{"doi":"10.1002/anie.202004991","title":"Probing Selectivity and Creating Structural Diversity Through Hybrid Polyketide Synthases","abstract":"Engineering polyketide synthases (PKS) to produce new metabolites requires an understanding of catalytic points of failure during substrate processing. Growing evidence indicates the thioesterase (TE) domain as a significant bottleneck within engineered PKS systems. We created a series of hybrid PKS modules bearing exchanged TE domains from heterologous pathways and challenged them with both native and non-native polyketide substrates. Reactions pairing wildtype PKS modules with non-native substrates primarily resulted in poor conversions to anticipated macrolactones. Likewise, product formation with native substrates and hybrid PKS modules bearing non-cognate TE domains was severely reduced. In contrast, non-native substrates were converted by most hybrid modules containing a substrate compatible TE, directly implicating this domain as the major catalytic gatekeeper and highlighting its value as a target for protein engineering to improve analog production in PKS pathways.","journal":"Angewandte Chemie International Edition","year":2020,"id":69052,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9561,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":367820,"name":"Jennifer J. Schmidt","orcid":null,"position":1,"is_corresponding":false},{"id":366205,"name":"Andrew N. Lowell","orcid":"0000-0001-5357-5279","position":2,"is_corresponding":false},{"id":366206,"name":"Douglas A. Hansen","orcid":"0000-0003-4681-650X","position":3,"is_corresponding":false},{"id":367821,"name":"Katherine M. Coburn","orcid":null,"position":4,"is_corresponding":false},{"id":367822,"name":"Joseph A. Chemler","orcid":null,"position":5,"is_corresponding":false},{"id":311103,"name":"David H. Sherman","orcid":"0000-0001-8334-3647","position":6,"is_corresponding":false},{"id":367819,"name":"Aaron A. Koch","orcid":null,"position":0,"is_corresponding":true}],"reference_count":25,"raw_metadata":null,"created_at":"2026-07-18T21:42:22.705573Z","pmid":"32357274","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":[]}