ArticleAntimicrobial agents and chemotherapy2010
Azole binding properties of Candida albicans sterol 14-alpha demethylase (CaCYP51).
Article in Antimicrobial agents and chemotherapy, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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61 citing papers in PubMed, 111 citations in OpenAlex.
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- Benzothiazole-thiazole hybrids as broad-spectrum antimicrobial agents: synthesis, SAR analysis, and molecular docking against bacterial and fungal targets.RSC advances · 2025Article
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- Elucidation of sterol biosynthesis pathway and its co-regulation with fatty acid biosynthesis in the oleaginous marine protistFrontiers in bioengineering and biotechnology · 2023Article
- Anti-Metabolites · 2022Article
- Azole-Resistant Alleles ofAntimicrobial agents and chemotherapy · 2022Article
- Cytochrome P450 168A1 from Pseudomonas aeruginosa is involved in the hydroxylation of biologically relevant fatty acids.PloS one · 2022Article
- Evolution-Based Protein Engineering for Antifungal Peptide Improvement.Molecular biology and evolution · 2021Article
- Structural Insights into the Azole Resistance of theJournal of fungi (Basel, Switzerland) · 2021Article
- Azole derivatives with naphthalene showing potent antifungal effects against planktonic and biofilm forms of Candida spp.: an in vitro and in silico study.International microbiology : the official journal of the Spanish Society for Microbiology · 2021Article
1 more citing papers are in PubMed but not listed here.
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8 authors at 2 institutions in 2 countries.
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Abstract
Purified Candida albicans sterol 14-α demethylase (CaCYP51) bound the CYP51 substrates lanosterol and eburicol, producing type I binding spectra with K(s) values of 11 and 25 μM, respectively, and a K(m) value of 6 μM for lanosterol. Azole binding to CaCYP51 was "tight" with both the type II spectral intensity (ΔA(max)) and the azole concentration required to obtain a half-ΔA(max) being proportional to the CaCYP51 concentration. Tight binding of fluconazole and itraconazole was confirmed by 50% inhibitory concentration determinations from CYP51 reconstitution assays. CaCYP51 had similar affinities for clotrimazole, econazole, itraconazole, ketoconazole, miconazole, and voriconazole, with K(d) values of 10 to 26 μM under oxidative conditions, compared with 47 μM for fluconazole. The affinities of CaCYP51 for fluconazole and itraconazole appeared to be 4- and 2-fold lower based on CO displacement studies than those when using direct ligand binding under oxidative conditions. Econazole and miconazole were most readily displaced by carbon monoxide, followed by clotrimazole, ketoconazole, and fluconazole, and then voriconazole (7.8 pmol min(-1)), but itraconzole could not be displaced by carbon monoxide. This work reports in depth the characterization of the azole binding properties of wild-type C. albicans CYP51, including that of voriconazole, and will contribute to effective screening of new therapeutic azole antifungal agents. Preliminary comparative studies with the I471T CaCYP51 protein suggested that fluconazole resistance conferred by this mutation was through a combination of increased turnover, increased affinity for substrate, and a reduced affinity for fluconazole in the presence of substrate, allowing the enzyme to remain functionally active, albeit at reduced velocity, at higher fluconazole concentrations.
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