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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 (Cf), 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 SN2 transition state. The bond forming from the nucleophilic methionine sulfur to the 5'-C of ATP is 2.03 Å at the transition state (bond order of 0.67). Departure of the leaving group triphosphate of ATP is well advanced and forms a 2.32 Å bond between the 5'-C of ATP and the oxygen of the triphosphate (bond order of 0.23). Interaction of MAT2A with its MAT2B regulatory subunit causes no change in the intrinsic KIEs, indicating the same transition state structure. The transition state for MAT2A is more advanced along the reaction coordinate (more product-like) than that from the near-symmetrical transition state of methionine adenosyltransferase from E. coli.

SUBMITTER: Firestone RS 

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

REPOSITORIES: biostudies-literature

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

Firestone Ross S RS   Schramm Vern L VL  

Journal of the American Chemical Society 20170920 39


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<sup>-/-</sup>. The remainder can be rendered MTAP<sup>-</sup> through MTAP inhibitors. We used kinetic isotope effect (KIE), commitment factor (C<sub>f</sub>), and bindi  ...[more]

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