Folate-dependent one-carbon metabolism pathways (None)

Folate-dependent one-carbon metabolism represents an integrated network of enzymatic pathways rather than a single therapeutic target. This metabolic system mediates the transfer of one-carbon units essential for numerous cellular processes. The pathway begins with dietary folic acid, which is enzymatically reduced by dihydrofolate reductase through two sequential steps—first to dihydrofolate and then to tetrahydrofolate (THF)—with each step requiring NADPH derived from vitamin B3. Tetrahydrofolate serves as the central acceptor and carrier of one-carbon units, which are primarily donated by serine through the action of serine hydroxymethyltransferase enzymes (cytoplasmic SHMT1 and mitochondrial SHMT2). The pathway operates in parallel within both cytosolic and mitochondrial compartments, producing various folate derivatives including 5,10-methylene-THF, 10-formyl-THF, and 5-methyl-THF, each serving distinct metabolic functions. These pathways are critical for DNA synthesis through both purine and pyrimidine biosynthesis, with thymidylate synthase using methylenetetrahydrofolate to convert dUMP to dTMP, a rate-limiting step in DNA replication. The pathway also supports DNA methylation through the methionine cycle, where 5-methyl-THF converts homocysteine to methionine, which subsequently produces S-adenosylmethionine (SAM), the universal methyl donor for over 100 methylation reactions including epigenetic DNA modifications. The system exhibits complex nutrient interactions, requiring vitamins B12, B6, and B2 (riboflavin) as cofactors for various enzymatic steps. Deficiencies or genetic polymorphisms, particularly in MTHFR, can disrupt homocysteine metabolism and overall pathway function. In cancer, upregulation of mitochondrial folate metabolism, particularly MTHFD2 and ALDH1L2, supports tumor growth, metastasis, and antioxidant defense by contributing to NADPH production. Rather than representing a single druggable target, this pathway system contains multiple discrete enzymatic targets that have been exploited therapeutically, most notably dihydrofolate reductase (DHFR), which is inhibited by methotrexate in cancer chemotherapy.

Other names

Folic acid metabolismFolate metabolismOne-carbon metabolismFolate cycleFolate-mediated one-carbon metabolismTHF-dependent pathwaysTetrahydrofolate metabolism

Rather than a single mechanism, this pathway system contains multiple targetable enzymes including Dihydrofolate reductase (DHFR) inhibition blocking conversion of folic acid to tetrahydrofolate, Thymidylate synthase inhibition preventing dTMP synthesis, Serine hydroxymethyltransferase (SHMT1/SHMT2) modulation, Methylenetetrahydrofolate dehydrogenase (MTHFD1/MTHFD2) targeting, and Methionine synthase pathway disruption.