methyleneTHF

5,10-methylene-tetrahydrofolate, often written as methyleneTHF, is a one-carbon carrying derivative of tetrahydrofolate (THF). It serves as a critical donor of one-carbon units in nucleotide biosynthesis, most notably in the formation of thymidylate (dTMP) from deoxyuridylate (dUMP) via thymidylate synthase, producing dihydrofolate (DHF) in the process. This reaction is essential for DNA replication and repair.

Biogenesis and metabolism: 5,10-methylene-THF is formed in the cytosol when serine donates a methylene group to THF, catalyzed by serine hydroxymethyltransferase, yielding glycine and 5,10-methylene-THF. The methylene-THF pool is interconvertible with 5,10-methenyl-THF and, ultimately, back to THF; dihydrofolate is reduced to THF by dihydrofolate reductase to continue the cycle. Additionally, 5,10-methylene-THF serves as a precursor to N10-formyl-THF, a formyl-group donor in purine nucleotide synthesis, linking its role to the broader folate-dependent one-carbon metabolism.

Clinical relevance: Folate metabolism is a common target in medicine. Inhibitors of dihydrofolate reductase, such as methotrexate, deplete THF and disrupt one-carbon transfers needed for DNA synthesis. Leucovorin (folinic acid) can be used to rescue normal cells by replenishing the THF pool. Folate deficiency can cause megaloblastic anemia and impair embryonic development, including neural tube formation.

In summary, methyleneTHF is a central one-carbon donor in folate metabolism, connecting amino acid metabolism to nucleotide biosynthesis and cellular growth.