{"doi":"10.1021/jacs.3c02109","title":"Fungal P450 Deconstructs the 2,5-Diazabicyclo[2.2.2]octane Ring <i>En Route</i> to the Complete Biosynthesis of 21<i>R</i>-Citrinadin A","abstract":"Prenylated indole alkaloids (PIAs) possess great structural diversity and show biological activities. Despite significant efforts in investigating the biosynthetic mechanism, the key step in the transformation of 2,5-diazabicyclo[2.2.2]octane-containing PIAs into a distinct class of pentacyclic compounds remains unknown. Here, using a combination of gene deletion, heterologous expression, and biochemical characterization, we show that a unique fungal P450 enzyme CtdY catalyzes the cleavage of the amide bond in the 2,5-diazabicyclo[2.2.2]octane system, followed by a decarboxylation step to form the 6/5/5/6/6 pentacyclic ring in 21 R -citrinadin A. We also demonstrate the function of a subsequent cascade of stereospecific oxygenases to further modify the 6/5/5/6/6 pentacyclic intermediate en route to the complete 21 R -citrinadin A biosynthesis. Our findings reveal a key enzyme CtdY for the pathway divergence in the biosynthesis of PIAs and uncover the complex late-stage post-translational modifications in 21 R -citrinadin A biosynthesis.","journal":"Journal of the American Chemical Society","year":2023,"id":346292,"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":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9516,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":867685,"name":"Qiuyue Nie","orcid":"0000-0002-2805-1462","position":1,"is_corresponding":false},{"id":488770,"name":"Zhiwen Liu","orcid":"0000-0002-9049-1303","position":2,"is_corresponding":false},{"id":1056097,"name":"Siddhant Patil","orcid":"0000-0002-4142-1456","position":3,"is_corresponding":false},{"id":460946,"name":"Xue Gao","orcid":"0000-0003-3213-9704","position":4,"is_corresponding":false},{"id":1056096,"name":"Shuai Liu","orcid":"0009-0005-0883-571X","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-19T01:11:48.317335Z","pmid":"37352463","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":[]}