Thymidylate synthase (Escherichia coli) (TS or ThyA)

Thymidylate synthase from Escherichia coli is a homodimeric enzyme that catalyzes the reductive methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) using 5,10-methylenetetrahydrofolate as both carbon donor and reductant[1][7][8]. This reaction is essential for de novo synthesis of thymidine nucleotides, and thus for DNA replication and cell proliferation in bacteria[1][3][7][8]. As the sole source of dTMP in E. coli, thymidylate synthase is indispensable for bacterial growth, making it a well-established antibiotic and chemotherapeutic target[1][3]. Drugs such as FdUMP irreversibly inhibit the enzyme by mimicking its substrate and forming a stable covalent intermediate at the active site, while folate analogs target its cofactor binding pocket[1]. The structure and function of E. coli thymidylate synthase have been elucidated by X-ray crystallography, and the enzyme has served as a model for rational drug design[2][5]. Resistance can occur via mutations in the thyA gene, underscoring both its therapeutic significance and the challenge of drug resistance in antimicrobial development[3][6].

Other names

ThyATSEC 2.1.1.45Thymidylate synthetase (archaic)E. coli thymidylate synthase

Irreversible inhibition by suicide substrates (e.g., FdUMP forms a stable covalent complex with enzyme); Competitive inhibition (with substrate or cofactor analogs)