ArticleProceedings of the National Academy of Sciences of the United States of America2023
Deciphering the evolution of flavin-dependent monooxygenase stereoselectivity using ancestral sequence reconstruction.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. 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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17 citing papers in PubMed, 34 citations in OpenAlex.
- Leveraging latent space models for enzyme discovery and sampling.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Deciphering the evolutionary origin of the enantioselectivity of short-chain dehydrogenases from plants toward 1-borneol.Nature communications · 2026Article
- Protein engineering: status report.Protein engineering, design & selection : PEDS · 2026Review
- Ancestral Sequence Reconstruction to Accelerate Non-heme Iron-dependent Biocatalyst Engineering.ACS central science · 2025Article
- Ancestral Sequence Reconstruction of the Ethylene-Forming Enzyme.Biochemistry · 2025Article
- Structural and Mechanistic Characterization of the Flavin-Dependent Monooxygenase and Oxidase Involved in Sorbicillinoid Biosynthesis.ACS chemical biology · 2025Article
- Enantiocomplementary Gut Bacterial Enzymes Metabolize Dietary Polyphenols.Journal of the American Chemical Society · 2025Article
- Enzymatic Ring Contraction for the Biosynthesis of Sulfur-Containing Cyclopentachromone.Journal of the American Chemical Society · 2025Article
- Ancestral Sequence Reconstruction for Designing Biocatalysts and Investigating their Functional Mechanisms.JACS Au · 2024Review
- Engineering the Reaction Pathway of a Non-heme Iron Oxygenase Using Ancestral Sequence Reconstruction.Journal of the American Chemical Society · 2024Article
- Evolutionary insights into the stereoselectivity of imine reductases based on ancestral sequence reconstruction.Nature communications · 2024Article
- Ancestral Sequence Reconstruction to Enable Biocatalytic Synthesis of Azaphilones.Journal of the American Chemical Society · 2024Article
- Ancestral Reconstruction and the Evolution of Protein Energy Landscapes.Annual review of biophysics · 2024Review
- Biocatalytic Stereoselective Oxidation of 2-Arylindoles.Journal of the American Chemical Society · 2024Article
- Guiding discovery of protein sequence-structure-function modeling.Bioinformatics (Oxford, England) · 2024Article
- Engineered and total biosynthesis of fungal specialized metabolites.Nature reviews. Chemistry · 2024Review
- Ion-Powered Rotary Motors: Where Did They Come from and Where They Are Going?International journal of molecular sciences · 2023Review
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7 authors at 2 institutions in 1 country.
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Abstract
Controlling the selectivity of a reaction is critical for target-oriented synthesis. Accessing complementary selectivity profiles enables divergent synthetic strategies, but is challenging to achieve in biocatalytic reactions given enzymes' innate preferences of a single selectivity. Thus, it is critical to understand the structural features that control selectivity in biocatalytic reactions to achieve tunable selectivity. Here, we investigate the structural features that control the stereoselectivity in an oxidative dearomatization reaction that is key to making azaphilone natural products. Crystal structures of enantiocomplementary biocatalysts guided the development of multiple hypotheses centered on the structural features that control the stereochemical outcome of the reaction; however, in many cases, direct substitutions of active site residues in natural proteins led to inactive enzymes. Ancestral sequence reconstruction (ASR) and resurrection were employed as an alternative strategy to probe the impact of each residue on the stereochemical outcome of the dearomatization reaction. These studies suggest that two mechanisms are active in controlling the stereochemical outcome of the oxidative dearomatization reaction: one involving multiple active site residues in AzaH and the other dominated by a single Phe to Tyr switch in TropB and AfoD. Moreover, this study suggests that the flavin-dependent monooxygenases (FDMOs) adopt simple and flexible strategies to control stereoselectivity, which has led to stereocomplementary azaphilone natural products produced by fungi. This paradigm of combining ASR and resurrection with mutational and computational studies showcases sets of tools for understanding enzyme mechanisms and provides a solid foundation for future protein engineering efforts.
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