Cui J; Cao D; Guo C; Min G; Liu M; Li L [Ad] Endereço: Department of Pathology, Capital Medical University, Beijing 100069, China. [Ti] Título: S-adenosylmethionine reduces the inhibitory effect of Aß on BDNF expression through decreasing methylation level of BDNF exon â…£ in rats. [So] Source: Biochem Biophys Res Commun;495(4):2609-2615, 2018 01 22. [Is] ISSN: 1090-2104 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The structure of brain-derived neurotrophic factor (BDNF) gene is complex, which is composed of eight non-coding exons and one coding exon, each of them has its own unique promoter. Multiple BDNF transcripts have distinct functional properties and epigenetic modulation of BDNF gene transcription is implicated in the neurological disorders. In the present study, rat models with amyloid-ß (Aß) intrahippocampal injection and PC12 cells were used to explore the role of DNA methylation in the promoters of BDNF exon â…£ and exon â…¥ in BDNF suppression caused by Aß. We found that Aß inhibited BDNF expression accompanying with hypermethylation in BDNF exon â…£ promoter, meanwhile, S-adenosylmethionine (SAM), primary methyl donor, reversed the low BDNF expression through demethylation in BDNF exon â…£ promoter. No methylation change was observed in BDNF exon â…¥ promoter. The alteration of DNA methylation caused by Aß or SAM was mediated by DNA methyltransferase 3A (DNMT3A). These data suggest that methylation change in BDNF exon â…£ is involved in the regulation of BDNF expression by Aß or SAM, and further support the view of specific epigenetic modifications of a certain BDNF gene transcript. [Mh] Termos MeSH primário: Peptídeos beta-Amiloides/metabolismo Fator Neurotrófico Derivado do Encéfalo/genética Fator Neurotrófico Derivado do Encéfalo/metabolismo Éxons/genética Hipocampo/metabolismo S-Adenosilmetionina/metabolismo [Mh] Termos MeSH secundário: Peptídeos beta-Amiloides/genética Animais Metilação de DNA/genética Regulação da Expressão Gênica/genética Masculino Ratos Ratos Sprague-Dawley [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Amyloid beta-Peptides); 0 (Brain-Derived Neurotrophic Factor); 7LP2MPO46S (S-Adenosylmethionine) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180222 [Lr] Data última revisão: 180222 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180107 [St] Status: MEDLINE

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[PMID]: 29199993 [Au] Autor: Pampa KJ; Madan Kumar S; Hema MK; Kumara K; Naveen S; Kunishima N; Lokanath NK [Ad] Endereço: Department of Studies in Biotechnology, University of Mysore, Manasagangotri, Mysuru, Karnataka 570 006, India. [Ti] Título: Crystal structure of SAM-dependent methyltransferase from Pyrococcus horikoshii. [So] Source: Acta Crystallogr F Struct Biol Commun;73(Pt 12):706-712, 2017 Dec 01. [Is] ISSN: 2053-230X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Methyltransferases (MTs) are enzymes involved in methylation that are needed to perform cellular processes such as biosynthesis, metabolism, gene expression, protein trafficking and signal transduction. The cofactor S-adenosyl-L-methionine (SAM) is used for catalysis by SAM-dependent methyltransferases (SAM-MTs). The crystal structure of Pyrococcus horikoshii SAM-MT was determined to a resolution of 2.1 Šusing X-ray diffraction. The monomeric structure consists of a Rossmann-like fold (domain I) and a substrate-binding domain (domain II). The cofactor (SAM) molecule binds at the interface between adjacent subunits, presumably near to the active site(s) of the enzyme. The observed dimeric state might be important for the catalytic function of the enzyme. [Mh] Termos MeSH primário: Metiltransferases/química Metiltransferases/metabolismo Pyrococcus horikoshii/enzimologia S-Adenosilmetionina/metabolismo [Mh] Termos MeSH secundário: Proteínas Arqueais/química Proteínas Arqueais/metabolismo Sítios de Ligação Cristalografia por Raios X Modelos Moleculares Conformação Proteica Domínios Proteicos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Archaeal Proteins); 7LP2MPO46S (S-Adenosylmethionine); EC 2.1.1.- (Methyltransferases) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180222 [Lr] Data última revisão: 180222 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171205 [St] Status: MEDLINE [do] DOI: 10.1107/S2053230X17016648

