ArticleNature communications2012
Diminishing returns and tradeoffs constrain the laboratory optimization of an enzyme.
Article in Nature communications, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 106 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
106 citing papers in PubMed.
- Epistasis: Just say no!The Journal of biological chemistry · 2026Review
- Overestimating zero-shot fitness prediction: Broad benchmarks mask local failures and practical limitations.bioRxiv : the preprint server for biology · 2026Article
- How far can you go? Extrapolating values of catalytic activity from known protein landscapes in natural and directed evolution.Chemical Society reviews · 2026Review
- AI-guided redesign of laboratory-evolved reverse transcriptases enhances prime editing.Nature biotechnology · 2026Article
- Single-molecule kinetic exploration of functional sub-states in an evolving phosphotriesterase.Nature communications · 2026Article
- Structural and evolutionary constraints of organophosphate resistance in dipteran carboxylesterases.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Cryptic phenotypic variation emerges rapidly during the adaptive evolution of a carbapenemase.Nature ecology & evolution · 2026Article
- Examining selection dynamics and limitations in multi-round protein selection of high diversity libraries.Protein engineering, design & selection : PEDS · 2026Article
- Directed evolution of a TNA polymerase identifies independent paths to fidelity and catalysis.Nature communications · 2025Article
- Investigating the determinants of performance in machine learning for protein fitness prediction.Protein science : a publication of the Protein Society · 2025Article
- Enzyme Enhancement Through Computational Stability Design Targeting NMR-Determined Catalytic Hotspots.Journal of the American Chemical Society · 2025Article
- How enzyme functions evolve: genetic, structural, and kinetic perspectives.Biophysical reviews · 2025Review
- From duplication to fusion: Expanding Dayhoff's model of protein evolution.Protein science : a publication of the Protein Society · 2025Review
- Computational Stabilization of a Non-Heme Iron Enzyme Enables Efficient Evolution of New Function.Angewandte Chemie (International ed. in English) · 2025Article
- Evolutionary insights into the stereoselectivity of imine reductases based on ancestral sequence reconstruction.Nature communications · 2024Article
- Mutations Selectively Evolving Peroxidase Activity Among Alternative Catalytic Functions of Human Glutathione Transferase P1-1.Antioxidants (Basel, Switzerland) · 2024Article
- Formalizing the law of diminishing returns in metabolic networks using an electrical analogy.Royal Society open science · 2024Article
- Effects of Clinical Mutations in the Second Coordination Sphere and Remote Regions on the Catalytic Mechanism of Non-Heme Fe(II)/2-Oxoglutarate-Dependent Aspartyl Hydroxylase AspH.Chemphyschem : a European journal of chemical physics and physical chemistry · 2024Article
- Evolution of Pyrrolysyl-tRNA Synthetase: From Methanogenesis to Genetic Code Expansion.Chemical reviews · 2024Review
- Addressing epistasis in the design of protein function.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
46 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
6 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Optimization processes, such as evolution, are constrained by diminishing returns-the closer the optimum, the smaller the benefit per mutation, and by tradeoffs-improvement of one property at the cost of others. However, the magnitude and molecular basis of these parameters, and their effect on evolutionary transitions, remain unknown. Here we pursue a complete functional transition of an enzyme with a >10(9)-fold change in the enzyme's selectivity using laboratory evolution. We observed strong diminishing returns, with the initial mutations conferring >25-fold higher improvements than later ones, and asymmetric tradeoffs whereby the gain/loss ratio of the new/old activity decreased 400-fold from the beginning of the trajectory to its end. We describe the molecular basis for these phenomena and suggest they have an important role in shaping natural proteins. These findings also suggest that the catalytic efficiency and specificity of many natural enzymes may be far from their optimum.
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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.