Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 8; pp. 2104 - 2109
• Main Authors: Murray, Ben, Antonyuk, Svetlana V., Marina, Alberto, Lu, Shelly C., Mato, Jose M., Hasnain, S. Samar, Rojas, Adriana L.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23.02.2016; National Acad Sciences
• Subjects: Adenosine triphosphatase; Amino acids; Biological Sciences; Catalysis; Catalytic Domain; Crystal structure; Crystallography, X-Ray; Enzymes; Humans; Ligands; Methionine Adenosyltransferase - chemistry; S-Adenosylmethionine - chemistry; X-ray crystallography; cell growth; liver cancer; methylation; methionine adenosyltransferase
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1510959113

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.