Intramolecular C–C Bond Formation Links Anthraquinone and Enediyne Scaffolds in Tiancimycin Biosynthesis

• DOI: 10.1021/jacs.2c08957
• Publication Date: 2022-10-24T20:56:55Z
• Authors: Chun Gui; Edward Kalkreuter; Yu-Chen Liu; Ajeeth Adhikari; Christiana N. Tei...; Dong Yang; Changsoo Chang; Ben Shen
• Keywords: Enediyne; Anthraquinones; Moiety; Natural product; Anthraquinones

First discovered in 1989, the anthraquinone-fused enediynes are a class of DNA-cleaving bacterial natural products composed DNA-intercalating anthraquinone moiety and 10-membered enediyne warhead. However, until recently, there has been lack genetically amenable hosts sequenced biosynthetic gene clusters available for solving questions surrounding these molecules. Herein, we have identified biochemically structurally characterized TnmK1, member α/β-hydrolase fold superfamily responsible C–C bond formation linking core together tiancimycin (TNM) biosynthesis. In doing so, two intermediates, TNM H I, biosynthesis, containing an unprecedented cryptic C16 aldehyde group, were identified. This plays key role TnmK1-catalyzed via Michael addition, representing first example this chemistry superfamily. Additionally, I shows sub-nanomolar cytotoxicity against selected cancer cell lines, indicating new mechanism action compared to previously known enediynes. Together, findings from study expected impact enzymology, product future efforts at discovery drug development.