{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T02:34:49Z","timestamp":1790390089436,"version":"4.1.0"},"reference-count":45,"publisher":"Portland Press Ltd.","issue":"1","license":[{"start":{"date-parts":[[2019,7,25]],"date-time":"2019-07-25T00:00:00Z","timestamp":1564012800000},"content-version":"vor","delay-in-days":2282,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,5,15]]},"abstract":"<jats:p>MAT (methionine adenosyltransferase) utilizes L-methionine and ATP to form SAM (S-adenosylmethionine), the principal methyl donor in biological methylation. Mammals encode a liver-specific isoenzyme, MAT1A, that is genetically linked with an inborn metabolic disorder of hypermethioninaemia, as well as a ubiquitously expressed isoenzyme, MAT2A, whose enzymatic activity is regulated by an associated subunit MAT2B. To understand the molecular mechanism of MAT functions and interactions, we have crystallized the ligand-bound complexes of human MAT1A, MAT2A and MAT2B. The structures of MAT1A and MAT2A in binary complexes with their product SAM allow for a comparison with the Escherichia coli and rat structures. This facilitates the understanding of the different substrate or product conformations, mediated by the neighbouring gating loop, which can be accommodated by the compact active site during catalysis. The structure of MAT2B reveals an SDR (short-chain dehydrogenase\/reductase) core with specificity for the NADP\/H cofactor, and harbours the SDR catalytic triad (YxxxKS). Extended from the MAT2B core is a second domain with homology with an SDR sub-family that binds nucleotide-sugar substrates, although the equivalent region in MAT2B presents a more open and extended surface which may endow a different ligand\/protein-binding capability. Together, the results of the present study provide a framework to assign structural features to the functional and catalytic properties of the human MAT proteins, and facilitate future studies to probe new catalytic and binding functions.<\/jats:p>","DOI":"10.1042\/bj20121580","type":"journal-article","created":{"date-parts":[[2013,2,21]],"date-time":"2013-02-21T09:49:28Z","timestamp":1361440168000},"page":"27-36","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["Insight into <i>S<\/i>-adenosylmethionine biosynthesis from the crystal structures of the human methionine adenosyltransferase catalytic and regulatory subunits"],"prefix":"10.1042","volume":"452","author":[{"given":"Naeem","family":"Shafqat","sequence":"first","affiliation":[{"name":"Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joao\u00a0R. 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Gastroenterol. Hepatol."},{"key":"2021112215383880800_B2","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0163-7258(96)00197-0","article-title":"S-adenosylmethionine synthesis: molecular mechanisms and clinical implications","volume":"73","author":"Mato","year":"1997","journal-title":"Pharmacol. Ther."},{"key":"2021112215383880800_B3","doi-asserted-by":"crossref","first-page":"5609","DOI":"10.1016\/S0021-9258(18)45617-7","article-title":"A kinetic isotope effect study and transition state analysis of the S-adenosylmethionine synthetase reaction","volume":"262","author":"Markham","year":"1987","journal-title":"J. Biol. Chem."},{"key":"2021112215383880800_B4","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/0955-2863(90)90070-2","article-title":"Methionine metabolism in mammals","volume":"1","author":"Finkelstein","year":"1990","journal-title":"J. Nutr. Biochem."},{"key":"2021112215383880800_B5","first-page":"1444","article-title":"Differential expression of methionine adenosyltransferase genes influences the rate of growth of human hepatocellular carcinoma cells","volume":"58","author":"Cai","year":"1998","journal-title":"Cancer Res."},{"key":"2021112215383880800_B6","doi-asserted-by":"crossref","first-page":"2359","DOI":"10.1074\/jbc.275.4.2359","article-title":"Cloning, expression, and functional characterization of the \u03b2 regulatory subunit of human methionine adenosyltransferase (MAT II)","volume":"275","author":"LeGros","year":"2000","journal-title":"J. Biol. Chem."},{"key":"2021112215383880800_B7","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1007\/978-1-4615-5871-2_46","article-title":"Structure\u2013function relationships of SDR hydroxysteroid dehydrogenases","volume":"414","author":"Oppermann","year":"1997","journal-title":"Adv. Exp. Med. Biol."},{"key":"2021112215383880800_B8","doi-asserted-by":"crossref","first-page":"29720","DOI":"10.1074\/jbc.274.42.29720","article-title":"Expression and functional interaction of the catalytic and regulatory subunits of human methionine adenosyltransferase in mammalian cells","volume":"274","author":"Halim","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2021112215383880800_B9","doi-asserted-by":"crossref","first-page":"20015","DOI":"10.1074\/jbc.M109.094821","article-title":"Novel function and intracellular localization of methionine adenosyltransferase 2\u03b2 splicing variants","volume":"285","author":"Xia","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2021112215383880800_B10","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.molcel.2011.02.018","article-title":"Methionine adenosyltransferase II serves as a transcriptional corepressor of Maf oncoprotein","volume":"41","author":"Katoh","year":"2011","journal-title":"Mol. 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Gastroenterol."