Tetrahydrofolian

Tetrahydrofolian, commonly called tetrahydrofolate (THF) or tetrahydrofolic acid in its acid form, is the fully reduced, active coenzyme form of folate. It acts as a carrier of one-carbon units in various oxidation states: formyl, formimino, methenyl, and methylene. THF participates in many reactions essential for nucleic acid and amino acid metabolism.

In nucleotide synthesis, THF donates one-carbon units to drive the formation of purines and thymidylate. 10-formyl-THF participates in purine biosynthesis via GAR transformylase, while 5,10-methylene-THF is used by thymidylate synthase to convert deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). In the methionine cycle, 5-methyl-THF serves as the methyl donor to homocysteine to regenerate methionine, reforming THF in the process.

Regeneration and cellular handling: dihydrofolate is reduced back to THF by dihydrofolate reductase (DHFR) using NADPH. THF can be polyglutamylated by folylpolyglutamate synthase, which traps it inside cells and influences enzyme interactions. Polyglutamylated forms vary in tissue distribution and enzyme affinity.

Clinical and nutritional relevance: folate deficiency impairs DNA synthesis, leading to megaloblastic anemia, and is associated with neural tube defects in pregnancy. antifolate drugs, such as methotrexate or trimethoprim, inhibit DHFR and disrupt THF regeneration, while antifolate-like effects can target thymidylate synthase. Dietary folates from leafy greens, legumes, and fortified foods help maintain body pools; requirements vary by age, sex, and reproductive status.