Tetrahydrofolate-dependent one-carbon metabolism (1C metabolism)

The tetrahydrofolate (THF)-dependent one-carbon metabolism pathway is a fundamental metabolic network responsible for the transfer of one-carbon units essential for the synthesis of purine and pyrimidine nucleotides, amino acids, and methyl groups (Ducker & Rabinowitz, 2017). Central to this pathway are enzymes such as dihydrofolate reductase (DHFR) and thymidylate synthase (TS), which utilize folate derivatives to produce thymidylate (dTMP) and other precursors necessary for DNA replication and repair (StatPearls, 2023). Because rapidly proliferating cells, including cancer cells and bacterial pathogens, have a high demand for DNA synthesis, this pathway is a major target for therapeutic intervention (Locasale, 2013). Antifolate drugs like methotrexate and antimetabolites like 5-fluorouracil disrupt this cycle, leading to "thymineless death" and cell cycle arrest (PubChem, 2024). While highly effective in treating various malignancies and infections, the pathway's essential role in healthy tissues like bone marrow and the intestinal epithelium leads to common side effects such as myelosuppression and mucositis (PubMed, 2021).

Other names

Folate cycleOne-carbon metabolismTHF-mediated 1C metabolismFolate-mediated one-carbon metabolismThymidylate synthesis pathway

Inhibition of enzymes within the folate cycle (e.g., DHFR, TS) to deplete nucleotide precursors (dTMP, purines), thereby inhibiting DNA synthesis and repair.