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[PMID]: 28747433 [Au] Autor: Blaszczyk AJ; Wang B; Silakov A; Ho JV; Booker SJ [Ad] Endereço: From the Department of Biochemistry and Molecular Biology. [Ti] Título: Efficient methylation of C2 in l-tryptophan by the cobalamin-dependent radical -adenosylmethionine methylase TsrM requires an unmodified N1 amine. [So] Source: J Biol Chem;292(37):15456-15467, 2017 09 15. [Is] ISSN: 1083-351X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: TsrM catalyzes the methylation of C2 in l-tryptophan (Trp). This reaction is the first step in the biosynthesis of the quinaldic acid moiety of the thiopeptide antibiotic thiostrepton, which exhibits potent activity against Gram-positive pathogens. TsrM is a member of the radical -adenosylmethionine (SAM) superfamily of enzymes, but it does not catalyze the formation of 5'-deoxyadenosin-5'-yl or any other SAM-derived radical. In addition to a [4Fe-4S] cluster, TsrM contains a cobalamin cofactor that serves as an intermediate methyl carrier in its reaction. However, how this cofactor donates a methyl moiety to the Trp substrate is unknown. Here, we showed that the unmodified N1 position of Trp is important for turnover and that 1-thia-Trp and 1-oxa-Trp serve as competitive inhibitors. We also showed that ß-cyclopropyl-Trp undergoes C2 methylation in the absence of cyclopropyl ring opening, disfavoring mechanisms that involve unpaired electron density at C3 of the indole ring. Moreover, we showed that all other indole-substituted analogs of Trp undergo methylation at varying but measurable rates and that the analog 7-aza-Trp, which is expected to temper the nucleophilicity of C2 in Trp, is a very poor substrate. Last, no formation of cob(II)alamin or substrate radicals was observed during the reaction with Trp or any molecule within a tested panel of Trp analogs. In summary, our results are most consistent with a mechanism that involves two polar nucleophilic displacements, the second of which requires deprotonation of the indole nitrogen in Trp during its attack on methylcobalamin. [Mh] Termos MeSH primário: Proteínas de Bactérias/metabolismo Metiltransferases/metabolismo S-Adenosilmetionina/metabolismo Staphylococcus/enzimologia Triptofano/metabolismo Vitamina B 12/química [Mh] Termos MeSH secundário: Proteínas de Bactérias/antagonistas & inibidores Proteínas de Bactérias/química Proteínas de Bactérias/genética Biocatálise Espectroscopia de Ressonância de Spin Eletrônica Inibidores Enzimáticos/síntese química Inibidores Enzimáticos/química Inibidores Enzimáticos/farmacologia Estabilidade Enzimática/efeitos dos fármacos Cinética Metilação/efeitos dos fármacos Metiltransferases/antagonistas & inibidores Metiltransferases/química Metiltransferases/genética Estrutura Molecular Proteínas Recombinantes de Fusão/química Proteínas Recombinantes de Fusão/metabolismo Proteínas Recombinantes/química Proteínas Recombinantes/metabolismo S-Adenosilmetionina/química Espectrofotometria Especificidade por Substrato Tioestreptona/biossíntese Triptofano/análogos & derivados Triptofano/química [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Bacterial Proteins); 0 (Enzyme Inhibitors); 0 (Recombinant Fusion Proteins); 0 (Recombinant Proteins); 7LP2MPO46S (S-Adenosylmethionine); 8DUH1N11BX (Tryptophan); EC 2.1.1.- (Methyltransferases); EC 2.1.1.230 (rRNA (adenosine-O-2'-)methyltransferase); HR4S203Y18 (Thiostrepton); P6YC3EG204 (Vitamin B 12) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 171230 [Lr] Data última revisão: 171230 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170728 [St] Status: MEDLINE [do] DOI: 10.1074/jbc.M117.778548

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[PMID]: 29021282 [Au] Autor: Tang S; Fang Y; Huang G; Xu X; Padilla-Banks E; Fan W; Xu Q; Sanderson SM; Foley JF; Dowdy S; McBurney MW; Fargo DC; Williams CJ; Locasale JW; Guan Z; Li X [Ad] Endereço: Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. [Ti] Título: Methionine metabolism is essential for SIRT1-regulated mouse embryonic stem cell maintenance and embryonic development. [So] Source: EMBO J;36(21):3175-3193, 2017 Nov 02. [Is] ISSN: 1460-2075 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Methionine metabolism is critical for epigenetic maintenance, redox homeostasis, and animal development. However, the regulation of methionine metabolism remains unclear. Here, we provide evidence that SIRT1, the most conserved mammalian NAD -dependent protein