Dihydrofolate reductase; Thymidylate synthase; Glycinamide ribonucleotide formyltransferase (DHFR; TS; GARFT)

Dihydrofolate reductase, thymidylate synthase, and glycinamide ribonucleotide formyltransferase are sequential enzymes in the folate metabolic pathway, required for biosynthesis of DNA and RNA components. DHFR catalyzes the reduction of dihydrofolate to tetrahydrofolate using NADPH, TS converts deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), and GARFT is involved in purine ring biosynthesis. DHFR and TS are sometimes present as a bifunctional enzyme in protozoa and plants, but in humans and most mammals, they are separate proteins. These enzymes are validated therapeutic targets for cancers, bacterial, and parasitic infections, and are subject to inhibition by various clinically useful antifolate drugs which block proliferation of rapidly dividing cells. The grouping of all three as a single target is not biochemically accurate.

Other names

DHFR — Dihydrofolate reductaseTS — Thymidylate synthaseTYMS (gene for TS)GARFT — Glycinamide ribonucleotide formyltransferaseDHFR-TS (bifunctional enzyme found in protozoa and plants)

Inhibition of DHFR blocks reduction of dihydrofolate to tetrahydrofolate, preventing synthesis of thymidylate, purines, and some amino acids; Inhibition of TS prevents synthesis of thymidylate from dUMP, directly impairing DNA synthesis; Inhibition of GARFT disrupts purine nucleotide biosynthesis