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.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.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.doi http://dx.doi.org/10.1021/acscatal.8b01004
• dc.identifier.issn 2155-5435
• dc.identifier.uri http://hdl.handle.net/10230/36691
• dc.language.iso eng
• dc.publisher American Chemical Society (ACS)
• dc.relation.ispartof ACS Catalysis 2018;8(6):4789-99
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BIO2016-79106-R
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/720297
• 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.rights.accessRights info:eu-repo/semantics/openAccess
• 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.title Selective Synthesis of the Human Drug Metabolite 5′-Hydroxypropranolol by an Evolved Self-Sufficient Peroxygenase
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion