ArticleeLife2015
Reverse evolution leads to genotypic incompatibility despite functional and active site convergence.
Article in eLife, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 82 citations in OpenAlex.
- Graph-based representations in modern protein science.The Biochemical journal · 2026Review
- Single-molecule kinetic exploration of functional sub-states in an evolving phosphotriesterase.Nature communications · 2026Article
- Episodic positive selection structurally stabilizes the Arabidopsis CONSTANS-like gene COL5 indicating adaptive evolution.Scientific reports · 2026Article
- Inference of Cytochrome P450 Evolutionary History Using Structural and Physicochemical Metrics.Genome biology and evolution · 2025Article
- (Reverse) Evolution of a Promiscuous Isochorismate Pyruvate Lyase into an Efficient Chorismate Mutase.Biochemistry · 2025Article
- Investigating the determinants of performance in machine learning for protein fitness prediction.Protein science : a publication of the Protein Society · 2025Article
- Robustness of Ancestral Sequence Reconstruction to Among-site and Among-lineage Evolutionary Heterogeneity.Molecular biology and evolution · 2025Article
- Addressing epistasis in the design of protein function.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Mechanistic conformational and substrate selectivity profiles emerging in the evolution of enzymes via parallel trajectories.Nature communications · 2024Article
- Selection of a promiscuous minimalist cAMP phosphodiesterase from a library of de novo designed proteins.Nature chemistry · 2024Article
- Mononuclear binding and catalytic activity of europium(III) and gadolinium(III) at the active site of the model metalloenzyme phosphotriesterase.Acta crystallographica. Section D, Structural biology · 2024Article
- Reduction of egg reappearance period of cyathostomins in naturally infected horses after increasing doses of ivermectin in Brazil: a grim picture for sustainable parasite control.Revista brasileira de parasitologia veterinaria = Brazilian journal of veterinary parasitology : Orgao Oficial do Colegio Brasileiro de Parasitologia Veterinaria · 2024Article
- High-Throughput Steady-State Enzyme Kinetics Measured in a Parallel Droplet Generation and Absorbance Detection Platform.Analytical chemistry · 2022Article
- Intragenic compensation through the lens of deep mutational scanning.Biophysical reviews · 2022Review
- Proteins' Evolution upon Point Mutations.ACS omega · 2022Article
- Evolutionary repair reveals an unexpected role of the tRNA modification m1G37 in aminoacylation.Nucleic acids research · 2021Article
- Epistasis shapes the fitness landscape of an allosteric specificity switch.Nature communications · 2021Article
- The adaptive landscape of a metallo-enzyme is shaped by environment-dependent epistasis.Nature communications · 2021Article
- UMI-linked consensus sequencing enables phylogenetic analysis of directed evolution.Nature communications · 2020Article
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Authors and funding
5 authors at 3 institutions in 3 countries.
Funding
Abstract
Understanding the extent to which enzyme evolution is reversible can shed light on the fundamental relationship between protein sequence, structure, and function. Here, we perform an experimental test of evolutionary reversibility using directed evolution from a phosphotriesterase to an arylesterase, and back, and examine the underlying molecular basis. We find that wild-type phosphotriesterase function could be restored (>10(4)-fold activity increase), but via an alternative set of mutations. The enzyme active site converged towards its original state, indicating evolutionary constraints imposed by catalytic requirements. We reveal that extensive epistasis prevents reversions and necessitates fixation of new mutations, leading to a functionally identical sequence. Many amino acid exchanges between the new and original enzyme are not tolerated, implying sequence incompatibility. Therefore, the evolution was phenotypically reversible but genotypically irreversible. Our study illustrates that the enzyme's adaptive landscape is highly rugged, and different functional sequences may constitute separate fitness peaks.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.