The Transition-State Structure for Human MAT2A from Isotope Effects.

ABSTRACT: Human methionine S-adenosyltransferase (MAT2A) catalyzes the formation of S-adenosylmethionine (SAM) from ATP and methionine. Synthetic lethal genetic analysis has identified MAT2A as an anticancer target in tumor cells lacking expression of 5'-methylthioadenosine phosphorylase (MTAP). Approximately 15% of human cancers are MTAP^-/-. The remainder can be rendered MTAP^- through MTAP inhibitors. We used kinetic isotope effect (KIE), commitment factor (C_f), and binding isotope effect (BIE) measurements combined with quantum mechanical (QM) calculations to solve the transition state structure of human MAT2A. The reaction is characterized by an advanced S_N2 transition state. The bond forming from the nucleophilic methionine sulfur to the 5'-C of ATP is

SUBMITTER: Firestone RS 

PROVIDER: S-EPMC5674783 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature