Genetic and physiological aspects of resistance to 5-fluoropyrimidines in Saccharomyces cerevisiae.
Mutants resistant to 5-fluorouracil, 5-fluorocytosine, and 5-fluorouridine were selected in yeast, and the mechanisms of their resistance were investigated. The investigated mutations map in seven different loci. (i) A mutation at the locus FUI 1 gives specifically resistance to 5-fluorouridine. (ii) Two loci are involved in a specific 5-fluorocytosine resistance: a mutation at locus FCY 1 produces a loss of cytosine deaminase activity; a mutation at locus FCY 2 results in the loss of the activity of a cytosine-specific permease. (iii) A mutation at the locus FUR 4 gives a simultaneous resistance to 5-fluorouracil and to 5-fluorouridine by loss in the activity of the uracil-specific permease. (iv) We found three types of mutants in the locus FUR 1. One is dominant and weakly resistant to 5-fluorouracil, 5-fluorocytosine, and 5-fluorouridine. The two others are recessive and are unable to catalyze one of the steps involved in uracil transformation into uridine 5'-monophosphate; this block-age explains their strong resistance to 5-fluorouracil and 5-fluorocytosine. Of these two mutants, one is resistant to 5-fluorouridine and the other is not. (v) Mutations at locus FUR 2 give resistance to 5-fluorouracil, 5-fluorocytosine, and 5-fluorouridine. These mutations are dominant and lead to a loss in the feedback regulation of the aspartic transcarbamylase activity by uridine triphosphate. (vi) The mutants FUR 3 are resistant to 5-fluorocytosine and 5-fluorouridine. They are dominant and physiologically related to the mutants of the locus FUR 1 but their mechanism of resistance is not understood.
D000619:Aminohydrolases / Q000378:metabolism; D002247:Carbon Isotopes; D002474:Cell-Free System; D002854:Chromatography, Paper; D002855:Chromatography, Thin Layer; D002874:Chromosome Mapping; D003596:Cytosine / Q000378:metabolism / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D005461:Fluorine / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology*; D005827:Genetics, Microbial; D026901:Membrane Transport Proteins / Q000378:metabolism; D009154:Mutation; D010759:Phosphorus Isotopes; D010770:Phosphotransferases / Q000378:metabolism; D012440:Saccharomyces / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D013053:Spectrophotometry; D014166:Transferases / Q000378:metabolism; D014498:Uracil / Q000378:metabolism; D014529:Uridine / Q000378:metabolism / Q000494:pharmacology*
D002247:Carbon Isotopes; D026901:Membrane Transport Proteins; D010759:Phosphorus Isotopes; D005461:Fluorine; D014498:Uracil; D003596:Cytosine; D014166:Transferases; D010770:Phosphotransferases; D000619:Aminohydrolases; D005472:Fluorouracil; D014529:Uridine