{"doi":"10.1038/s41589-019-0386-3","title":"Higher-order epistasis shapes the fitness landscape of a xenobiotic-degrading enzyme","abstract":null,"journal":"Nature Chemical Biology","year":2019,"id":589000,"datarank":2.720504890518926,"base_score":4.919980925828125,"endowment":4.919980925828125,"self_citation_contribution":0.7379971388742189,"citation_network_contribution":1.9825077516447074,"self_endowment_contribution":0.7379971388742189,"citer_contribution":1.9825077516447074,"corpus_percentile":null,"corpus_rank":null,"citation_count":136,"citer_count":107,"citers_with_citation_signal":76,"citers_with_endowment":76,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1506940,"name":"Dave W Anderson","orcid":null,"position":1,"is_corresponding":false},{"id":1506941,"name":"Florian Baier","orcid":null,"position":2,"is_corresponding":false},{"id":1412543,"name":"Elias Dohmen","orcid":"0000-0002-7203-2314","position":3,"is_corresponding":false},{"id":1506942,"name":"Nansook Hong","orcid":null,"position":4,"is_corresponding":false},{"id":1506943,"name":"Paul D Carr","orcid":null,"position":5,"is_corresponding":false},{"id":578349,"name":"Shina Caroline Lynn Kamerlin","orcid":"0000-0002-3190-1173","position":6,"is_corresponding":false},{"id":294181,"name":"Colin J. Jackson","orcid":"0000-0001-6150-3822","position":7,"is_corresponding":false},{"id":645105,"name":"Erich Bornberg‐Bauer","orcid":"0000-0002-1826-3576","position":8,"is_corresponding":false},{"id":214793,"name":"Nobuhiko Tokuriki","orcid":"0000-0002-8235-1829","position":9,"is_corresponding":false},{"id":449679,"name":"Gloria Yang","orcid":"0000-0003-1083-3041","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Higher-order epistasis shapes the fitness landscape of a xenobiotic-degrading enzyme","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.","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"31636435","pmcid":null,"openalex_id":null,"authors":[],"funders":[{"funder_name":"Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada","grant_id":"RGPIN 418262-12","title":null},{"funder_name":"Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada","grant_id":"RGPIN 2017-04909","title":null},{"funder_name":"Human Frontier Science Program","grant_id":"RGP0006/2013","title":null},{"funder_name":"Natural Sciences and Engineering Research Council of Canada","grant_id":"unidentified","title":"unidentified"}],"total_grants":4,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"closed","license":"Springer TDM","oa_locations":[{"url":"http://www.nature.com/articles/s41589-019-0386-3.pdf","host_type":"publisher"},{"url":"http://www.nature.com/articles/s41589-019-0386-3","host_type":"publisher"},{"url":"https://doi.org/10.1038/s41589-019-0386-3","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/31636435","host_type":""},{"url":"https://dx.doi.org/10.1038/s41589-019-0386-3","host_type":""},{"url":"https://doi.org/https://doi.org/10.1038/s41589-019-0386-3","host_type":""}],"fields_of_study":["0301 basic medicine","0303 health sciences","03 medical and health sciences"],"mesh_terms":["Methyl Parathion","Hydrolases","Xenobiotics","Epistasis, Genetic"],"keywords":["Hydrolases","Epistasis, Genetic","Methyl Parathion","Xenobiotics"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-23T11:30:15.043879Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}