510methyleneTHF

5,10-methylene-tetrahydrofolate, often abbreviated as 5,10-CH2-THF, is a form of tetrahydrofolate (THF) that carries a single-carbon methylene group. It is a key intermediate in folate-mediated one-carbon metabolism and serves as a temporary reservoir for one-carbon units used in nucleotide synthesis and amino acid metabolism.

In DNA synthesis, 5,10-CH2-THF donates a methylene group to deoxyuridine monophosphate (dUMP) to form deoxythymidine monophosphate (dTMP). This reaction is catalyzed by thymidylate synthase and yields dihydrofolate (DHF) as a byproduct. DHF is subsequently reduced by dihydrofolate reductase (DHFR) back to THF, which can be converted again to 5,10-CH2-THF by serine hydroxymethyltransferase using serine as the one-carbon donor, thus sustaining the cycle.

The folate cycle also connects 5,10-CH2-THF to other one-carbon pools. Through the action of methylenetetrahydrofolate reductase (MTHFR), 5,10-CH2-THF can be converted to 5-methyl-THF, which serves as the main methyl donor for the remethylation of homocysteine to methionine in a reaction catalyzed by methionine synthase. This interconversion links nucleotide synthesis with the methionine cycle and methylation reactions in cells.

Clinical relevance arises because folate metabolism is essential for DNA replication and repair. Disruptions can cause megaloblastic anemia and contribute to developmental defects. Antifolate drugs, such as methotrexate and trimethoprim, target enzymes in this pathway, affecting 5,10-CH2-THF–dependent reactions.