Dihydrofolate reductase and other folate-dependent nucleotide synthesis enzymes

Dihydrofolate reductase (DHFR) and associated folate-dependent enzymes, such as thymidylate synthase (TS) and glycinamide ribonucleotide transformylase (GART), are essential components of the folate cycle required for de novo nucleotide biosynthesis [1][2]. DHFR catalyzes the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate, a critical cofactor that carries one-carbon units for the synthesis of purines and thymidylate [1][4]. Because rapidly dividing cells, including cancer cells and microbial pathogens, have an elevated requirement for DNA precursors, these enzymes are primary targets for chemotherapy and antimicrobial therapy [3]. Antifolate drugs like methotrexate and pemetrexed inhibit these enzymes to induce 'thymineless death' and prevent DNA replication [3][4]. Additionally, species-specific inhibitors such as trimethoprim and pyrimethamine exploit structural differences in microbial DHFR to treat bacterial and protozoal infections [5]. Clinical use of these inhibitors is often limited by systemic toxicities, such as bone marrow suppression and mucosal damage, due to the fundamental role of folate metabolism in all proliferating human tissues [4]. (Citations: [1] UniProt P00374; [2] UniProt P04818; [3] PubChem CID 135410875; [4] StatPearls NBK507829; [5] StatPearls NBK513232)

Other names

Folate cycle enzymesAntifolate targetsOne-carbon metabolism enzymesThymidylate synthase and dihydrofolate reductase pathway

Inhibition of folate reduction and one-carbon transfer reactions, leading to the depletion of reduced folate pools and essential nucleotide precursors (dTMP and purines), which results in the arrest of DNA synthesis and cellular proliferation.