ArticleJournal of the American Chemical Society2018
Overriding Traditional Electronic Effects in Biocatalytic Baeyer-Villiger Reactions by Directed Evolution.
Article in Journal of the American Chemical Society, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- A programmable bifunctional flavoenzyme for direct amine-to-ester conversion.Science advances · 2026Article
- Protein engineering: status report.Protein engineering, design & selection : PEDS · 2026Review
- Redesigning Enzymes for Biocatalysis: Exploiting Structural Understanding for Improved Selectivity.Frontiers in molecular biosciences · 2022Review
- The Unexplored Importance of Fleeting Chiral Intermediates in Enzyme-Catalyzed Reactions.Journal of the American Chemical Society · 2021Article
- Synthesis of unstrained Criegee intermediates: inverse α-effect and other protective stereoelectronic forces can stop Baeyer-Villiger rearrangement of γ-hydroperoxy-γ-peroxylactones.Chemical science · 2020Article
- Aqueous microdroplets containing only ketones or aldehydes undergo Dakin and Baeyer-Villiger reactions.Chemical science · 2019Article
- Chemo-enzymatic cascades to produce cycloalkenes from bio-based resources.Nature communications · 2019Article
- Stabilization of cyclohexanone monooxygenase by computational and experimental library design.Biotechnology and bioengineering · 2019Article
- Unleashing the Synthetic Power of Plant Oxygenases: From Mechanism to Application.Plant physiology · 2019Review
- Phosphothreonine (pThr)-Based Multifunctional Peptide Catalysis for Asymmetric Baeyer-Villiger Oxidations of Cyclobutanones.ACS catalysis · 2019Article
- Side-Chain Pruning Has Limited Impact on Substrate Preference in a Promiscuous Enzyme.ACS catalysis · 2018Article
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7 authors.
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Abstract
Controlling the regioselectivity of Baeyer-Villiger (BV) reactions remains an ongoing issue in organic chemistry, be it by synthetic catalysts or enzymes of the type Baeyer-Villiger monooxygenases (BVMOs). Herein, we address the challenging problem of switching normal to abnormal BVMO regioselectivity by directed evolution using three linear ketones as substrates, which are not structurally biased toward abnormal reactivity. Upon applying iterative saturation mutagenesis at sites lining the binding pocket of the thermostable BVMO from Thermocrispum municipale DSM 44069 (TmCHMO) and using 4-phenyl-2-butanone as substrate, the regioselectivity was reversed from 99:1 (wild-type enzyme in favor of the normal product undergoing 2-phenylethyl migration) to 2:98 in favor of methyl migration when applying the best mutant. This also stands in stark contrast to the respective reaction using the synthetic reagent m-CPBA, which provides solely the normal product. Reversal of regioselectivity was also achieved in the BV reaction of two other linear ketones. Kinetic parameters and melting temperatures revealed that most of the evolved mutants retained catalytic activity, as well as thermostability. In order to shed light on the origin of switched regioselectivity in reactions of 4-phenyl-2-butanone and phenylacetone, extensive QM/MM and MD simulations were performed. It was found that the mutations introduced by directed evolution induce crucial changes in the conformation of the respective Criegee intermediates and transition states in the binding pocket of the enzyme. In mutants that destabilize the normally preferred migration transition state, a reversal of regioselectivity is observed. This conformational control of regioselectivity overrides electronic control, which normally causes preferential migration of the group that is best able to stabilize positive charge. The results can be expected to aid future protein engineering of BVMOs.
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