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Volume 31, Number 5—May 2025
Research
Exponential Clonal Expansion of 5-Fluorocytosine–Resistant Candida tropicalis and New Insights into Underlying Molecular Mechanisms
Nissrine Abou-Chakra, Karen Marie Thyssen Astvad, Jan Martinussen, Amalie Sofie Eilsø Munksgaard, and Maiken Cavling Arendrup
Table 1
Metabolism and mode of action of 5-fluorocytosine in study of clonal expansion of 5-fluorocytosine–resistant Candida tropicalis, Denmark*
| Step | Process | Enzyme/mechanism | Outcome |
|---|---|---|---|
| Uptake | 5-fluorocytosine is taken up into fungal cells | Transport protein purine-cytosine permease (encoded by FCY2; primary uptake mechanism) | Initiates the antifungal activity of the metabolic pathway |
| Conversion to 5-FU | 5-fluorocytosine is metabolized into 5-FU | Cytosine deaminase (encoded by FCY1); selective action due to lack of enzyme in mammalian cells | 5-fluorocytosine → 5-FU |
| Formation of 5-FUMP | 5-FU is converted into 5-FUMP | Uracil phosphoribosyl transferase (encoded by FUR1) | 5-FU → 5-FUMP |
| Phosphorylation to 5-FUDP | 5-FUMP is phosphorylated to 5-FUDP | Phosphorylation by specific kinases (e.g., uridine monophosphate kinase) | 5-FUMP → 5-FUDP |
| Formation of 5-FUTP | 5-FUDP is further phosphorylated to 5-FUTP | Phosphorylation reactions | 5-FUDP → 5-FUTP; integration into RNA leads to dysfunctional RNA and inhibition of RNA synthesis |
| Formation of 5-FdUDP | 5-FUDP is reduced to 5-FdUDP | Ribonucleotide reductase | 5-FUDP → 5-FdUDP |
| Formation of 5-FdUTP | 5-FdUDP is phosphorylated to 5-FdUTP | Phosphorylation reactions | 5-FdUDP → 5-FdUTP; incorporation into DNA inhibits DNA synthesis and repair |
| Dephosphorylation to 5-FdUMP | 5-FdUTP is dephosphorylated to 5-FdUDP, which is subsequently reduced to 5-FdUMP, inhibiting TS | Dephosphorylation reactions Ribonucleotide reductase |
The irreversible inhibition of TS leads to depletion of dTMP and dTTP, disrupting nucleotide pools, leading to DNA damage, potential apoptosis, and "thymine-less death" |
*5-FdUMP, 5-fluoro-deoxyuridine monophosphate; 5-FU, 5-fluoro-uracil; 5-FUMP, 5-fluoro-uridine monophosphate; 5-FUDP, 5-fluoro-uridine diphosphate; 5-FUTP, 5-fluoro-uridine triphosphate; 5-FdUDP, 5-fluoro-deoxyuridine diphosphate; 5-FdUTP, 5-fluoro-deoxyuridine triphosphate; dTMP, deoxythymidine monophosphate; dTTP, deoxythymidine triphosphate; TS, thymidylate synthase.
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