ArticleNature chemical biology2019
Higher-order epistasis shapes the fitness landscape of a xenobiotic-degrading enzyme.
Article in Nature chemical biology, 2019. 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 62 papers.
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Who cites it
62 citing papers in PubMed, 132 citations in OpenAlex.
- Graph-based representations in modern protein science.The Biochemical journal · 2026Review
- Emergence and evolution of protein-coding de novo genes.Nature reviews. Genetics · 2026Review
- How far can you go? Extrapolating values of catalytic activity from known protein landscapes in natural and directed evolution.Chemical Society reviews · 2026Review
- Studying the evolutionary potential of ancestral aryl sulfatases in the alkaline phosphatase family with droplet microfluidics.The Analyst · 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
- Graph attention with structural features improves the generalizability of identifying functional sequences at a protein interface.bioRxiv : the preprint server for biology · 2025Article
- Article
- Learning sequence-function relationships with scalable, interpretable Gaussian processes.bioRxiv : the preprint server for biology · 2025Article
- Exploring the deletion landscape ofbioRxiv : the preprint server for biology · 2025Article
- Evolutionary-scale enzymology enables exploration of a rugged catalytic landscape.Science (New York, N.Y.) · 2025Article
- Importance of higher-order epistasis in protein sequence-function relationships.bioRxiv : the preprint server for biology · 2025Article
- Exploring Large Protein Sequence Space through Homology- and Representation-based Hierarchical Clustering.Molecular biology and evolution · 2025Article
- Evolution of pollutant biodegradation.Applied microbiology and biotechnology · 2025Review
- Evolutionary insights into the stereoselectivity of imine reductases based on ancestral sequence reconstruction.Nature communications · 2024Article
- Applications of ancestral sequence reconstruction for understanding the evolution of plant specialized metabolism.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2024Review
- Mutations Selectively Evolving Peroxidase Activity Among Alternative Catalytic Functions of Human Glutathione Transferase P1-1.Antioxidants (Basel, Switzerland) · 2024Article
- Understanding epistatic networks in the B1 β-lactamases through coevolutionary statistical modeling and deep mutational scanning.Nature communications · 2024Article
- The simplicity of protein sequence-function relationships.Nature communications · 2024Article
- Opportunities and challenges in design and optimization of protein function.Nature reviews. Molecular cell biology · 2024Review
- Sampling Strategies for Experimentally Mapping Molecular Fitness Landscapes Using High-Throughput Methods.Journal of molecular evolution · 2024Article
2 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
10 authors at 4 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Characterizing the adaptive landscapes that encompass the emergence of novel enzyme functions can provide molecular insights into both enzymatic and evolutionary mechanisms. Here, we combine ancestral protein reconstruction with biochemical, structural and mutational analyses to characterize the functional evolution of methyl-parathion hydrolase (MPH), an organophosphate-degrading enzyme. We identify five mutations that are necessary and sufficient for the evolution of MPH from an ancestral dihydrocoumarin hydrolase. In-depth analyses of the adaptive landscapes encompassing this evolutionary transition revealed that the mutations form a complex interaction network, defined in part by higher-order epistasis, that constrained the adaptive pathways available. By also characterizing the adaptive landscapes in terms of their functional activities towards three additional organophosphate substrates, we reveal that subtle differences in the polarity of the substrate substituents drastically alter the network of epistatic interactions. Our work suggests that the mutations function collectively to enable substrate recognition via subtle structural repositioning.
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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.