{"doi":"10.1021/jacs.2c08957","title":"Intramolecular C–C Bond Formation Links Anthraquinone and Enediyne Scaffolds in Tiancimycin Biosynthesis","abstract":"First discovered in 1989, the anthraquinone-fused enediynes are a class of DNA-cleaving bacterial natural products composed of a DNA-intercalating anthraquinone moiety and a 10-membered enediyne warhead. However, until recently, there has been a lack of genetically amenable hosts and sequenced biosynthetic gene clusters available for solving the biosynthetic questions surrounding these molecules. Herein, we have identified and biochemically and structurally characterized TnmK1, a member of the α/β-hydrolase fold superfamily responsible for the C-C bond formation linking the anthraquinone moiety and enediyne core together in tiancimycin (TNM) biosynthesis. In doing so, two intermediates, TNM H and TNM I, in anthraquinone-fused enediyne biosynthesis, containing an unprecedented cryptic C16 aldehyde group, were identified. This aldehyde plays a key role in the TnmK1-catalyzed C-C bond formation via a Michael addition, representing the first example of this chemistry for the α/β-hydrolase fold superfamily. Additionally, TNM I shows sub-nanomolar cytotoxicity against selected cancer cell lines, indicating a new mechanism of action compared to previously known anthraquinone-fused enediynes. Together, the findings from this study are expected to impact enzymology, natural product biosynthesis, and future efforts at enediyne discovery and drug development.","journal":"Journal of the American Chemical Society","year":2022,"id":269810,"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":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9488,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":379253,"name":"Edward Kalkreuter","orcid":"0000-0002-8241-4455","position":1,"is_corresponding":false},{"id":379255,"name":"Yuchen Liu","orcid":"0000-0002-7232-144X","position":2,"is_corresponding":false},{"id":682172,"name":"Ajeeth Adhikari","orcid":"0000-0002-6928-6217","position":3,"is_corresponding":false},{"id":764618,"name":"Christiana N. Teijaro","orcid":"0000-0001-5375-0241","position":4,"is_corresponding":false},{"id":753410,"name":"Dong Yang","orcid":"0000-0003-2917-0663","position":5,"is_corresponding":false},{"id":477425,"name":"Changsoo Chang","orcid":"0000-0003-1860-2969","position":6,"is_corresponding":false},{"id":379257,"name":"Ben Shen","orcid":"0000-0002-9750-5982","position":7,"is_corresponding":false},{"id":933045,"name":"Chun Gui","orcid":"0000-0002-2945-5856","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T00:27:22.602796Z","pmid":"36279548","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":[]}