Activation of Two Sequential H-transfers in the Thymidylate Synthase Catalyzed Reaction.

ABSTRACT: Thymidylate synthase (TSase) catalyzes the de novo biosynthesis of thymidylate, a precursor for DNA, and is thus an important target for chemotherapeutics and antibiotics. Two sequential C-H bond cleavages catalyzed by TSase are of particular interest: a reversible proton abstraction from the 2'-deoxy-uridylate substrate, followed by an irreversible hydride transfer forming the thymidylate product. QM/MM calculations of the former predicted a mechanism where the abstraction of the proton leads to formation of a novel nucleotide-folate intermediate that is not covalently bound to the enzyme (Wang, Z.; Ferrer, S.; Moliner, V.; Kohen, A. Biochemistry2013, 52, 2348-2358). Existence of such intermediate would hold promise as a target for a new class of drugs. Calcula

SUBMITTER: Islam Z 

PROVIDER: S-EPMC4643671 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature