Azole Antifungal Sensitivity of Sterol 14α-Demethylase (CYP51) and CYP5218 from Malassezia globosa.
Azole Antifungal Sensitivity of Sterol 14α-Demethylase (CYP51) and CYP5218 from Malassezia globosa.
复制标题
来自球形马拉色菌的甾醇 14α-脱甲基酶 (CYP51) 和 CYP5218 的唑类抗真菌敏感性。
DOI：
10.1038/srep27690
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发表时间：
2016
影响因子：
4.6
通讯作者：
Kelly,StevenL
中科院分区：
文献类型：
--
作者：
Warrilow,AndrewGS;Price,ClaireL;Parker,JosieE;Rolley,NicolaJ;Smyrniotis,ChristopherJ;Hughes,DavidD;Thoss,Vera;Nes,WDavid;Kelly,DianeE;Holman,TheodoreR;Kelly,StevenL
Malassezia globosacytochromes P450 CYP51 and CYP5218 are sterol 14α-demethylase (the target of azole antifungals) and a putative fatty acid metabolism protein (and a potential azole drug target), respectively. Lanosterol, eburicol and obtusifoliol bound to CYP51 withKdvalues of 32, 23 and 28 μM, respectively, catalyzing sterol 14α-demethylation with respective turnover numbers of 1.7 min−1, 5.6 min−1and 3.4 min−1. CYP5218 bound a range of fatty acids with linoleic acid binding strongest (Kd36 μM), although no metabolism could be detected in reconstitution assays or role in growth on lipids. Clotrimazole, fluconazole, itraconazole, ketoconazole, voriconazole and ketaminazole bound tightly to CYP51 (Kd≤ 2 to 11 nM). In contrast, fluconazole did not bind to CYP5218, voriconazole and ketaminazole bound weakly (Kd~107 and ~12 μM), whereas ketoconazole, clotrimazole and itraconazole bound strongest to CYP5218 (Kd~1.6, 0.5 and 0.4 μM) indicating CYP5218 to be only a secondary target of azole antifungals. IC50determinations confirmedM. globosaCYP51 was strongly inhibited by azole antifungals (0.15 to 0.35 μM). MIC100studies showed itraconazole should be considered as an alternative to ketoconazole given the potency and safety profiles and the CYP51 assay system can be used in structure-activity studies in drug development.
