Candida glabrata dihydrofolate reductase (CgDHFR)

Candida glabrata dihydrofolate reductase (CgDHFR) is an essential enzyme in the fungal pathogen Candida glabrata, responsible for the reduction of dihydrofolate to tetrahydrofolate (UniProt: P50891). This reaction is a key step in the metabolic pathway that provides one-carbon units for the biosynthesis of thymidylate, purine nucleotides, and certain amino acids (PubMed: 23163355). By maintaining the pool of tetrahydrofolate, CgDHFR supports DNA synthesis and overall cell growth, making it a vital target for antifungal therapy. Inhibition of this enzyme results in a deficiency of essential nucleotides, leading to the cessation of DNA replication and eventual cell death. Given that Candida glabrata is a leading cause of hospital-acquired candidiasis and frequently exhibits resistance to standard azole treatments, CgDHFR represents a significant target for new drug development (PubMed: 25654378). A major challenge in targeting CgDHFR is ensuring high selectivity to avoid inhibiting human dihydrofolate reductase, which could lead to adverse effects like bone marrow toxicity. Current research focuses on developing novel antifolates, such as propargyl-linked compounds, that can effectively bypass common resistance mutations in the fungal enzyme.

Other names

Dihydrofolate reductaseDFR1CgDFR15,6,7,8-tetrahydrofolate:NADP+ oxidoreductase

Competitive inhibition of the dihydrofolate reductase enzyme, preventing the conversion of dihydrofolate to tetrahydrofolate, which results in the depletion of nucleotide precursors and inhibition of DNA synthesis.