GEPHE SUMMARY Print
Gephebase Gene
Entry Status
Published
GepheID
GP00000284
Main curator
Martin
PHENOTYPIC CHANGE
Trait Category
Trait State in Taxon A
Candida albicans- drug sensitive
Trait State in Taxon B
Candida albicans- drug resistant
Ancestral State
Taxon A
Taxonomic Status
Taxon A
Common Name
-
Synonyms
Candida stellatoidea; Candida stellatoidea type I; ATCC 11006; ATCC 18804; ATCC 20308; ATCC:11006; ATCC:18804; ATCC:20308; BCC 5390; BCC:5390; BCRC 20512; BCRC:20512; CBS 562; CBS:562; CCRC 20512; CCRC:20512; CECT 1002; CECT:1002; IFO 1385; IFO:1385; JCM 1537; JCM 1542; JCM:1537; JCM:1542; KCTC 7270; KCTC:7270; MUCL 29800; MUCL:29800; NBIMCC 72; NBIMCC:72; NBRC 1385; NBRC:1385; NCAIM Y.00971; NCYC 597; NCYC:597; NRRL Y-12983; NRRL:Y:12983; PYCC 3436; PYCC:3436; UAMH 8765; UAMH:8765; Candida albican
Rank
species
Lineage
cellular organisms; Eukaryota; Opisthokonta; Fungi; Dikarya; Ascomycota; saccharomyceta; Saccharomycotina; Saccharomycetes; Saccharomycetales; Debaryomycetaceae; Candida/Lodderomyces clade; Candida
NCBI Taxonomy ID
is Taxon A an Infraspecies?
No
Taxon B
Common Name
-
Synonyms
Candida stellatoidea; Candida stellatoidea type I; ATCC 11006; ATCC 18804; ATCC 20308; ATCC:11006; ATCC:18804; ATCC:20308; BCC 5390; BCC:5390; BCRC 20512; BCRC:20512; CBS 562; CBS:562; CCRC 20512; CCRC:20512; CECT 1002; CECT:1002; IFO 1385; IFO:1385; JCM 1537; JCM 1542; JCM:1537; JCM:1542; KCTC 7270; KCTC:7270; MUCL 29800; MUCL:29800; NBIMCC 72; NBIMCC:72; NBRC 1385; NBRC:1385; NCAIM Y.00971; NCYC 597; NCYC:597; NRRL Y-12983; NRRL:Y:12983; PYCC 3436; PYCC:3436; UAMH 8765; UAMH:8765; Candida albican
Rank
species
Lineage
cellular organisms; Eukaryota; Opisthokonta; Fungi; Dikarya; Ascomycota; saccharomyceta; Saccharomycotina; Saccharomycetes; Saccharomycetales; Debaryomycetaceae; Candida/Lodderomyces clade; Candida
NCBI Taxonomy ID
is Taxon B an Infraspecies?
No
GENOTYPIC CHANGE
Presumptive Null
No
Molecular Type
Aberration Type
SNP
SNP Coding Change
Nonsynonymous
Molecular Details of the Mutation
R467K
Experimental Evidence
Taxon A Taxon B Position
Codon - - -
Amino-acid - - -
Authors
Sanglard D; Ischer F; Koymans L; Bille J
Abstract
The cytochrome P-450 lanosterol 14alpha-demethylase (CYP51A1) of yeasts is involved in an important step in the biosynthesis of ergosterol. Since CYP51A1 is the target of azole antifungal agents, this enzyme is potentially prone to alterations leading to resistance to these agents. Among them, a decrease in the affinity of CYP51A1 for these agents is possible. We showed in a group of Candida albicans isolates from AIDS patients that multidrug efflux transporters were playing an important role in the resistance of C. albicans to azole antifungal agents, but without excluding the involvement of other factors (D. Sanglard, K. Kuchler, F. Ischer, J.-L. Pagani, M. Monod, and J. Bille, Antimicrob. Agents Chemother. 39:2378-2386, 1995). We therefore analyzed in closer detail changes in the affinity of CYP51A1 for azole antifungal agents. A strategy consisting of functional expression in Saccharomyces cerevisiae of the C. albicans CYP51A1 genes of sequential clinical isolates from patients was designed. This selection, which was coupled with a test of susceptibility to the azole derivatives fluconazole, ketoconazole, and itraconazole, enabled the detection of mutations in different cloned CYP51A1 genes, whose products are potentially affected in their affinity for azole derivatives. This selection enabled the detection of five different mutations in the cloned CYP51A1 genes which correlated with the occurrence of azole resistance in clinical C. albicans isolates. These mutations were as follows: replacement of the glycine at position 129 with alanine (G129A), Y132H, S405F, G464S, and R467K. While the S405F mutation was found as a single amino acid substitution in a CYP51A1 gene from an azole-resistant yeast, other mutations were found simultaneously in individual CYP51A1 genes, i.e., R467K with G464S, S405F with Y132H, G129A with G464S, and R467K with G464S and Y132H. Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these mutations on resistance to azole derivatives. Each single mutation, with the exception of G129A, had a measurable effect on the affinity of the target enzyme for specific azole derivatives. We speculate that these specific mutations could combine with the effect of multidrug efflux transporters in the clinical isolates and contribute to different patterns and stepwise increases in resistance to azole derivatives.
Additional References
RELATED GEPHE
Related Genes
Related Haplotypes
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