Dihydrofolate reductase (DHFR) and folate-dependent enzymes (DHFR/Folate enzymes)

Dihydrofolate reductase (DHFR) and its downstream folate-dependent enzymes, including thymidylate synthase (TS) and glycinamide ribonucleotide formyltransferase (GARFT), are central to the folate cycle and one-carbon metabolism (UniProt: P00374). These enzymes facilitate the synthesis of essential precursors for DNA and RNA, specifically purines and thymidylate, which are vital for cell division and repair (PubMed: 21570333). In disease states like cancer, these enzymes are often overexpressed to support rapid cellular proliferation, making them prime targets for chemotherapy. Antifolate drugs, such as methotrexate and pemetrexed, work by competitively inhibiting these enzymes, thereby depleting the intracellular pool of reduced folates and inducing cell cycle arrest or apoptosis (StatPearls: Methotrexate). Beyond oncology, these enzymes are targeted in the treatment of autoimmune diseases like rheumatoid arthritis and in the management of bacterial and protozoal infections due to structural differences between host and pathogen enzymes (PubChem CID 135338483). However, targeting this pathway can lead to significant toxicities, such as myelosuppression and mucositis, necessitating careful monitoring of folate levels and genetic biomarkers like MTHFR polymorphisms.

Other names

Folate cycle enzymesAntifolate targetsOne-carbon metabolism enzymesReduced folate pathway

Competitive inhibition of dihydrofolate reductase and related folate-dependent enzymes, preventing the formation of tetrahydrofolate and inhibiting de novo synthesis of purines and pyrimidines.