Gui_2022_J.Am.Chem.Soc__

Reference

Title : Intramolecular C-C Bond Formation Links Anthraquinone and Enediyne Scaffolds in Tiancimycin Biosynthesis - Gui_2022_J.Am.Chem.Soc__
Author(s) : Gui C , Kalkreuter E , Liu YC , Adhikari A , Teijaro CN , Yang D , Chang C , Shen B
Ref : Journal of the American Chemical Society , : , 2022
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 alpha/beta-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 alpha/beta-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.

PubMedSearch : Gui_2022_J.Am.Chem.Soc__
PubMedID: 36279548
Gene_locus related to this paper: strsp-TnmK1

Related information

Citations formats

Gui C, Kalkreuter E, Liu YC, Adhikari A, Teijaro CN, Yang D, Chang C, Shen B (2022)
Intramolecular C-C Bond Formation Links Anthraquinone and Enediyne Scaffolds in Tiancimycin Biosynthesis
Journal of the American Chemical Society :

Gui C, Kalkreuter E, Liu YC, Adhikari A, Teijaro CN, Yang D, Chang C, Shen B (2022)
Journal of the American Chemical Society :