Reduced folate-dependent enzymes

Reduced folate-dependent enzymes are a group of proteins that utilize reduced folate cofactors, such as tetrahydrofolate (THF), to facilitate the transfer of one-carbon units in essential metabolic pathways [1]. These enzymes, including dihydrofolate reductase (DHFR), thymidylate synthase (TS), and glycinamide ribonucleotide formyltransferase (GARFT), play a critical role in the de novo synthesis of purines and thymidylate, which are fundamental building blocks for DNA and RNA synthesis and repair [1, 4]. Because rapidly dividing cells, such as cancer cells or activated immune cells, have a high demand for nucleotide precursors, these enzymes are primary targets for therapeutic intervention [2, 5]. Drugs known as antifolates, such as methotrexate and pemetrexed, competitively inhibit these enzymes to disrupt DNA replication and induce apoptosis [2, 3]. Beyond oncology, these enzymes are targeted in the treatment of autoimmune disorders like rheumatoid arthritis and psoriasis to modulate immune cell proliferation, and they serve as targets for antimicrobial agents that exploit structural differences between human and microbial enzyme isoforms [2].

Other names

Folate-dependent enzymesOne-carbon metabolism enzymesEnzymes of the folate cycleAntifolate targets

Inhibition of folate-dependent one-carbon transfer reactions required for the synthesis of DNA precursors, primarily through competitive inhibition of dihydrofolate reductase, thymidylate synthase, and formyltransferases, leading to the depletion of intracellular reduced folate pools.