Raltitrexed and the new thymidylate synthase inhibitors Hugo ER Ford, David Cunningham

Thymidylate synthase (TS) is a critical enzyme in the de novo synthesis of thymidylate (dTMP), which is the only nucleotide specifically required for DNA

synthesis. The enzyme acts by reductive methylation of 2-deoxyuridylate (dUMP), requiring the donation of a methyl group. This is provided by the folate cofactor 5,10-methylenetetrahydrofolate. In this respect, it is one of a number of folate-dependent enzymes involved in purine and thymidine nucleotide synthesis and metabolism (Figure 51.1).