ArticleChemical science2021
MD simulations and QM/MM calculations reveal the key mechanistic elements which are responsible for the efficient C-H amination reaction performed by a bioengineered P450 enzyme.
Article in Chemical science, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 41 citations in OpenAlex.
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- Residue-Level Affinity Decomposition via Quantum Electron Density: A Multivariable Framework Applied to HIV-1 Protease Inhibitors.The journal of physical chemistry. B · 2026Article
- Local Electric Fields Originate Unusual Kinetic Isotope Effects in the Hydrogen Abstraction Reactions of the Functionally Analogous P450 and TauD Enzymes.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
- Origins of Catalysis in Non-Heme Fe(II)/2-Oxoglutarate-Dependent Histone Lysine Demethylase KDM4A with Differently Methylated Histone H3 Peptides.Chemistry (Weinheim an der Bergstrasse, Germany) · 2025Article
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- Stereoselective Construction of β-, γ-, and δ-Lactam Rings via Enzymatic C-H Amidation.Nature catalysis · 2024Article
- HowJACS Au · 2023Article
- Role of mutations in a chemoenzymatic enantiodivergent C(spChemical science · 2023Article
- Stereoselective Construction of β-, γ-, and δ-Lactam Rings via Enzymatic C-H Amidation.Research square · 2023Article
- Biocatalytic Intramolecular C-H aminations via Engineered Heme Proteins: Full Reaction Pathways and Axial Ligand Effects.Chemistry (Weinheim an der Bergstrasse, Germany) · 2022Article
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
An enzyme which is capable of catalyzing C-H amination reactions is considered to be a dream tool for chemists due to its pharmaceutical potential and greener approach. Recently, the Arnold group achieved this feat using an engineered CYP411 enzyme, which further undergoes a random directed evolution which increases its efficiency and selectivity. The present study provides mechanistic insight and the root cause of the success of these mutations to enhance the reactivity and selectivity of the mutant enzyme. This is achieved by means of comprehensive MD simulations and hybrid QM/MM calculations. The study shows that the efficient C-H amination by the engineered CYP411 is a combined outcome of electronic and steric effects. The mutation of the axial cysteine ligand to serine relays electron density to the Fe ion in the heme, and thereby enhances the bonding capability of the heme-iron to the nitrogen atom of the tosyl azide. In comparison, the native cysteine-ligated P450 cannot bind the tosyl azide. Additionally, the A78V and A82L mutations in P411 provide 'bulk' to the active site which increases the enantioselectivity
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