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Selective Synthesis of the Human Drug Metabolite 5′-Hydroxypropranolol by an Evolved Self-Sufficient Peroxygenase

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dc.contributor.author Gomez de Santos, Patricia
dc.contributor.author Cañellas, Marina
dc.contributor.author Tieves, Florian
dc.contributor.author Younes, Sabry H. H.
dc.contributor.author Molina-Espeja, Patricia
dc.contributor.author Hofrichter, Martin
dc.contributor.author Hollmann, Frank
dc.contributor.author Guallar i Tasies, Víctor
dc.contributor.author Alcalde, Miguel Angel
dc.date.accessioned 2019-02-28T08:44:55Z
dc.date.available 2019-02-28T08:44:55Z
dc.date.issued 2018
dc.identifier.citation Gomez de Santos P, Cañellas M, Tieves F, Younes SHH, Molina-Espeja P, Hofrichter M, Hollmann F, Guallar V, Alcalde M. Selective Synthesis of the Human Drug Metabolite 5′-Hydroxypropranolol by an Evolved Self-Sufficient Peroxygenase. ACS Catalysis 2018;8(6):4789-99. DOI 10.1021/acscatal.8b01004
dc.identifier.issn 2155-5435
dc.identifier.uri http://hdl.handle.net/10230/36691
dc.description.abstract Propranolol is a widely used beta-blocker that is metabolized by human liver P450 monooxygenases into equipotent hydroxylated human drug metabolites (HDMs). It is paramount for the pharmaceutical industry to evaluate the toxicity and activity of these metabolites, but unfortunately, their synthesis has hitherto involved the use of severe conditions, with poor reaction yields and unwanted byproducts. Unspecific peroxygenases (UPOs) catalyze the selective oxyfunctionalization of C–H bonds, and they are of particular interest in synthetic organic chemistry. Here, we describe the engineering of UPO from Agrocybe aegerita for the efficient synthesis of 5′-hydroxypropranolol (5′-OHP). We employed a structure-guided evolution approach combined with computational analysis, with the aim of avoiding unwanted phenoxyl radical coupling without having to dope the reaction with radical scavengers. The evolved biocatalyst showed a catalytic efficiency enhanced by 2 orders of magnitude and 99% regioselectivity for the synthesis of 5′-OHP. When the UPO mutant was combined with an H2O2 in situ generation system using methanol as sacrificial electron donor, total turnover numbers of up to 264 000 were achieved, offering a cost-effective and readily scalable method to rapidly prepare 5′-OHP.
dc.description.sponsorship This work was supported by the European Union Project H2020-BBI-PPP-2015-2-720297-ENZOX2 and the COST Action CM1303 Systems Biocatalysis, the Spanish Government Projects BIO2016-79106-R-Lignolution and CTQ2016-70138-R, and the CSIC Project PIE-201580E042.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher American Chemical Society (ACS)
dc.relation.ispartof ACS Catalysis 2018;8(6):4789-99
dc.rights Copyright © 2018 American Chemical Society. This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
dc.title Selective Synthesis of the Human Drug Metabolite 5′-Hydroxypropranolol by an Evolved Self-Sufficient Peroxygenase
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1021/acscatal.8b01004
dc.subject.keyword 5′-hydroxypropranolol
dc.subject.keyword Directed evolution
dc.subject.keyword Human drug metabolites
dc.subject.keyword In situ H2O2 generation system
dc.subject.keyword Peroxidative activity
dc.subject.keyword Peroxygenative activity
dc.subject.keyword Unspecific peroxygenase
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BIO2016-79106-R
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/720297
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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