ArticleNature communications2017
De novo active sites for resurrected Precambrian enzymes.
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 38 papers.
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Who cites it
38 citing papers in PubMed.
- Emergence of specific binding and catalysis from a designed generalist binding protein.Nature chemistry · 2026Article
- An enzymatic microfluidic sensor for β-lactam antibiotics based on cross-linked ancestral β-lactamase crystals.Nanoscale advances · 2026Article
- Structure-activity relationships in catalytic amyloids.Journal of inorganic biochemistry · 2026Article
- Dynamic signature of activity-stability tradeoff in lactamase evolution.Nature communications · 2026Article
- A resurrected ancestor of Cas12a expands target access and substrate recognition for nucleic acid editing and detection.Nature biotechnology · 2025Article
- Protometabolic functions of pyridoxal: A link between early amino acid synthesis and enzyme evolution.The FEBS journal · 2025Article
- Enzyme Enhancement Through Computational Stability Design Targeting NMR-Determined Catalytic Hotspots.Journal of the American Chemical Society · 2025Article
- Transition Path Sampling Based Free Energy Calculations of Evolution's Effect on Rates in β-Lactamase: The Contributions of Rapid Protein Dynamics to Rate.The journal of physical chemistry. B · 2024Article
- The Evolution of the Acylation Mechanism inACS catalysis · 2024Article
- Extant Sequence Reconstruction: The Accuracy of Ancestral Sequence Reconstructions Evaluated by Extant Sequence Cross-Validation.Journal of molecular evolution · 2024Article
- Performance prediction of polypeptide derivatives as efficient potential microbial inhibitors: a computational approach.International journal of biochemistry and molecular biology · 2024Article
- Computational design of highly efficient thermostable MHET hydrolases and dual enzyme system for PET recycling.Communications biology · 2023Article
- Fishing for Catalysis: Experimental Approaches to Narrowing Search Space in Directed Evolution of Enzymes.JACS Au · 2023Review
- Loop dynamics and the evolution of enzyme activity.Nature reviews. Chemistry · 2023Review
- Protection of Catalytic Cofactors by Polypeptides as a Driver for the Emergence of Primordial Enzymes.Molecular biology and evolution · 2023Article
- Conformational exchange divergence along the evolutionary pathway of eosinophil-associated ribonucleases.Structure (London, England : 1993) · 2023Article
- Evolution of CRISPR-associated endonucleases as inferred from resurrected proteins.Nature microbiology · 2023Article
- NMR-guided directed evolution.Nature · 2022Article
- Active site center redesign increases protein stability preserving catalysis in thioredoxin.Protein science : a publication of the Protein Society · 2022Article
- Efficient Base-Catalyzed Kemp Elimination in an Engineered Ancestral Enzyme.International journal of molecular sciences · 2022Article
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Authors and funding
12 authors.
Funding
Abstract
Protein engineering studies often suggest the emergence of completely new enzyme functionalities to be highly improbable. However, enzymes likely catalysed many different reactions already in the last universal common ancestor. Mechanisms for the emergence of completely new active sites must therefore either plausibly exist or at least have existed at the primordial protein stage. Here, we use resurrected Precambrian proteins as scaffolds for protein engineering and demonstrate that a new active site can be generated through a single hydrophobic-to-ionizable amino acid replacement that generates a partially buried group with perturbed physico-chemical properties. We provide experimental and computational evidence that conformational flexibility can assist the emergence and subsequent evolution of new active sites by improving substrate and transition-state binding, through the sampling of many potentially productive conformations. Our results suggest a mechanism for the emergence of primordial enzymes and highlight the potential of ancestral reconstruction as a tool for protein engineering.
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