ArticleNature communications2017
A redox-mediated Kemp eliminase.
Article in Nature communications, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Enzyme Enhancement Through Computational Stability Design Targeting NMR-Determined Catalytic Hotspots.Journal of the American Chemical Society · 2025Article
- Mechanistic Perspective on C-N and C-S Bond Construction Catalyzed by Cytochrome P450 Enzymes.ACS bio & med chem Au · 2025Review
- In situ enzymatic control of colloidal phoresis and catalysis through hydrolysis of ATP.Nature communications · 2024Article
- Article
- Choose Your Own Adventure: A Comprehensive Database of Reactions Catalyzed by Cytochrome P450 BM3 Variants.ACS catalysis · 2024Review
- Electrostatics as a Guiding Principle in Understanding and Designing Enzymes.Journal of chemical theory and computation · 2024Review
- Prediction of Thermostability of Enzymes Based on the Amino Acid Index (AAindex) Database and Machine Learning.Molecules (Basel, Switzerland) · 2023Article
- Fishing for Catalysis: Experimental Approaches to Narrowing Search Space in Directed Evolution of Enzymes.JACS Au · 2023Review
- Design of Heme Enzymes with a Tunable Substrate Binding Pocket Adjacent to an Open Metal Coordination Site.Journal of the American Chemical Society · 2023Article
- NMR-guided directed evolution.Nature · 2022Article
- Efficient Base-Catalyzed Kemp Elimination in an Engineered Ancestral Enzyme.International journal of molecular sciences · 2022Article
- Perpetuating enzymatically induced spatiotemporal pH and catalytic heterogeneity of a hydrogel by nanoparticles.Chemical science · 2022Article
- Enhancing aChemical science · 2020Article
- MinimalistACS catalysis · 2019Article
- Human Enzymes for Organic Synthesis.Angewandte Chemie (International ed. in English) · 2018Review
- The evolution of multiple active site configurations in a designed enzyme.Nature communications · 2018Article
- Structure and function of the cytochrome P450 peroxygenase enzymes.Biochemical Society transactions · 2018Review
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
The acid/base-catalysed Kemp elimination of 5-nitro-benzisoxazole forming 2-cyano-4-nitrophenol has long served as a design platform of enzymes with non-natural reactions, providing new mechanistic insights in protein science. Here we describe an alternative concept based on redox catalysis by P450-BM3, leading to the same Kemp product via a fundamentally different mechanism. QM/MM computations show that it involves coordination of the substrate's N-atom to haem-Fe(II) with electron transfer and concomitant N-O heterolysis liberating an intermediate having a nitrogen radical moiety Fe(III)-N· and a phenoxyl anion. Product formation occurs by bond rotation and H-transfer. Two rationally chosen point mutations cause a notable increase in activity. The results shed light on the prevailing mechanistic uncertainties in human P450-catalysed metabolism of the immunomodulatory drug leflunomide, which likewise undergoes redox-mediated Kemp elimination by P450-BM3. Other isoxazole-based pharmaceuticals are probably also metabolized by a redox mechanism. Our work provides a basis for designing future artificial enzymes.
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