TY - JOUR
T1 - Mutations in Saccharomyces cerevisiae sterol C5-desaturase conferring resistance to the CYP51 inhibitor fluconazole
AU - Jackson, Colin J.
AU - Lamb, David Christopher
AU - Manning, Nigel J.
AU - Kelly, Diane Elizabeth
AU - Kelly, Steven Lewis
N1 - Jackson, C. J., Lamb, D. C., Manning, N. J., Kelly, D. E., Kelly, S. L. (2003). Mutations in Saccharomyces cerevisiae sterol C5-desaturase conferring resistance to the CYP51 inhibitor fluconazole. Biochemical and Biophysical Research Communications, 309, (4), 999-1004.
PY - 2003/10/3
Y1 - 2003/10/3
N2 - Understanding fluconazole resistance is important as it emerged as a serious clinical problem for this CYP51, sterol 14α-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, 14α-methylergosta-8,24(28)-dien-3β,6α-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.
AB - Understanding fluconazole resistance is important as it emerged as a serious clinical problem for this CYP51, sterol 14α-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, 14α-methylergosta-8,24(28)-dien-3β,6α-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.
KW - Sterol C5-desaturase
KW - Cytochrome P450 inhibition
KW - Fluconazole
KW - Antifungal resistance
KW - Mutation
U2 - 10.1016/j.bbrc.2003.08.098
DO - 10.1016/j.bbrc.2003.08.098
M3 - Article
SN - 0006-291X
VL - 309
SP - 999
EP - 1004
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 4
ER -