Folate-dependent one-carbon transfer enzymes (FOCM enzymes)

Folate-dependent one-carbon transfer enzymes are a specialized group of metabolic proteins that facilitate the transfer of single-carbon units for essential biosynthetic reactions. These enzymes, which include dihydrofolate reductase (DHFR), thymidylate synthase (TYMS), and methylenetetrahydrofolate reductase (MTHFR), are central to the de novo synthesis of purines and thymidylate required for DNA replication and repair. They also play a vital role in the methionine cycle, providing methyl groups for the synthesis of S-adenosylmethionine (SAM), the universal methyl donor for epigenetic regulation. Because of their indispensable role in cell proliferation, these enzymes have been primary targets for chemotherapy for decades, with "antifolate" drugs like methotrexate and 5-fluorouracil being staples in cancer treatment. Beyond oncology, these enzymes are targeted in the treatment of autoimmune diseases and infectious diseases due to their role in immune cell expansion and microbial growth. Recent research has also highlighted their importance in mitochondrial redox balance and the management of neurodegenerative disorders associated with elevated homocysteine levels.

Other names

Folate-mediated one-carbon metabolism (FOCM) enzymesOne-carbon (1C) metabolism enzymesFolate cycle enzymesAntifolate targetsFolate-dependent transferases

Inhibition of folate-dependent enzymes to deplete tetrahydrofolate pools, leading to the suppression of DNA synthesis, induction of thymineless death, and inhibition of cellular methylation reactions [4, 6, 11].