Cytochrome P450 of fungi: primary target for azole antifungal agents.

Y Yoshida
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引用次数: 135

Abstract

Cytochromes of fungi are essentially similar to those of animals. Cytochromes of fungi constitute two electron transport systems occurring in mitochondria and the endoplasmic reticulum. The former system, called the respiratory chain, contributes to cellular respiration and ATP generation, whereas the later system, named the microsomal electron transport system, is responsible for biosynthesis of several cellular components. The oxidative metabolism of lanosterol, that is included in the biosynthetic pathway of ergosterol, is one of the important functions of the microsomal electron transport system, which is catalyzed by P450(14DM). Many azole antifungal agents avidly combine with P450(14DM) and inhibit the oxidative removal of C-32 (the 14 alpha-demethylation) of lanosterol. This inhibition causes depletion of ergosterol and accumulation of 14-methylsterols in the membrane of fungal cells. Such change in sterol composition disturbs membrane function and results in growth inhibition and death of the fungal cells. Accordingly, P450(14DM) is considered as the primary target for azole antifungal agents. Cytochrome P450, which mediates the 14 alpha-demethylation of lanosterol, is also present in mammalian cells. Mammalian cells contain various species of cytochrome P450 which are responsible for many important cellular metabolic functions. If azole antifungal agents inhibit mammalian cytochrome P450 too, their systemic use may result in potentially significant adverse reactions. The high selectivity of azole antifungal agents for fungal P450(14DM) will be necessary for their systemic application. Binding ability of an azole antifungal agent to P450(14DM) is predominantly determined by the substituent at N-1 of the azole group, and the substituent must interact with the substrate site of the cytochrome. Extensive modification of the N-1 substituents and the screening of newly developed compounds with respect to the selectivity to fungal P450(14DM) with some conventional methods will be necessary. For this project, a biochemical understanding of cytochrome P450 and other cytochromes is important.

真菌细胞色素P450:唑类抗真菌药物的主要靶点。
真菌的细胞色素本质上与动物的细胞色素相似。真菌的细胞色素构成两个电子传递系统,分别发生在线粒体和内质网。前一个系统,称为呼吸链,有助于细胞呼吸和ATP的产生,而后一个系统,称为微粒体电子传递系统,负责几种细胞成分的生物合成。羊毛甾醇的氧化代谢是麦角甾醇生物合成途径中包含的重要功能之一,是微粒体电子传递系统的重要功能之一,该系统由P450(14DM)催化。许多唑类抗真菌药物与P450(14DM)结合,抑制羊毛甾醇C-32 (14 α -去甲基化)的氧化去除。这种抑制导致麦角甾醇的消耗和14-甲基甾醇在真菌细胞膜中的积累。这种固醇成分的变化扰乱了膜功能,导致真菌细胞的生长抑制和死亡。因此,P450(14DM)被认为是唑类抗真菌药物的主要靶点。介导羊毛甾醇14 α -去甲基化的细胞色素P450也存在于哺乳动物细胞中。哺乳动物细胞中含有多种细胞色素P450,它们负责许多重要的细胞代谢功能。如果唑类抗真菌药物也抑制哺乳动物细胞色素P450,那么它们的全身使用可能会导致潜在的重大不良反应。唑类抗真菌药物对真菌P450(14DM)的高选择性将是其系统应用所必需的。唑类抗真菌药物与P450(14DM)的结合能力主要取决于N-1上的取代基,该取代基必须与细胞色素的底物位点相互作用。利用传统方法对N-1取代基进行广泛的修饰和筛选新开发的化合物对真菌P450(14DM)的选择性是必要的。在这个项目中,对细胞色素P450和其他细胞色素的生化理解是很重要的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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