Dihydrofolate reductase and Thymidylate synthase (DHFR and TYMS (for human), DHFR-TS (for bifunctional forms in many protozoa/plants))

Dihydrofolate reductase and Thymidylate synthase are essential enzymes in the folate pathway that work sequentially to enable DNA synthesis and cell proliferation. Thymidylate synthase catalyzes the methylation of dUMP to dTMP, the only de novo source of thymidylate, which is vital for DNA replication. Dihydrofolate reductase regenerates tetrahydrofolate from dihydrofolate—a step necessary to sustain the one-carbon transfer cycles required for the synthesis of nucleotides and amino acids. In mammals, these are distinct enzymes; in plants, protozoa, and some pathogens, a bifunctional dihydrofolate reductase-thymidylate synthase protein exists. Both enzymes are validated therapeutic targets in cancer, parasitic, and bacterial diseases, with several clinically important inhibitors directed against them. Major therapeutic challenges include toxicity to healthy proliferating cells and the evolution of drug resistance.

Other names

DHFRTYMSThymidylate synthase (TS)Dihydrofolate reductase (DHFR)Dihydrofolate reductase-thymidylate synthase (bifunctional, especially in protozoa and plants)

Inhibition of thymidylate synthase blocks dTMP production, arresting DNA synthesis and cell division. Inhibition of dihydrofolate reductase depletes reduced folates, interfering with both nucleotide biosynthesis and cellular redox homeostasis. Some inhibitors exploit structural differences between human and microbial enzymes for selective toxicity.