QM/MM study of thymidylate synthase: enzymatic motions and the temperature dependence of the rate limiting step.

ABSTRACT: Thymidylate synthase (TS) is an enzyme that catalyzes a complex cascade of reactions. A theoretical study of the reduction of an exocyclic methylene intermediate by hydride transfer from the 6S position of 5,6,7,8-tetrahydrofolate (H(4)folate), to form 2'-deoxyuridine 5'-monophosphate (dTMP) and 7,8-dihydrofolate (H(2)folate), has been carried out using hybrid quantum mechanics/molecular mechanics methods. This step is of special interest because it is the rate-limiting step of the reaction catalyzed by TS. The acceptor of this hydride is an intermediate that is covalently bound to the enzyme via a thioether bond to an overall conserved active site cysteine residue (Cys146 in Escherichia coli). Heretofore, whether the hydride transfer precedes the thiol abstraction that releases the produc

SUBMITTER: Kanaan N 

PROVIDER: S-EPMC4765328 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature