Figure 3.

Mechanism of thymidylate synthase inhibition by 5-FU. TS catalyzes the conversion of dUMP to dTMP with 5,10-methylene tetrahydrofolate (CH2THF) as the methyl donor. The 5-FU active metabolite fluorodeoxyuridine monophosphate (FdUMP) forms a stable triple complex with TS and CH2THF, blocking access of dUMP to the nucleotide-binding site and inhibiting dTMP synthesis. This results in deoxynucleotide (dNTP) pool imbalances and increased levels of deoxyuridine triphosphate (dUTP), both of which cause DNA damage. The pyrophosphatase dUTPase and uracil-DNA glycosylase (UDG) affect the degree of DNA damage caused by dUTP. Thymidine kinase (TK) can promote the synthesis of dTMP. Adapted from [53].