Sterol 14-demethylase P450 (CYP51) provides a breakthrough for the discussion on the evolution of cytochrome P450 gene superfamily

Biodiversity is the most characteristic feature of cytochrome P450. Finding of CYP51 distributing widely in biological kingdoms provided breakthroughs for the discussion on the evolution and diversification of P450. Molecular phylogenetic analysis demonstrated that CYP51 appeared in the prokaryotic era and distributed into most kingdoms concomitant with phylogenetic diverg ence. This is the first evolutionary evidence indicating the prokaryotic or igin of P450. Modification of substrate specificity of eukaryotic CYP51s oc curred independently to adapt to the different sterol precursors existing i n each kingdom. Formation of CYP51 variants through the mutation of active site and the selection of the advantageous ones from them were demonstrated by the emergence of azole-resistant CYP51s in Candida albicans under the e nvironments rich in stoic antifungal agents. These findings illustrate the most probable core process of P450 diversification consisting of modificati on of active site and selection of the resulting variants through interacti on with endogenous and exogenous chemicals. (C) 2000 Academic Press.