ArticleAntimicrobial agents and chemotherapy2012
S279 point mutations in Candida albicans Sterol 14-α demethylase (CYP51) reduce in vitro inhibition by fluconazole.
Article in Antimicrobial agents and chemotherapy, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 33 citations in OpenAlex.
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- Relative contributions of the ERG11Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases · 2026Article
- Repurposing FDA-Approved Drugs for Eumycetoma Treatment: Homology Modeling and Computational Screening of CYP51 Inhibitors.International journal of molecular sciences · 2025Article
- Reduced Susceptibility to Azoles in Cryptococcus gattii Correlates with the Substitution R258L in a Substrate Recognition Site of the Lanosterol 14-α-Demethylase.Microbiology spectrum · 2023Article
- The Set1 Histone H3K4 Methyltransferase Contributes to Azole Susceptibility in a Species-Specific Manner by Differentially Altering the Expression of Drug Efflux Pumps and the Ergosterol Gene Pathway.Antimicrobial agents and chemotherapy · 2022Article
- Antifungal Activity of Fibrate-Based Compounds and Substituted Pyrroles That Inhibit the Enzyme 3-Hydroxy-methyl-glutaryl-CoA Reductase ofMicrobiology spectrum · 2022Article
- Azole-Resistant Alleles ofAntimicrobial agents and chemotherapy · 2022Article
- Identification of 1, 2, 4-Triazine and Its Derivatives Against Lanosterol 14-Demethylase (CYP51) Property ofFrontiers in medical technology · 2022Article
- A New Variant of Mutational and Polymorphic Signatures in theInfection and drug resistance · 2022Article
- The Evolution of Azole Resistance inAntimicrobial agents and chemotherapy · 2019Article
- Steroids hydroxylation catalyzed by the monooxygenase mutantActa pharmaceutica Sinica. B · 2017Article
- Contribution of clinically derived mutations in ERG11 to azole resistance in Candida albicans.Antimicrobial agents and chemotherapy · 2015Article
- Resistance to antifungals that target CYP51.Journal of chemical biology · 2014Review
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7 authors at 1 institution in 1 country.
Funding
Abstract
The effects of S279F and S279Y point mutations in Candida albicans CYP51 (CaCYP51) on protein activity and on substrate (lanosterol) and azole antifungal binding were investigated. Both S279F and S279Y mutants bound lanosterol with 2-fold increased affinities (K(s), 7.1 and 8.0 μM, respectively) compared to the wild-type CaCYP51 protein (K(s), 13.5 μM). The S279F and S279Y mutants and the wild-type CaCYP51 protein bound fluconazole, voriconazole, and itraconazole tightly, producing typical type II binding spectra. However, the S279F and S279Y mutants had 4- to 5-fold lower affinities for fluconazole, 3.5-fold lower affinities for voriconazole, and 3.5- to 4-fold lower affinities for itraconazole than the wild-type CaCYP51 protein. The S279F and S279Y mutants gave 2.3- and 2.8-fold higher 50% inhibitory concentrations (IC₅₀s) for fluconazole in a CYP51 reconstitution assay than the wild-type protein did. The increased fluconazole resistance conferred by the S279F and S279Y point mutations appeared to be mediated through a combination of a higher affinity for substrate and a lower affinity for fluconazole. In addition, lanosterol displaced fluconazole from the S279F and S279Y mutants but not from the wild-type protein. Molecular modeling of the wild-type protein indicated that the oxygen atom of S507 interacts with the second triazole ring of fluconazole, assisting in orientating fluconazole so that a more favorable binding conformation to heme is achieved. In contrast, in the two S279 mutant proteins, this S507-fluconazole interaction is absent, providing an explanation for the higher K(d) values observed.
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