THE CATALYTIC MECHANISM AND STRUCTURE OF THYMIDYLATE SYNTHASE

Thymidylate synthase (TS, EC 2.1.1.45) catalyzes the reductive methyla tion of dUMP by CH(2)H(4)folate to produce dTMP and H(2)folate. Knowle dge of the catalytic mechanism and structure of TS has increased subst antially over recent years. Major advances were derived from crystal s tructures of TS bound to various ligands, the ability to overexpress T S in heterologous hosts, and the numerous mutants that have been prepa red and analyzed. These advances, coupled with previous knowledge, hav e culminated in an in-depth understanding of many important molecular details of the reaction. We review aspects of TS catalysis that are mo st pertinent to understanding the current status of the structure and catalytic mechanism of the enzyme. Included is a discussion of availab le sources and assays for TS, a description of the enzyme's chemical m echanism and crystal structure, and a summary of data obtained from mu tagenesis experiments.