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S279 Point Mutations in Candida albicans Sterol 14-  Demethylase (CYP51) Reduces in vitro Inhibition by Fluconazole. / A. G. S Warrilow; J. G. L Mullins; C. M Hull; J. E Parker; D. C Lamb; D. E Kelly; S. L Kelly; Jonathan Mullins; Diane Kelly; Josie Parker; Claire Hull; Andrew Warrilow

Antimicrobial Agents and Chemotherapy

Swansea University Authors: Jonathan, Mullins, Diane, Kelly, Josie, Parker, Claire, Hull, Andrew, Warrilow

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DOI (Published version): 10.1128/AAC.05389-11

Abstract

<p><span>The effects of S279F and S279Y point mutations in Candida albicans CYP51 (CaCYP51) on activity and on substrate (lanosterol) and azole antifungal binding were investigated. Both S279F and S279Y bound lanosterol with two-fold increased affinities (K(s) 7.1 and 8.0 &mu;M) comp...

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Published in: Antimicrobial Agents and Chemotherapy
ISSN: 0066-4804 1098-6596
Published: 2012
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URI: https://cronfa.swan.ac.uk/Record/cronfa6838
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Abstract: <p><span>The effects of S279F and S279Y point mutations in Candida albicans CYP51 (CaCYP51) on activity and on substrate (lanosterol) and azole antifungal binding were investigated. Both S279F and S279Y bound lanosterol with two-fold increased affinities (K(s) 7.1 and 8.0 &mu;M) compared to the wild-type CaCYP51 protein (K(s) 13.5 &mu;M). S279F, S279Y and wild-type CaCYP51 proteins bound fluconazole, voriconazole and itraconazole tightly, producing typical type II binding spectra. However, S279F and S279Y 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. S279F and S279Y gave 2.3- and 2.8-fold higher IC(50) values for fluconazole using a CYP51 reconstitution assay than the wild-type protein. The increased fluconazole resistance conferred by S279F and S279Y point mutations appear to be mediated through a combination of higher affinity for substrate and lower affinity for fluconazole. In addition, lanosterol displaced fluconazole from S279F and S279Y but not from the wild-type protein. Molecular modeling of wild-type protein indicated 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 the heme was achieved. In contrast, in the two S279 mutant proteins this S507-fluconazole interaction was absent providing an explanation for the higher K(d) values observed.</span></p>
College: Swansea University Medical School