Tetrahydrofolate

Tetrahydrofolate (THF) is the active coenzyme form of folate (vitamin B9) and a central carrier of one‑carbon units in cellular metabolism. Dietary folates are absorbed and converted within cells, where they are reduced by dihydrofolate reductase to THF and typically retained as polyglutamates to increase cellular retention and enzyme affinity.

THF participates in three major one‑carbon pools. In nucleotide biosynthesis, 5,10‑methylenetetrahydrofolate donates a methylene group for the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) via thymidylate synthase, with THF being regenerated to dihydrofolate and then THF by DHFR. In purine synthesis, 10‑formyl‑THF donates formyl groups in two steps (via GAR transformylase and AICAR transformylase). In amino acid metabolism, 5‑methyl‑THF is the methyl donor for remethylating homocysteine to methionine through methionine synthase, a reaction that also depends on vitamin B12.

THF forms are interconvertible: 5,10‑methylenetetrahydrofolate, 5,10‑methenyltetrahydrofolate, 10‑formyl‑THF, and 5‑formyl‑THF (folinic acid) act as donors or reservoirs of one‑carbon units as needed. The cycle is linked to the methionine cycle and is regulated by folate intake and DHFR activity.

Clinical relevance: folate deficiency impairs DNA synthesis, causing megaloblastic anemia and increased risk of neural tube defects. Drugs such as methotrexate inhibit DHFR and disrupt THF regeneration; folinic acid (leucovorin) rescue is used clinically to mitigate toxicity.