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

Folate-dependent one-carbon metabolism enzymes (FOCM enzymes) comprise a critical network of proteins that facilitate the transfer of one-carbon units for essential biosynthetic processes. These enzymes, including dihydrofolate reductase (DHFR) and thymidylate synthase (TYMS), are vital for the de novo synthesis of purines and thymidylate, which are required for DNA replication and repair. Beyond nucleotide synthesis, this pathway supports amino acid homeostasis (serine, glycine, and methionine) and provides methyl groups for epigenetic modifications such as DNA and histone methylation. Dysregulation of FOCM is linked to various pathologies, most notably cancer, where increased metabolic demand drives tumor proliferation. Additionally, impairments in this pathway are associated with cardiovascular disease, neurodegeneration, and developmental anomalies like neural tube defects. Pharmacological targeting of these enzymes, primarily through antifolate drugs like methotrexate and pemetrexed, has been a cornerstone of chemotherapy for decades. These drugs typically act by inhibiting key enzymes to deplete cellular folate pools, thereby halting DNA synthesis and inducing apoptosis in rapidly dividing cells.

Other names

Folate-mediated one-carbon metabolism (FOCM) enzymesOne-carbon metabolism enzymesFolate cycle enzymesAntifolate targetsFolate-dependent enzymes

Inhibition of key enzymes (e.g., DHFR, TYMS) to deplete tetrahydrofolate pools, thereby blocking de novo nucleotide synthesis, inhibiting DNA replication, and disrupting cellular methylation and redox balance.