deacetylase, is critically involved in modulating methionine metabolism, thereby impacting maintenance of mouse embryonic stem cells (mESCs) and subsequent embryogenesis. We demonstrate that SIRT1-deficient mESCs are hypersensitive to methionine restriction/depletion-induced differentiation and apoptosis, primarily due to a reduced conversion of methionine to S-adenosylmethionine. This reduction markedly decreases methylation levels of histones, resulting in dramatic alterations in gene expression profiles. Mechanistically, we discover that the enzyme converting methionine to S-adenosylmethionine in mESCs, methionine adenosyltransferase 2a (MAT2a), is under control of Myc and SIRT1. Consistently, SIRT1 KO embryos display reduced expression and histone methylation and are sensitive to maternal methionine restriction-induced lethality, whereas maternal methionine supplementation increases the survival of SIRT1 KO newborn mice. Our findings uncover a novel regulatory mechanism for methionine metabolism and highlight the importance of methionine metabolism in SIRT1-mediated mESC maintenance and embryonic development. [Mh] Termos MeSH primário: Desenvolvimento Embrionário/genética Epigênese Genética Metionina Adenosiltransferase/genética Metionina/metabolismo Células-Tronco Embrionárias Murinas/metabolismo Sirtuína 1/genética [Mh] Termos MeSH secundário: Acetilação Animais Apoptose Diferenciação Celular Embrião de Mamíferos Histonas/genética Histonas/metabolismo Metabolômica Metionina/administração & dosagem Metionina Adenosiltransferase/metabolismo Metilação Camundongos Camundongos Endogâmicos C57BL Camundongos Knockout Análise em Microsséries Células-Tronco Embrionárias Murinas/citologia Proteínas Proto-Oncogênicas c-myc/genética Proteínas Proto-Oncogênicas c-myc/metabolismo S-Adenosilmetionina/metabolismo Sirtuína 1/deficiência [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Histones); 0 (Myc protein, mouse); 0 (Proto-Oncogene Proteins c-myc); 7LP2MPO46S (S-Adenosylmethionine); AE28F7PNPL (Methionine); EC 2.5.1.6 (Methionine Adenosyltransferase); EC 3.5.1.- (Sirt1 protein, mouse); EC 3.5.1.- (Sirtuin 1) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171110 [Lr] Data última revisão: 171110 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171013 [St] Status: MEDLINE [do] DOI: 10.15252/embj.201796708

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[PMID]: 28927791 [Au] Autor: Yang H; Ouyang Y; Ma H; Cong H; Zhuang C; Lok WT; Wang Z; Zhu X; Sun Y; Hong W; Wang H [Ad] Endereço: School of Pharmacy, Ningxia Medical University, Yinchuan 750004, PR China. [Ti] Título: Design and synthesis of novel PRMT1 inhibitors and investigation of their binding preferences using molecular modelling. [So] Source: Bioorg Med Chem Lett;27(20):4635-4642, 2017 10 15. [Is] ISSN: 1464-3405 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Protein arginine methyltransferase 1 (PRMT1) catalyses the methylation of substrate arginine by transferring the methyl group from SAM (S-adenosyl-l-methionine), which leads to the formation of S-adenosyl homocysteine (SAH) and methylated arginine. We have shown previously that the Asp84 on PRMT1 could be a potential inhibitor binding site. In the current study, 28 compounds were designed and synthesized that were predicted to bind the Asp84 and substrate arginine sites together. Among them, 6 compounds were identified as potential PRMT1 inhibitors, and showed strong inhibitory effects on cancer cell lines, especially HepG2. The most potent PRMT1 inhibitor, compound 13d, was selected for molecular dynamic simulations to investigate binding poses. Based on the free energy calculations and structural analysis, we predicted that the ethylenediamine group would tightly bind to Asp84, and the trifluoromethyl group should occupy part of substrate arginine binding site, which is consistent with our original goal. Our results show for the first time that PRMT1 inhibitors can target the Asp84 binding site, which will be helpful for future drug discovery studies. [Mh] Termos MeSH primário: Desenho de Drogas Inibidores Enzimáticos/síntese química Proteína-Arginina N-Metiltransferases/antagonistas & inibidores Proteínas Repressoras/antagonistas & inibidores [Mh] Termos MeSH secundário: Antineoplásicos/síntese química Antineoplásicos/química Antineoplásicos/farmacologia Sítios de Ligação Domínio Catalítico Linhagem Celular Tumoral