},{"key":"2021112215383880800_B17","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1021\/bi035611t","article-title":"Crystal structure of the S-adenosylmethionine synthetase ternary complex: a novel catalytic mechanism of S-adenosylmethionine synthesis from ATP and Met","volume":"43","author":"Komoto","year":"2004","journal-title":"Biochemistry"},{"key":"2021112215383880800_B18","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/S0022-2836(03)00728-9","article-title":"Crystal structures of methionine adenosyltransferase complexed with substrates and products reveal the methionine-ATP recognition and give insights into the catalytic mechanism","volume":"331","author":"Gonzalez","year":"2003","journal-title":"J. Mol. 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Crystallogr."},{"key":"2021112215383880800_B22","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1107\/S0907444996012255","article-title":"Refinement of macromolecular structures by the maximum-likelihood method","volume":"53","author":"Murshudov","year":"1997","journal-title":"Acta Crystallogr. D: Biol. Crystallogr."},{"key":"2021112215383880800_B23","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1107\/S0907444994003112","article-title":"The CCP4 suite: programs for protein crystallography","volume":"50","author":"Collaborative Computational Project, Number 4","year":"1994","journal-title":"Acta Crystallogr. D: Biol. Crystallogr."},{"key":"2021112215383880800_B24","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1107\/S0108767307043930","article-title":"A short history of SHELX","volume":"64","author":"Sheldrick","year":"2008","journal-title":"Acta Crystallogr., Sect. A: Found. Crystallogr."},{"key":"2021112215383880800_B25","first-page":"215","article-title":"Automated structure solution with autoSHARP","volume":"364","author":"Vonrhein","year":"2007","journal-title":"Methods Mol. Biol."},{"key":"2021112215383880800_B26","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/8263","article-title":"Automated protein model building combined with iterative structure refinement","volume":"6","author":"Perrakis","year":"1999","journal-title":"Nat. Struct. Biol."},{"key":"2021112215383880800_B27"},{"key":"2021112215383880800_B28","doi-asserted-by":"crossref","first-page":"2212","DOI":"10.1038\/nprot.2007.321","article-title":"The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability","volume":"2","author":"Niesen","year":"2007","journal-title":"Nat. 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Invest."},{"key":"2021112215383880800_B35","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1007\/s10545-005-4497-5","article-title":"Methionine adenosyltransferase (MAT) I\/III deficiency with concurrent hyperhomocysteinaemia: two novel cases","volume":"28","author":"Linnebank","year":"2005","journal-title":"J. Inherit. Metab. Dis."},{"key":"2021112215383880800_B36","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1038\/nmeth1118","article-title":"In situ proteolysis for protein crystallization and structure determination","volume":"4","author":"Dong","year":"2007","journal-title":"Nat. Methods"},{"key":"2021112215383880800_B37","doi-asserted-by":"crossref","first-page":"15835","DOI":"10.1073\/pnas.0605224103","article-title":"Chemical screening methods to identify ligands that promote protein stability, protein crystallization, and structure determination","volume":"103","author":"Vedadi","year":"2006","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021112215383880800_B38","doi-asserted-by":"crossref","DOI":"10.1002\/0471250953.bi0505s14","article-title":"Using Dali for structural comparison of proteins","volume-title":"Current Protocols in Bioinformatics","author":"Holm","year":"2006"},{"key":"2021112215383880800_B39","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/S0969-2126(02)00770-0","article-title":"Variation on a theme of SDR. dTDP-6-deoxy-L-lyxo-4-hexulose reductase (RmlD) shows a new Mg2+-dependent dimerization mode","volume":"10","author":"Blankenfeldt","year":"2002","journal-title":"Structure"},{"key":"2021112215383880800_B40","doi-asserted-by":"crossref","first-page":"15131","DOI":"10.1074\/jbc.M100220200","article-title":"Human UDP-galactose 4-epimerase. Accommodation of UDP-N-acetylglucosamine within the active site","volume":"276","author":"Thoden","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2021112215383880800_B41","doi-asserted-by":"crossref","first-page":"15578","DOI":"10.1021\/bi0266683","article-title":"Structure of the MUR1 GDP-mannose 4,6-dehydratase from Arabidopsis thaliana: implications for ligand binding and specificity","volume":"41","author":"Mulichak","year":"2002","journal-title":"Biochemistry"},{"key":"2021112215383880800_B42","doi-asserted-by":"crossref","first-page":"32107","DOI":"10.1074\/jbc.M304104200","article-title":"The negative transcriptional regulator NmrA discriminates between oxidized and reduced dinucleotides","volume":"278","author":"Lamb","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021112215383880800_B43","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/nsmb924","article-title":"CtBP represses p300-mediated transcriptional activation by direct association with its bromodomain","volume":"12","author":"Kim","year":"2005","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2021112215383880800_B44","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.jmb.2008.05.077","article-title":"Structural analysis of the recognition of the negative regulator NmrA and DNA by the zinc finger from the GATA-type transcription factor AreA","volume":"381","author":"Kotaka","year":"2008","journal-title":"J. Mol. Biol."},{"key":"2021112215383880800_B45","doi-asserted-by":"crossref","first-page":"11004","DOI":"10.1074\/jbc.M708697200","article-title":"An NADPH sensor protein (HSCARG) down-regulates nitric oxide synthesis by association with argininosuccinate synthetase and is essential for epithelial cell viability","volume":"283","author":"Zhao","year":"2008","journal-title":"J. Biol. 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