ArticleNature catalysis2024
Epistasis arises from shifting the rate-limiting step during enzyme evolution of a β-lactamase.
Article in Nature catalysis, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed.
- Deep Learning-driven synergistic engineering of PET hydrolase for post-consumer PET depolymerization.Synthetic and systems biotechnology · 2027Article
- Molecular Characterization and In Silico Functional Insights into Carbapenem Resistance in ClinicalPathogens (Basel, Switzerland) · 2026Article
- Dual functional genomics reveals a broad and convergent landscape of asciminib resistance in BCR::ABL1.Genome medicine · 2026Article
- Deciphering functional diversity and structural determinants of substrate specificity in fungal glycoside hydrolase family 5_5 cellulases.Applied and environmental microbiology · 2026Article
- Single-molecule kinetic exploration of functional sub-states in an evolving phosphotriesterase.Nature communications · 2026Article
- Free energy perturbations in enzyme kinetic models reveal cryptic epistasis.PLoS computational biology · 2026Article
- Functional bottlenecks can emerge from non-epistatic underlying traits.PLoS computational biology · 2026Article
- Mapping functional dynamics hotspots for protein engineering with NMR peak intensity analysis.Protein engineering, design & selection : PEDS · 2026Article
- Article
- Structural comparison of substrate-binding pockets of serine β-lactamases in classes A, C, and D.Journal of enzyme inhibition and medicinal chemistry · 2025Review
- Design and biological evaluation of peptide disruptors targeting YAP1-TEAD interaction for oral cancer.BMC oral health · 2025Article
- Phosphate ions modulate enzyme activity and epistatic effects in two clavulanic acid-resistant β-lactamase mutants.Protein science : a publication of the Protein Society · 2025Article
- Directed evolution of a beta-lactamase samples a wide variety of conformational states.Protein science : a publication of the Protein Society · 2025Article
- Effect of Mutations on the Evolution of Extended Spectrum β-lactamases (ESBL).The protein journal · 2025Review
- Distal mutations enhance catalysis in designed enzymes by facilitating substrate binding and product release.Nature communications · 2025Article
- Sparse modeling of interactions enables fast detection of genome-wide epistasis in biobank-scale studies.American journal of human genetics · 2025Article
- Regioselective Hydration of Terpenes with Cofactor-Independent Carotenoid 1,2-Hydratase.Angewandte Chemie (International ed. in English) · 2025Article
- A Thermodynamic Cycle to Predict the Competitive Inhibition Outcomes of an Evolving Enzyme.Journal of chemical theory and computation · 2025Article
- Intramolecular epistasis correlates with divergence of specificity in promiscuous and bifunctional NSAR/OSBS enzymes.Protein science : a publication of the Protein Society · 2025Article
- A thermodynamic cycle to predict the competitive inhibition outcomes of an evolving enzyme.bioRxiv : the preprint server for biology · 2025Article
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Authors and funding
8 authors.
Funding
Abstract
Epistasis, the non-additive effect of mutations, can provide combinatorial improvements to enzyme activity that substantially exceed the gains from individual mutations. Yet the molecular mechanisms of epistasis remain elusive, undermining our ability to predict pathogen evolution and engineer biocatalysts. Here we reveal how directed evolution of a β-lactamase yielded highly epistatic activity enhancements. Evolution selected four mutations that increase antibiotic resistance 40-fold, despite their marginal individual effects (≤2-fold). Synergistic improvements coincided with the introduction of super-stochiometric burst kinetics, indicating that epistasis is rooted in the enzyme's conformational dynamics. Our analysis reveals that epistasis stemmed from distinct effects of each mutation on the catalytic cycle. The initial mutation increased protein flexibility and accelerated substrate binding, which is rate-limiting in the wild-type enzyme. Subsequent mutations predominantly boosted the chemical steps by fine-tuning substrate interactions. Our work identifies an overlooked cause for epistasis: changing the rate-limiting step can result in substantial synergy that boosts enzyme activity.
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