Kittelmann, Matthias, Worsch, Anne, Girhard, Marco, von Bühler, Clemens , Tieves, Florian , Czaja, Rico , Vogel, Andreas , Grumaz, Christian , Sohn, Kai , Lütz, Stephan and Urlacher, Vlada (2018) A novel cytochrome P450 monooxygenase from Streptomyces platensis resembles activities of human drug metabolizing P450s. Biotechnol Bioeng..

Abstract

Cytochrome P450 monooxygenases (P450) are versatile enzymes which play essential roles in C-source assimilation, secondary metabolism and in degradations of endo- and exogenous xenobiotics. In humans, several P450 isoforms constitute the largest part of phase I metabolizing enzymes and catalyze oxidation reactions which convert lipophilic xenobiotics, including drugs, to more water soluble species. Recombinant human P450s and microorganisms are applied in the pharmaceutical industry for the synthesis of drug metabolites for pharmacokinetics and toxicity studies. Compared to the membrane-bound eukaryotic P450s, prokaryotic ones exhibit some advantageous features, such as high stability and generally easier heterologous expression. Here, we describe a novel P450 from Streptomyces platensis DSM 40041 classified as CYP107L that efficiently converts several commercial drugs of various size and properties. This P450 was identified by screening of actinobacterial strains for amodiaquine and ritonavir metabolizing activities, followed by genome sequencing and expression of the annotated S. platensis P450s in E. coli. Performance of CYP107L in biotransformations of amodiaquine, ritonavir, amitriptyline and thioridazine resembles activities of the main human metabolizing P450s, namely CYPs 3A4, 2C8, 2C19 and 2D6. For application in the pharmaceutical industry, an E. coli whole cell biocatalyst expressing CYP107L was developed and evaluated for preparative amodiaquine metabolite production.

Item Type:	Article
Date Deposited:	25 Jul 2018 00:45
Last Modified:	25 Jul 2018 00:45
URI:	https://oak.novartis.com/id/eprint/34210