Y132H substitution in Candida albicans sterol 14α-demethylase confers fluconazole resistance by preventing binding to haem
Y132H substitution in Candida albicans sterol 14α-demethylase confers fluconazole resistance by preventing binding to haem
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DOI：
10.1016/s0378-1097(99)00478-4
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发表时间：
1999-11-15
影响因子：
2.1
通讯作者：
Kelly, DE
中科院分区：
文献类型：
--
作者：
Kelly, SL;Lamb, DC;Kelly, DE
真菌细胞色素P450甾醇14 α-脱甲基酶（CYP 51）是麦角甾醇生物合成所必需的，并且是唑类抗真菌化合物的靶标。白念珠菌临床分离株CYP 51中Y132 H氨基酸替换可通过蛋白质的新变化引起氟康唑耐药。氟康唑与突变蛋白的结合不涉及与血红素的正常相互作用，如诱导I型光谱变化所示。这与野生型蛋白质形成对比，其中氟康唑抑制反映在与作为第六配体的血红素的配位中，并且其中获得典型的II型光谱。Y132 H取代的发生没有血红素环境或活性的剧烈扰动，允许抗性突变体产生麦角固醇并保持适应性，这是自然界中抗性的有效策略。(C)1999年，欧洲微生物学会联合会。由Elsevier Science B. V.出版，版权所有。
Fungal cytochrome P450 sterol 14 alpha-demethylase (CYP51) is required for ergosterol biosynthesis and is the target for azole antifungal compounds. The amino acid substitution Y132H in CYP51 from clinical isolates of Candida albicans can cause fluconazole resistance by a novel change in the protein. Fluconazole binding to the mutant protein did not involve normal interaction with haem as shown by inducing a Type I spectral change. This contrasted to the wild-type protein where fluconazole inhibition was reflected in coordination to haem as a sixth ligand and where the typical Type II spectrum was obtained. The Y132H substitution occurred without drastic perturbation of the haem environment or activity allowing resistant mutants to produce ergosterol and retain fitness, an efficient strategy for resistance in nature. (C) 1999 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved.