Dihydrofolate synthase (FolC) (DHFS)

Dihydrofolate synthase (DHFS), encoded by the folC gene in Mycobacterium tuberculosis, is a critical bifunctional enzyme that also exhibits folylpolyglutamate synthase (FPGS) activity (UniProt: P9WNJ3). It catalyzes the ATP-dependent addition of a glutamate residue to dihydropteroate to form dihydrofolate, and subsequently adds additional glutamate residues to folate derivatives to facilitate their intracellular retention and co-enzymatic activity (PubMed: 11250895). Because the folate biosynthetic pathway is essential for the production of DNA precursors and certain amino acids, DHFS represents a vital target for antitubercular drug development (PubMed: 25667141). Inhibition of this enzyme disrupts one-carbon metabolism, leading to the depletion of essential nucleotides and eventual bacterial cell death. The enzyme is also involved in the metabolic activation of the prodrug para-aminosalicylic acid (PAS), which is converted into antimetabolites that inhibit the folate pathway (PubMed: 23236173). While traditional antifolates like sulfonamides target other steps in the pathway, DHFS is increasingly recognized as a potential target for overcoming resistance or enhancing the efficacy of existing treatments (PubMed: 30256615).

Other names

FolCFolylpolyglutamate synthaseFPGSDihydrofolate synthetaseFolylpoly-gamma-glutamate synthetase

Inhibition of the ATP-dependent ligation of L-glutamate to dihydropteroate and subsequent polyglutamylation of folates, leading to the depletion of intracellular folate pools and cessation of DNA synthesis (PubMed: 25667141).