Molecular mechanism of thymidylate synthase-catalyzed reaction and interaction of the enzyme with 2- and/or 4-substituted analogues of dUMP and 5-fluoro-dUMP

Abstract

Thymidylate synthase is a target enzyme in anticancer, antiviral, antifungal and antiprotozoan chemotherapy. With two dUMP analogues, 5-fluoro-dUMP (FdUMP) and 5-(trifluoromethyl)-dUMP (CF3dUMP), strong thymidylate synthase inhibitors and active forms of drugs, the inhibition mechanism is based on the reaction mechanism. Recent comparative studies of new dUMP analogues, containing more than one substituent in the pyrimidine ring, showed that substitution of the pyrimidine ring C(4)=O group in FdUMP by either C(4)=N-OH group (in N4-hydroxy-FdCMP) or C(4)=S group (in 4-thio-FdUMP) preserves high inhibitory potency of the drug but may alter its specificity for thymidylate synthases from various sources, which differ in sensitivity to slow-binding inhibition by FdUMP. Informations suggesting mechanisms responsible for the foregoing have been reviewed, including results of molecular modeling studies suggesting interaction of the pyrimidine C(4)=O group, or its modification, with the N5,10-methylene-tetrahydrofolate N(10) in the thymidylate synthase reaction.