SUMMARY PARAGRAPH for FUR1
Fur1p is a uracil phosphoribosyltransferase (UPRTase) that catalyzes the conversion of uracil into uridine 5'-monophosphate (UMP) in the pyrimidine salvage pathway (1, 2). Uracil induces FUR1 and represses genes encoding the de novo pyrimidine biosynthetic enzymes (3), resulting in increased uracil phosphoribosyltransferase activity and decreased de novo biosynthesis of pyrimidines. FUR1 is repressed in response to lithium chloride during growth on galactose (4). FUR1 and ARP1 are convergently transcribed with the predicted polyadenylation signal of FUR1 residing in the C-terminal coding region of ARP1 (5).
fur1 null mutants are typically inviable unless supplemented with uracil and uridine, and because fur1 nulls cannot convert 5-fluorouracil (5-FU) to 5-fluoroUMP, which is toxic, the mutants are also resistant to 5-fluorocytidine, 5-fluorouridine, and 5-FU (2, 6, 1, 7). Disruption of FUR1 results in doubling times three-fold longer than wild type (8), and is synthetically lethal in ura3 null mutants (9). FUR1 is similar to Candida albicans FUR1 (10) and the Streptococcus salivarius uracil phosphoribosyltransferase gene (11).
Fur1p is of biomedical interest for use in cancer therapies because it can catalyze the conversion of 5-FU to 5-fluorouridine-5'-monophosphate, which can then be converted by mammalian enzymes into the toxic compounds 5-FUTP and 5-fluoro-dUMP (12). 5-FUTP can be incorporated into RNA in place of UTP, resulting in the inhibition of the nuclear processing of ribosomal and mRNAs, and 5-FdUMP irreversibly inhibits thymidylate synthase, preventing DNA synthesis (12). Expression of Fur1p increases tumor cell sensitivity to 5-FU, and expression of cytosine deaminase Fcy1p in tumor cells increases their sensitivity to 5-fluorocytosine (5-FC) (12). Tumor cells expressing a chimeric "suicide" protein, produced from a synthetic gene containing the FCY1 and FUR1 coding sequences fused in frame, display increased sensitivity to 5-FU, and significantly increased sensitivity to 5-FC (12). In a mouse model of tumor progression, injection of the fusion gene into tumors, in conjunction with the systemic administration of 5-FC, led to substantial delays in tumor growth, suggesting that the synthetic suicide gene may constitute a potent candidate for therapeutic cancer gene therapy (12).
Last updated: 2005-11-25