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

Folate-dependent single-carbon transfer enzymes constitute a critical metabolic network responsible for the activation and transfer of one-carbon units (such as methyl, formyl, and methylene groups) required for essential biosynthetic pathways. These enzymes, which include dihydrofolate reductase (DHFR), thymidylate synthase (TYMS), and serine hydroxymethyltransferase (SHMT), facilitate the de novo synthesis of purines and thymidylate, which are indispensable for DNA and RNA replication. Additionally, they support the methionine cycle, providing methyl groups for the methylation of DNA, proteins, and lipids, thereby playing a central role in epigenetic regulation and cellular signaling. Because rapidly proliferating cells, such as malignant tumor cells and bacterial pathogens, have an exceptionally high demand for these nucleotide building blocks, this enzyme class has been a primary target for therapeutic intervention for decades. Antifolate drugs like methotrexate and pemetrexed exploit this dependency to treat various cancers, while inhibitors like trimethoprim and pyrimethamine are used to combat bacterial and protozoal infections. Beyond oncology and infectious disease, these enzymes are also targeted in the treatment of autoimmune conditions like rheumatoid arthritis and are critical factors in preventing developmental defects such as neural tube disorders.

Other names

One-carbon metabolism enzymesFolate-mediated one-carbon metabolism enzymesFolate cycle enzymes1C metabolism enzymesFolate-dependent enzymes

Inhibition of folate-mediated one-carbon transfer reactions, primarily through the competitive inhibition of dihydrofolate reductase (DHFR), thymidylate synthase (TYMS), or glycinamide ribonucleotide transformylase (GART), thereby depleting the cellular pool of tetrahydrofolate and disrupting the synthesis of DNA, RNA, and proteins.