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

Patricia Gomez De Santos, Marina Cañellas, Florian Tieves, Sabry H.H. Younes, Patricia Molina-Espeja, Martin Hofrichter, Frank Hollmann, Victor Guallar, Miguel Alcalde

Research output: Contribution to journalArticleScientificpeer-review

21 Citations (Scopus)
31 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)4789-4799
Number of pages11
JournalACS Catalysis
Volume8
Issue number6
DOIs
Publication statusPublished - 2018

Keywords

  • 5′-hydroxypropranolol
  • directed evolution
  • human drug metabolites
  • in situ HO generation system
  • peroxidative activity
  • peroxygenative activity
  • unspecific peroxygenase

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