ArticleThe Journal of biological chemistry2013
Key mutations alter the cytochrome P450 BM3 conformational landscape and remove inherent substrate bias.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 77 citations in OpenAlex.
- Expanding the Biocatalytic Toolbox: A Singular P450 Enzyme Efficiently Produces Diverse Pharmaceutical Metabolites.ACS omega · 2026Article
- Computational Design of CYP102A1 Variants for Biosynthesis of a Next-Generation Antiplatelet Drug DT-678.ACS synthetic biology · 2026Article
- Drug Metabolism by Engineered Toluene o-Xylene Monooxygenases of Pseudomonas sp. OX1.Biotechnology and bioengineering · 2026Article
- Characterisation of a Self-Sufficient Cytochrome P450 Enzyme From the Bacterium Thermosporothrix hazakensis and Its Conversion Into a Peroxygenase.Microbial biotechnology · 2025Article
- Structure-Function Analysis of the Self-Sufficient CYP102 Family Provides New Insights into Their Biochemistry.International journal of molecular sciences · 2025Article
- Choose Your Own Adventure: A Comprehensive Database of Reactions Catalyzed by Cytochrome P450 BM3 Variants.ACS catalysis · 2024Review
- Designing cytochrome P450 enzymes for use in cancer gene therapy.Frontiers in bioengineering and biotechnology · 2024Review
- Melatonin Activation by Human Cytochrome P450 Enzymes: A Comparison between Different Isozymes.Molecules (Basel, Switzerland) · 2023Article
- The Versatile Biocatalyst of Cytochrome P450 CYP102A1: Structure, Function, and Engineering.Molecules (Basel, Switzerland) · 2023Review
- Designing Artificial Metalloenzymes by Tuning of the Environment beyond the Primary Coordination Sphere.Chemical reviews · 2022Review
- A Promiscuous Bacterial P450: The Unparalleled Diversity of BM3 in Pharmaceutical Metabolism.International journal of molecular sciences · 2021Review
- Growth-Based, High-Throughput Selection for NADH Preference in an Oxygen-Dependent Biocatalyst.ACS synthetic biology · 2021Article
- Mapping protein-protein interactions in homodimeric CYP102A1 by crosslinking and mass spectrometry.Biophysical chemistry · 2021Article
- Engineering the biomimetic cofactors of NMNH for cytochrome P450 BM3 based on binding conformation refinement.RSC advances · 2021Article
- Structural basis for plant lutein biosynthesis from α-carotene.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Characterization of the structure and interactions of P450 BM3 using hybrid mass spectrometry approaches.The Journal of biological chemistry · 2020Article
- A Modified Arrhenius Approach to Thermodynamically Study Regioselectivity in Cytochrome P450-Catalyzed Substrate Conversion.Chembiochem : a European journal of chemical biology · 2020Article
- Cryo-EM reveals the architecture of the dimeric cytochrome P450 CYP102A1 enzyme and conformational changes required for redox partner recognition.The Journal of biological chemistry · 2020Article
- An integrated screening system for the selection of exemplary substrates for natural and engineered cytochrome P450s.Scientific reports · 2019Article
- Production of metabolites of the anti-cancer drug noscapine using a P450Biotechnology reports (Amsterdam, Netherlands) · 2019Article
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Authors and funding
6 authors at 1 institution in 1 country.
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Abstract
Cytochrome P450 monooxygenases (P450s) have enormous potential in the production of oxychemicals, due to their unparalleled regio- and stereoselectivity. The Bacillus megaterium P450 BM3 enzyme is a key model system, with several mutants (many distant from the active site) reported to alter substrate selectivity. It has the highest reported monooxygenase activity of the P450 enzymes, and this catalytic efficiency has inspired protein engineering to enable its exploitation for biotechnologically relevant oxidations with structurally diverse substrates. However, a structural rationale is lacking to explain how these mutations have such effects in the absence of direct change to the active site architecture. Here, we provide the first crystal structures of BM3 mutants in complex with a human drug substrate, the proton pump inhibitor omeprazole. Supported by solution data, these structures reveal how mutation alters the conformational landscape and decreases the free energy barrier for transition to the substrate-bound state. Our data point to the importance of such "gatekeeper" mutations in enabling major changes in substrate recognition. We further demonstrate that these mutants catalyze the same 5-hydroxylation reaction as performed by human CYP2C19, the major human omeprazole-metabolizing P450 enzyme.
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