Thymidylate synthase, Glycinamide ribonucleotide formyltransferase (GARFT), and Dihydrofolate reductase (DHFR)

These three enzymes comprise the core folate pathway required for nucleotide synthesis and thus cell division. Inhibition of one or more of these enzymes is a well-established approach for cancer chemotherapy (e.g., methotrexate, pemetrexed, raltitrexed) and antiparasitic treatments (e.g., pyrimethamine for malaria). However, toxicity and resistance remain clinical challenges. In protozoal parasites (e.g., *Plasmodium*, *Leishmania*), DHFR and TS can exist as a bifunctional enzyme; in humans, they are monofunctional and encoded by separate genes. Enzymes in this pathway are commonly anticancer and anti-infective therapeutic targets due to their role in cell proliferation. If seeking information on a single protein, specify which; if seeking multi-target pharmacology, note that combination therapies targeting these pathways are common in clinical oncology.

Other names

TYMSEC 2.1.1.45EC 2.1.2.2GAR transformylaseDHFRDYRDHFRP1EC 1.5.1.3Thymidylate synthaseGlycinamide ribonucleotide formyltransferaseDihydrofolate reductase

Collectively, inhibition of these enzymes disrupts essential steps in de novo purine and pyrimidine (thymidylate) nucleotide biosynthesis by interfering with folate metabolism, leading to DNA/RNA synthesis blockade and cytotoxicity, particularly in rapidly proliferating cells.