Benchmarking of laboratory evolved unspecific peroxygenases for the synthesis of human drug metabolites |
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Authors: | Patricia Gomez de Santos Fadia V. Cervantes Florian Tieves Francisco J. Plou Frank Hollmann Miguel Alcalde |
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Affiliation: | 1. Department of Biocatalysis, Institute of Catalysis, CSIC, 28049 Madrid, Spain;2. EvoEnzyme, S.L., C/Marie Curie nº2, 28049 Madrid, Spain;3. Department of Biotechnology, Delft University of Technology, van der Massweg 9, 2629HZ Delft, the Netherlands |
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Abstract: | By mimicking the role of human liver P450 monooxygenases, fungal unspecific peroxygenases (UPOs) can perform a range of highly selective oxyfunctionalization reactions on pharmacological compounds, including O-dealkylations and hydroxylations, thereby simulating drug metabolism. Here we have benchmarked human drug metabolite (HDM) synthesis by several evolved UPO mutants, focusing on dextromethorphan, naproxen and tolbutamide. The HDM from dextromethorphan was prepared at the semi-preparative scale as a proof of production. The structural analysis of mutations involved in the synthesis of HDMs highlights the heme access channel as the main feature on which to focus when designing evolved UPOs. These variants are becoming emergent tools for the cost-effective synthesis of HDMs from next-generation drugs. |
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Keywords: | Unspecific peroxygenase Human drug metabolites Dextromethorphan Tolbutamide Naproxen Heme access channel |
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