Experimental and Computational Studies Delineate the Role of Asparagine 177 in Hydride Transfer for E. coli Thymidylate Synthase.

ABSTRACT: Thymidylate synthase (TSase), an enzyme responsible for the de novo biosynthesis of 2'-deoxythymidine 5'-monophosphate (thymidylate, dTMP) necessary for DNA synthesis, has been a drug target for decades. TSase is a highly conserved enzyme across species ranging from very primitive organisms to mammals. Among the many conserved active site residues, an asparagine (N177, using Escherichia coli residues numbering) appears to make direct hydrogen bonds with both the C4=O4 carbonyl of the 2'-deoxyuridine 5'-monophosphate (uridylate, dUMP) substrate and its pyrimidine ring's N3. Recent studies have reassessed the TSase catalytic mechanism, focusing on the degree of negative charge accumulation at the O4 carbonyl of the substrate during two critical H-transfers - a proton abstractio

SUBMITTER: Gurevic I 

PROVIDER: S-EPMC6605054 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature