{"doi":"10.1002/chem.202500012","title":"Crystal Structure and Catalytic Mechanism of the <i>cis</i>‐Eunicellane Cyclase AriE","abstract":"Abstract Eunicellane diterpenoids, with over 360 known examples characterized by a cis ‐ or trans ‐6/10‐bicyclic carbon skeleton, exhibit diverse biological activities. To date, five eunicellane cyclases (ECs) have been reported: cis ‐ECs (Bnd4, CpDTS2 and EcTPS1) and trans ‐ECs (AlbS and MicA), yet the structural basis and molecular mechanisms governing their distinct cis ‐ or trans ‐cyclization modes remain unsolved. Here, we present the crystal structure of a cis ‐EC AriE from Amycolatopsis arida , which catalyzes geranylgeranyl diphosphate to form cis ‐6/10‐fused bicyclic benditerpe‐2,6,15‐triene ( 1 ) in aridacin biosynthesis. Through surface entropy reduction, we obtained the 1.87 Å resolution structure of AriE D128A . Structure‐guided mutagenesis identified W73 as a key regulatory hotspot controlling product diversity, with its variants generating diverse diterpene products. Y203A converted AriE into a highly specific (–)‐( R )‐cembrene A synthase. Our findings provide the first structural insights into this type of terpene synthase and demonstrate the feasibility of engineering EC variants for selective product formation.","journal":"Chemistry - A European Journal","year":2025,"id":539299,"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":0.9436,"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":870271,"name":"Qian Yang","orcid":"0000-0002-4923-4014","position":1,"is_corresponding":false},{"id":244557,"name":"Jingyi He","orcid":"0000-0001-6429-4886","position":2,"is_corresponding":false},{"id":1426438,"name":"Xinru Sun","orcid":"0009-0006-6261-0842","position":3,"is_corresponding":false},{"id":870268,"name":"Xingming Pan","orcid":"0000-0002-4265-872X","position":4,"is_corresponding":false},{"id":1046683,"name":"Huimin Xu","orcid":"0000-0002-0007-1306","position":5,"is_corresponding":false},{"id":568959,"name":"Jeffrey D. Rudolf","orcid":"0000-0003-2718-9651","position":6,"is_corresponding":false},{"id":379256,"name":"Liao‐Bin Dong","orcid":"0000-0002-2943-1299","position":7,"is_corresponding":false},{"id":870270,"name":"Fang‐Ru Li","orcid":"0000-0002-7788-5754","position":0,"is_corresponding":true}],"reference_count":34,"raw_metadata":null,"created_at":"2026-07-19T02:52:30.048313Z","pmid":"40265331","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":[]}