MTHFD1

MTHFD1, short for methylenetetrahydrofolate dehydrogenase (NADP+) 1, is a human gene that encodes the cytosolic trifunctional enzyme C-1-tetrahydrofolate synthase. The enzyme contains three catalytic activities within a single polypeptide: methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase, and formyltetrahydrofolate synthetase. Through these activities, MTHFD1 participates in the folate-mediated one‑carbon metabolism pathway, interconverting different one‑carbon forms of tetrahydrofolate that are used for nucleotide biosynthesis and other folate-dependent processes.

In cellular metabolism, MTHFD1 supports the supply of one‑carbon units needed for de novo synthesis of purines and thymidylate. The enzyme helps convert 5,10‑methylene‑THF to 5,10‑methenyl‑THF and subsequently to 10‑formyl‑THF, while also facilitating the formation of formyl-THF. These interconnected reactions link thymidylate synthesis and purine ring assembly, contributing to DNA replication and repair as well as broader cellular methylation reactions.

Clinical and genetic relevance is centered on how MTHFD1 variants influence folate status and one‑carbon metabolism. Polymorphisms in MTHFD1 have been studied for associations with neural tube defect risk and folate-related traits, with results varying across populations. The gene and protein are also of interest in discussions of antifolate drug responses, since altered folate metabolism can affect sensitivity to chemotherapy.

MTHFD1 is broadly expressed and localized to the cytosol. It may exist in different splice forms, and it functions alongside other folate-cycle enzymes to support cellular one‑carbon metabolism.