Folate-mediated one-carbon metabolism enzymes (FOCM enzymes)

Folate-mediated one-carbon (1C) metabolism is a fundamental metabolic network that facilitates the transfer of one-carbon units for the synthesis of purines, thymidylate, and amino acids, as well as the generation of methyl groups for epigenetic regulation [4, 5]. This pathway is essential for DNA replication and repair, making it a critical target in rapidly proliferating cells such as cancer cells and pathogens [1, 6]. Key enzymes in this pathway include dihydrofolate reductase (DHFR), thymidylate synthase (TYMS), and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), which are targeted by a class of drugs known as antifolates [4, 10]. Methotrexate and 5-fluorouracil are classic examples of drugs that inhibit these enzymes to disrupt DNA synthesis and induce cell death in oncology [7, 10]. Beyond cancer, these enzymes are targeted in the treatment of autoimmune diseases like rheumatoid arthritis and infectious diseases like malaria and bacterial infections [6, 8]. The therapeutic use of these inhibitors often requires monitoring for toxicities such as myelosuppression and gastrointestinal distress, which can sometimes be mitigated by the administration of folinic acid [6, 9]. Genetic variations in these enzymes, such as polymorphisms in MTHFR, can significantly influence drug efficacy and patient safety [7, 8]. This metabolic network's compartmentalization between the cytosol and mitochondria provides additional opportunities for selective therapeutic intervention [4, 5].

Other names

One-carbon metabolism enzymesFolate cycle enzymesC1 metabolism enzymesFolate-dependent enzymes

Inhibition of enzymes involved in the transfer of one-carbon units, leading to the depletion of nucleotide precursors and disruption of DNA synthesis and methylation [4, 10].