Parallel reaction pathways and noncovalent intermediates in thymidylate synthase revealed by experimental and computational tools.

ABSTRACT: Thymidylate synthase was one of the most studied enzymes due to its critical role in molecular pathogenesis of cancer. Nevertheless, many atomistic details of its chemical mechanism remain unknown or debated, thereby imposing limits on design of novel mechanism-based anticancer therapeutics. Here, we report unprecedented isolation and characterization of a previously proposed intact noncovalent bisubstrate intermediate formed in the reaction catalyzed by thymidylate synthase. Free-energy surfaces of the bisubstrate intermediates interconversions computed with quantum mechanics/molecular mechanics (QM/MM) methods and experimental assessment of the corresponding kinetics indicate that the species is the most abundant productive intermediate along the reaction coordinate, whereas accumulation

SUBMITTER: Kholodar SA 

PROVIDER: S-EPMC6187185 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature