{"doi":"10.1002/anie.202504982","title":"Structural Basis of Sequential Enantioselective Epoxidation by a Flavin‐Dependent Monooxygenase in Lasalocid A Biosynthesis","abstract":"Polyether polyketides are a structurally diverse group of natural products known for their antimicrobial and antiproliferative activities. Lasalocid A is a canonical natural polyether produced by the soil bacterium Streptomyces lasalocidi. In lasalocid A biosynthesis, a polyene polyketide intermediate is converted into a bisepoxide by the flavin-dependent monooxygenase enzyme Lsd18. Remarkably, Lsd18 acts on two distinct C═C groups in the substrate molecule, forming two (R,R) epoxides. We have determined the X-ray crystal structures of Lsd18 in the substrate-free, substrate-bound, and product-bound forms. Our work has revealed that Lsd18 has an extra-large substrate-binding pocket that allows the polyene to adopt different conformations within the enzyme pocket. This feature enables Lsd18 to epoxidate both of the C═C groups. Additionally, a subpocket located near the Lsd18 active site controls stereoselectivity by dictating which face of the C═C group is placed next to the flavin. Molecular understanding of how Lsd18 transforms a polyene into a bisepoxide during lasalocid A biosynthesis lays the foundation for the production of designer polyethers for drug development.","journal":"Angewandte Chemie International Edition","year":2025,"id":539198,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9464,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1063076,"name":"Yaming Deng","orcid":null,"position":1,"is_corresponding":false},{"id":1426734,"name":"Dayan Viera","orcid":null,"position":2,"is_corresponding":false},{"id":447300,"name":"Xiaopeng Liu","orcid":"0000-0001-9856-0150","position":3,"is_corresponding":false},{"id":1062457,"name":"Ning Liu","orcid":"0000-0002-8282-5393","position":4,"is_corresponding":false},{"id":1426368,"name":"Yulu Hu","orcid":"0000-0002-4472-3409","position":5,"is_corresponding":false},{"id":1426369,"name":"Xiangdong Hu","orcid":"0000-0002-8644-6454","position":6,"is_corresponding":false},{"id":1426370,"name":"Hao Wei","orcid":"0000-0003-4917-6421","position":7,"is_corresponding":false},{"id":1426371,"name":"Quan Zhou","orcid":"0000-0002-1196-0803","position":8,"is_corresponding":false},{"id":1426372,"name":"Ting Lan","orcid":"0000-0001-7821-9537","position":9,"is_corresponding":false},{"id":1426373,"name":"Wei He","orcid":"0009-0007-2546-9111","position":10,"is_corresponding":false},{"id":1062460,"name":"Xi Chen","orcid":"0000-0001-8295-2854","position":11,"is_corresponding":false},{"id":646800,"name":"Chu‐Young Kim","orcid":"0000-0003-3744-7802","position":12,"is_corresponding":false},{"id":1062456,"name":"Qian Wang","orcid":"0000-0002-1346-9524","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T02:52:30.048313Z","pmid":"40199722","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":[]}