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Human FMO2-based microbial whole-cell catalysts for drug metabolite synthesis

Geier, Martina and Bachler, Thorsten and Hanlon, Steven P. and Eggimann, Fabian and Kittelmann, Matthias and Weber, Hansjörg and Luetz, Stephan and Wirz, Beat and Winkler, Margit (2015) Human FMO2-based microbial whole-cell catalysts for drug metabolite synthesis. Journal Microbial Cell Factories, 14 (82).


Background: Getting access to authentic human drug metabolites is an important issue during the drug discovery and development process. Employing recombinant microorganisms as whole-cell biocatalysts constitutes an elegant alternative to organic synthesis to produce these compounds. The present work aimed for the generation of an efficient whole-cell catalyst based on the flavin monooxygenase isoform 2 (FMO2), which is part of the human phase I metabolism.
Results: We show for the first time the functional expression of human FMO2 in E. coli. Truncations of the C-terminal membrane anchor region did not result in soluble FMO2 protein, but had a significant effect on levels of recombinant protein. The FMO2 biocatalysts were employed for substrate screening purposes, revealing trifluoperazine and propranolol as FMO2 substrates. Biomass cultivation on the 100 L scale afforded active catalyst for biotransformations on preparative scale. The whole-cell conversion of trifluoperazine resulted in perfectly selective oxidation to 48 mg (46% yield) of the corresponding N1-oxide with a purity >98%.
Conclusions: The generated FMO2 whole-cell catalysts are not only useful as screening tool for human metabolites of drug molecules but more importantly also for their chemo- and regioselective preparation on the multi-milligram scale.

Item Type: Article
Keywords: Flavin monooxygenase isoform 2, Escherichia coli, Whole-cell biocatalysis, Drug metabolites, Trifluoperazine, Propranolol, FMO2
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45


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