title: Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes.
abstract: The principal methyl donor of the cell, S-adenosylmethionine (SAMe), is produced by the highly conserved family of methionine adenosyltranferases (MATs) via an ATP-driven process. These enzymes play an important role in the preservation of life, and their dysregulation has been tightly linked to liver and colon cancers. We present crystal structures of human MATα2 containing various bound ligands, providing a "structural movie" of the catalytic steps. High- to atomic-resolution structures reveal the structural elements of the enzyme involved in utilization of the substrates methionine and adenosine and in formation of the product SAMe. MAT enzymes are also able to produce S-adenosylethionine (SAE) from substrate ethionine. Ethionine, an S-ethyl analog of the amino acid methionine, is known to induce steatosis and pancreatitis. We show that SAE occupies the active site in a manner similar to SAMe, confirming that ethionine also uses the same catalytic site to form the product SAE.
authors: Molecular Biophysics Group, Institute of Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZX, England; Structural Biology Unit, Center for Cooperative Research in Biosciences, 48160 Derio, Spain;
authors: Ben
authors: B
authors: Murray
authors: Molecular Biophysics Group, Institute of Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZX, England;
authors: Svetlana V
authors: SV
authors: Antonyuk
authors: Structural Biology Unit, Center for Cooperative Research in Biosciences, 48160 Derio, Spain;
authors: Alberto
authors: A
authors: Marina
authors: Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
authors: Shelly C
authors: SC
authors: Lu
authors: CIC bioGUNE, CIBERehd, Parque Tecnologico Bizkaia, 801A-1.48160 Derio, Spain.
authors: Jose M
authors: JM
authors: Mato
authors: Molecular Biophysics Group, Institute of Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZX, England; s.s.hasnain@liv.ac.uk arojas@cicbiogune.es.
authors: S Samar
authors: SS
authors: Hasnain
authors: Structural Biology Unit, Center for Cooperative Research in Biosciences, 48160 Derio, Spain; s.s.hasnain@liv.ac.uk arojas@cicbiogune.es.
authors: Adriana L
authors: AL
authors: Rojas
mesh_terms: D002384:Catalysis; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D008716:Methionine Adenosyltransferase / Q000737:chemistry*; D012436:S-Adenosylmethionine / Q000737:chemistry*
chemical_list: D012436:S-Adenosylmethionine; C527161:MAT2A protein, human; D008716:Methionine Adenosyltransferase
keywords: X-ray crystallography; cell growth; liver cancer; methionine adenosyltransferase; methylation