Sobrevivência Celular/efeitos dos fármacos Inibidores Enzimáticos/química Inibidores Enzimáticos/farmacologia Células Hep G2 Seres Humanos Simulação de Dinâmica Molecular Proteína-Arginina N-Metiltransferases/metabolismo Proteínas Repressoras/metabolismo S-Adenosilmetionina/metabolismo Relação Estrutura-Atividade Termodinâmica [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Enzyme Inhibitors); 0 (Repressor Proteins); 7LP2MPO46S (S-Adenosylmethionine); EC 2.1.1.319 (PRMT1 protein, human); EC 2.1.1.319 (Protein-Arginine N-Methyltransferases) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171125 [Lr] Data última revisão: 171125 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170921 [St] Status: MEDLINE

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[PMID]: 28920931 [Au] Autor: Manz C; Kobitski AY; Samanta A; Keller BG; Jäschke A; Nienhaus GU [Ad] Endereço: Institute of Applied Physics, Karlsruhe Institute of Technology, Karlsruhe, Germany. [Ti] Título: Single-molecule FRET reveals the energy landscape of the full-length SAM-I riboswitch. [So] Source: Nat Chem Biol;13(11):1172-1178, 2017 Nov. [Is] ISSN: 1552-4469 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: S-adenosyl-L-methionine (SAM) ligand binding induces major structural changes in SAM-I riboswitches, through which gene expression is regulated via transcription termination. Little is known about the conformations and motions governing the function of the full-length Bacillus subtilis yitJ SAM-I riboswitch. Therefore, we have explored its conformational energy landscape as a function of Mg and SAM ligand concentrations using single-molecule Förster resonance energy transfer (smFRET) microscopy and hidden Markov modeling analysis. We resolved four conformational states both in the presence and the absence of SAM and determined their Mg -dependent fractional populations and conformational dynamics, including state lifetimes, interconversion rate coefficients and equilibration timescales. Riboswitches with terminator and antiterminator folds coexist, and SAM binding only gradually shifts the populations toward terminator states. We observed a pronounced acceleration of conformational transitions upon SAM binding, which may be crucial for off-switching during the brief decision window before expression of the downstream gene. [Mh] Termos MeSH primário: Bacillus subtilis/metabolismo Transferência Ressonante de Energia de Fluorescência/métodos Conformação de Ácido Nucleico RNA Bacteriano/química Riboswitch [Mh] Termos MeSH secundário: Bacillus subtilis/química Ligantes Magnésio/química Magnésio/metabolismo Modelos Moleculares S-Adenosilmetionina/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Ligands); 0 (RNA, Bacterial); 0 (Riboswitch); 7LP2MPO46S (S-Adenosylmethionine); I38ZP9992A (Magnesium) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171026 [Lr] Data última revisão: 171026 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170919 [St] Status: MEDLINE [do] DOI: 10.1038/nchembio.2476

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[PMID]: 28911116 [Au] Autor: Krishnamohan A; Jackman JE [Ad] Endereço: The Ohio State Biochemistry Program, Center for RNA Biology, and Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA. [Ti] Título: Mechanistic features of the atypical tRNA m1G9 SPOUT methyltransferase, Trm10. [So] Source: Nucleic Acids Res;45(15):9019-9029, 2017 Sep 06. [Is] ISSN: 1362-4962 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The tRNA m1G9 methyltransferase (Trm10) is a member of the SpoU-TrmD (SPOUT) superfamily of methyltransferases, and Trm10 homologs are widely conserved throughout Eukarya and Archaea. Despite possessing the trefoil knot characteristic of SPOUT enzymes, Trm10 does not share the same quaternary structure or key sequences with other members of the SPOUT family, suggesting a novel mechanism of catalysis. To investigate the mechanism of m1G9 methylation by Trm10, we performed a biochemical and kinetic analysis of Trm10 and variants with alterations in highly conserved residues, using crystal structures solved in the absence of tRNA as a guide. Here we demonstrate that a previously proposed general base residue (D210 in Saccharomyces cerevisiae Trm10) is not likely to play this suggested role in the chemistry of methylation. Instead, pH-rate analysis suggests that D210 and other conserved carboxylate-containing residues at the