Cytosine deaminase-uracil phosphoribosyltransferase fusion protein (FCU1) (FCU1)

The Uracil phosphoribosyltransferase (UPRT) domain of FCU1 is a functional component of a synthetic bifunctional fusion protein used in suicide gene therapy (Erbs et al., 2000; PubMed: 10706102). FCU1 is derived from the yeast Saccharomyces cerevisiae and consists of cytosine deaminase (CD) fused to UPRT (Foloppe et al., 2008; PubMed: 18216813). While the CD domain converts the non-toxic prodrug 5-fluorocytosine (5-FC) into 5-fluorouracil (5-FU), the UPRT domain further catalyzes the conversion of 5-FU into 5-fluorouridine monophosphate (5-FUMP). This sequential enzymatic activity bypasses the rate-limiting steps of 5-FU activation in human cells, significantly enhancing the local production of cytotoxic metabolites (Dias et al., 2010; PubMed: 20406921). This approach, often delivered via viral vectors or oncolytic viruses like TG4023, aims to sensitize tumor cells to 5-FC while limiting systemic toxicity (Transgene, 2023). The UPRT domain is essential for maximizing the therapeutic index of 5-FC-based gene therapy by ensuring efficient conversion to active nucleotide analogs that inhibit DNA and RNA synthesis.

Other names

CD-UPRTFCY1-FUR1 fusion proteinBifunctional cytosine deaminase/uracil phosphoribosyltransferaseFUR1 domain of FCU1Yeast cytosine deaminase-uracil phosphoribosyltransferase

The UPRT domain of the FCU1 fusion protein catalyzes the phosphoribosylation of 5-fluorouracil (5-FU) to 5-fluorouridine monophosphate (5-FUMP), which is a critical step in the metabolic activation of the prodrug 5-fluorocytosine (5-FC) into cytotoxic nucleotides that inhibit thymidylate synthase and incorporate into RNA and DNA (Erbs et al., 2000; PubMed: 10706102).