Methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1 (MTHFD1)

Methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1 (MTHFD1), commonly known as C1-tetrahydrofolate synthase, is a trifunctional cytoplasmic enzyme that plays a pivotal role in one-carbon metabolism [1, 3, 8]. It catalyzes three sequential reactions—dehydrogenase, cyclohydrolase, and synthetase—that interconvert folate derivatives to provide one-carbon units for the de novo synthesis of purines and thymidylate, as well as for the remethylation of homocysteine to methionine [7, 17]. Because of its essential role in providing nucleotides for DNA replication, MTHFD1 is a key therapeutic target in cancer, where its inhibition can disrupt the proliferation of rapidly dividing tumor cells [2, 3, 11]. While traditional antifolates like methotrexate and pemetrexed exert their effects partly through this pathway, novel selective inhibitors are being explored to improve efficacy and reduce off-target effects [2, 4]. However, therapeutic intervention carries significant safety concerns, including myelosuppression and potential developmental defects, as evidenced by the association of MTHFD1 variants with neural tube defects [5, 7, 9].

Other names

C1-tetrahydrofolate synthaseC1-THF synthaseTrifunctional folate-dependent enzymeMTHFCMTHFDFTHFS

Inhibition of folate-dependent one-carbon transfer, leading to depletion of purine and thymidylate pools and induction of folate trapping.