active site collaborate to establish an active site environment that promotes a single ionization that is required for catalysis. Moreover, Trm10 does not depend on a catalytic metal ion, further distinguishing it from the other known SPOUT m1G methyltransferase, TrmD. These results provide evidence for a non-canonical tRNA methyltransferase mechanism that characterizes the Trm10 enzyme family. [Mh] Termos MeSH primário: Ácido Aspártico/química RNA de Transferência/química S-Adenosilmetionina/química Proteínas de Saccharomyces cerevisiae/química Saccharomyces cerevisiae/enzimologia tRNA Metiltransferases/química [Mh] Termos MeSH secundário: Sequência de Aminoácidos Ácido Aspártico/metabolismo Sítios de Ligação Biocatálise Domínio Catalítico Clonagem Molecular Cristalografia por Raios X Escherichia coli/genética Escherichia coli/metabolismo Expressão Gênica Concentração de Íons de Hidrogênio Isoenzimas/química Isoenzimas/genética Isoenzimas/metabolismo Cinética Metilação Modelos Moleculares Ligação Proteica Conformação Proteica em alfa-Hélice Domínios e Motivos de Interação entre Proteínas RNA de Transferência/metabolismo Proteínas Recombinantes/química Proteínas Recombinantes/genética Proteínas Recombinantes/metabolismo S-Adenosil-Homocisteína/química S-Adenosil-Homocisteína/metabolismo S-Adenosilmetionina/metabolismo Saccharomyces cerevisiae/genética Proteínas de Saccharomyces cerevisiae/genética Proteínas de Saccharomyces cerevisiae/metabolismo Alinhamento de Sequência Homologia de Sequência de Aminoácidos Especificidade por Substrato tRNA Metiltransferases/genética tRNA Metiltransferases/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Isoenzymes); 0 (Recombinant Proteins); 0 (Saccharomyces cerevisiae Proteins); 30KYC7MIAI (Aspartic Acid); 7LP2MPO46S (S-Adenosylmethionine); 9014-25-9 (RNA, Transfer); 979-92-0 (S-Adenosylhomocysteine); EC 2.1.1.- (TRM10 protein, S cerevisiae); EC 2.1.1.- (tRNA Methyltransferases) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171114 [Lr] Data última revisão: 171114 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170916 [St] Status: MEDLINE [do] DOI: 10.1093/nar/gkx620

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[PMID]: 28895719 [Au] Autor: Mahanta N; Hudson GA; Mitchell DA [Ad] Endereço: Department of Chemistry, University of Illinois at Urbana-Champaign , 600 South Mathews Avenue, Urbana, Illinois 61801, United States. [Ti] Título: Radical S-Adenosylmethionine Enzymes Involved in RiPP Biosynthesis. [So] Source: Biochemistry;56(40):5229-5244, 2017 Oct 10. [Is] ISSN: 1520-4995 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Ribosomally synthesized and post-translationally modified peptides (RiPPs) display a diverse range of structures and continue to expand as a natural product class. Accordingly, RiPPs exhibit a wide array of bioactivities, acting as broad and narrow spectrum growth suppressors, antidiabetics, and antinociception and anticancer agents. Because of these properties, and the complex repertoire of post-translational modifications (PTMs) that give rise to these molecules, RiPP biosynthesis has been intensely studied. RiPP biosynthesis often involves enzymes that perform unique chemistry with intriguing reaction mechanisms, which attract chemists and biochemists alike to study and re-engineer these pathways. One particular type of RiPP biosynthetic enzyme is the so-called radical S-adenosylmethionine (rSAM) enzyme, which utilizes radical-based chemistry to install several distinct PTMs. Here, we describe the rSAM enzymes characterized over the past decade that catalyze six reaction types from several RiPP biosynthetic pathways. We present the current state of mechanistic understanding and conclude with possible directions for future characterization of this enzyme family. [Mh] Termos MeSH primário: Biocatálise Enzimas/metabolismo Peptídeos/metabolismo Processamento de Proteína Pós-Traducional S-Adenosilmetionina/metabolismo [Mh] Termos MeSH secundário: Sequência de Aminoácidos Seres Humanos Peptídeos/química [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Enzymes); 0 (Peptides); 7LP2MPO46S (S-Adenosylmethionine) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171019 [Lr] Data última revisão: 171019 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170913 [St] Status: MEDLINE [do] DOI: 10.1021/acs.biochem.7b00771

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