ArticleNature chemical biology2013
Evolution of a designed retro-aldolase leads to complete active site remodeling.
Article in Nature chemical biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 95 papers.
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Who cites it
95 citing papers in PubMed.
- Predicting Activation Barriers With Ring and Bond Critical Points in the Kemp Elimination Reaction.Chemphyschem : a European journal of chemical physics and physical chemistry · 2026Article
- Zero-shot design of abioRxiv : the preprint server for biology · 2026Article
- A Cu(I)-catalysed click reaction generates ROS-triggered cleavable linkages in aqueous media.Nature chemistry · 2026Article
- Deep Prior Framework: integrating functional specificity with general plausibility for targeted protein evolution.Briefings in bioinformatics · 2026Article
- Review
- Article
- Modeling protein-small molecule conformational ensembles with PLACER.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Distal mutations enhance catalysis in designed enzymes by facilitating substrate binding and product release.Nature communications · 2025Article
- Modeling protein-small molecule conformational ensembles with PLACER.bioRxiv : the preprint server for biology · 2025Article
- Article
- Designing Enzymatic Reactivity with an Expanded Palette.Chembiochem : a European journal of chemical biology · 2025Review
- A Foundational Shift in Models for Enzyme Function.Journal of the American Chemical Society · 2025Review
- Biocatalytic asymmetric aldol addition into unactivated ketones.Nature chemistry · 2024Article
- Nucleotide-mediated modulation of chemoselective protein functionalization in a liquid-like condensed phase.Communications chemistry · 2024Article
- Spiers Memorial Lecture: Engineering biocatalysts.Faraday discussions · 2024Article
- Designing Michaelases: exploration of novel protein scaffolds for iminium biocatalysis.Faraday discussions · 2024Article
- A transaminase-mediated aldol reaction and applications in cascades to styryl pyridines.Catalysis science & technology · 2024Article
- A non-canonical nucleophile unlocks a new mechanistic pathway in a designed enzyme.Nature communications · 2024Article
- Design of efficient artificial enzymes using crystallographically-enhanced conformational sampling.bioRxiv : the preprint server for biology · 2023Article
- Exploring the Protein Sequence Space with Global Generative Models.Cold Spring Harbor perspectives in biology · 2023Review
35 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors.
Funding
Abstract
Evolutionary advances are often fueled by unanticipated innovation. Directed evolution of a computationally designed enzyme suggests that pronounced molecular changes can also drive the optimization of primitive protein active sites. The specific activity of an artificial retro-aldolase was boosted >4,400-fold by random mutagenesis and screening, affording catalytic efficiencies approaching those of natural enzymes. However, structural and mechanistic studies reveal that the engineered catalytic apparatus, consisting of a reactive lysine and an ordered water molecule, was unexpectedly abandoned in favor of a new lysine residue in a substrate-binding pocket created during the optimization process. Structures of the initial in silico design, a mechanistically promiscuous intermediate and one of the most evolved variants highlight the importance of loop mobility and supporting functional groups in the emergence of the new catalytic center. Such internal competition between alternative reactive sites may have characterized the early evolution of many natural enzymes.
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Registered trials
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