Benchmarking of laboratory evolved unspecific peroxygenases for the synthesis of human drug metabolites

Patricia Gomez de Santos; Fadia V. Cervantes; Florian Tieves; Francisco J. Plou; Frank Hollmann; Miguel Alcalde

doi:10.1016/j.tet.2019.02.013

Benchmarking of laboratory evolved unspecific peroxygenases for the synthesis of human drug metabolites

Patricia Gomez de Santos, Fadia V. Cervantes, Florian Tieves, Francisco J. Plou, Frank Hollmann, Miguel Alcalde^*

^*Corresponding author for this work

BT/Biocatalysis

Research output: Contribution to journal › Article › Scientific › peer-review

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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.

Original language	English
Pages (from-to)	1827-1831
Number of pages	5
Journal	Tetrahedron
Volume	75
Issue number	13
DOIs	https://doi.org/10.1016/j.tet.2019.02.013
Publication status	Published - 29 Mar 2019

Bibliographical note

Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.

Keywords

Dextromethorphan
Heme access channel
Human drug metabolites
Naproxen
Tolbutamide
Unspecific peroxygenase

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10.1016/j.tet.2019.02.013

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title = "Benchmarking of laboratory evolved unspecific peroxygenases for the synthesis of human drug metabolites",

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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AU - Tieves, Florian

AU - Plou, Francisco J.

AU - Hollmann, Frank

AU - Alcalde, Miguel

N1 - Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.

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AB - 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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Benchmarking of laboratory evolved unspecific peroxygenases for the synthesis of human drug metabolites

Abstract

Bibliographical note

Keywords

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