Mutations in Saccharomyces cerevisiae sterol C5-desaturase conferring resistance to the CYP51 inhibitor fluconazole.
Understanding fluconazole resistance is important as it emerged as a serious clinical problem for this CYP51, sterol 14alpha-demethylase, inhibitor. One mechanism, observed first in Saccharomyces cerevisiae, was through defective sterol C5-desaturase (Erg3p) required to form the fungistatic sterol end-product resulting from CYP51 inhibition, 14alpha-methylergosta-8,24(28)-dien-3beta,6alpha-diol. Here, we report molecular changes resulting in both blocked mutants and also leaky mutants in which reduced ergosterol levels were detected. Blocked mutants exhibited nonsense and frameshift mutations, while leaky mutants contained missense mutations that were generally in conserved positions based on the alignment of sterol C5-desaturases and located mainly between residues 250 and 282.
D000595:Amino Acid Sequence; D001483:Base Sequence; D065607:Cytochrome P-450 Enzyme Inhibitors; D017931:DNA Primers; D004352:Drug Resistance, Microbial / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015725:Fluconazole / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009154:Mutation; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology*; D017386:Sequence Homology, Amino Acid; D058886:Sterol 14-Demethylase
D065607:Cytochrome P-450 Enzyme Inhibitors; D017931:DNA Primers; D004791:Enzyme Inhibitors; D015725:Fluconazole; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase