Folate-dependent enzymes in nucleotide synthesis

Folate-dependent enzymes in nucleotide synthesis represent a critical group of metabolic proteins that facilitate the transfer of one-carbon units necessary for the de novo production of purines and thymidylate (dTMP). Key members of this group include Dihydrofolate reductase (DHFR), Thymidylate synthase (TYMS), and transformylases such as Glycinamide ribonucleotide transformylase (GART) and Aminoimidazole carboxamide ribonucleotide transformylase (ATIC) [2, 13]. These enzymes are essential for DNA replication and repair, making them primary targets for "antifolate" chemotherapeutic agents used to treat various malignancies [1, 5]. In cancer, rapidly dividing cells have a high demand for nucleotides, and inhibiting these enzymes leads to the depletion of essential precursors, causing cell cycle arrest and "thymineless death" [3, 8]. Beyond oncology, these enzymes are targeted in the treatment of autoimmune diseases like rheumatoid arthritis and in the management of certain bacterial and protozoal infections [2, 12]. However, because these pathways are also active in healthy rapidly dividing tissues, drugs targeting them often cause significant side effects such as bone marrow suppression and gastrointestinal distress [8, 11].

Other names

Folate cycle enzymesOne-carbon metabolism enzymesAntifolate targetsNucleotide biosynthesis enzymesFolate-dependent transformylases

Inhibition of enzymes involved in the transfer of one-carbon units, leading to the depletion of tetrahydrofolate pools and the cessation of de novo purine and thymidylate synthesis.