Thymidylate Synthase

Thymidylate synthase is an enzyme that catalyzes the reaction that follows (Figure 22.18):

> dUMP + 5,10-Methylene-THF <=> dTMP + Dihydrofolate

The reaction is part of the de novo synthesis pathway of dTMP.

5-Fluorodeoxyuridine monophosphate (FdUMP) is a molecule that is a mechanism-based inhibitor. Irreversible binding of FdUMP to thymidylate synthase occurs only in the presence of 5,10-methylenetetrahydrofolate. Crystallographic analysis of thymidylate synthase with dUMP and an analog of 5,10-methylenetetrahydrofolate (that could not be acted on by the enzyme) reveals that thymidylate synthase normally makes a transient covalent bond in the process of catalysis of the reaction. Apparently FdUMP's structure traps the enzyme-substrate covalent bond and prevents it from breaking down.

See also: De Novo Pyrimidine Nucleotide Metabolism, Figure 22.17, Drug Design