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

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.