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Production of recombinant human aldehyde oxidase in E. coli and optimization of its application for preparative synthesis of oxidized drug metabolites

Mateus Rodrigues, Diogo Filipe and Kittelmann, Matthias and Eggimann, Fabian and Bachler, Thorsten and Abad, Sandra and Hanlon, Steven and Camattari, Andrea and Glieder, Anton and Wirz, Beat and Winkler, Margit and Luetz, Stephan (2014) Production of recombinant human aldehyde oxidase in E. coli and optimization of its application for preparative synthesis of oxidized drug metabolites. ChemCatChem, 6 (4). pp. 1028-1042.

Abstract

Recombinant human aldehyde oxidase (AO) was expressed in Escherichia coli. Different cell disruption methods and conditions of cell culture in shake flasks and bioreactors and of biotransformation on an analytical scale were tested in order to optimize the synthesis of oxidized AO drug metabolites.
The enzyme yield was increased 24-fold by optimizing the cell culture conditions. The highest yield was achieved in a 25 l stirred tank bioreactor under non-oxygen-limited conditions and high lactose feed rate. Suspensions of highly concentrated and well aerated whole cells at neutral pH and relatively low temperatures led to the best conversion. The solvent for the substrate and the buffering agent for the biotransformation had an important influence. In a biotransformation with AO, 210 mg of famciclovir were converted to diacetylpenciclovir with a yield of 82%. The optimized protocol represents a viable method for the preparative synthesis of oxidized AO metabolites of drugs.

Item Type: Article
Keywords: aldehyde oxidase; biotransformations; drug oxidation; metabolism; preparative synthesis
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/20447

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