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


ABSTRACT: 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.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 N (1)-oxide with a purity >98%.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.

SUBMITTER: Geier M 

PROVIDER: S-EPMC4464233 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Geier Martina M   Bachler Thorsten T   Hanlon Steven P SP   Eggimann Fabian K FK   Kittelmann Matthias M   Weber Hansjörg H   Lütz Stephan S   Wirz Beat B   Winkler Margit M  

Microbial cell factories 20150612


<h4>Background</h4>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.<h4>Results</h4>We show for the f  ...[more]

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