8E19

Crystal structure of TnmK1 complexed with TNM H

8E19 の概要

• エントリーDOI: 10.2210/pdb8e19/pdb
• 関連するPDBエントリー: 8E18
• 分子名称: Secreted hydrolase, (1R,8S,13S)-8-[(4-hydroxy-9,10-dioxo-9,10-dihydroanthracen-1-yl)amino]-12-methoxy-10-methylbicyclo[7.3.1]trideca-9,11-diene-2,6-diyne-13-carbaldehyde, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (5 entities in total)
• 機能のキーワード: biosynthesis, hydrolase
• 由来する生物種: Streptomyces sp. CB03234
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 53035.79

構造登録者

Liu, Y.-C.,Gui, C.,Shen, B. (登録日: 2022-08-10, 公開日: 2022-11-09, 最終更新日: 2023-10-18)

主引用文献

Gui, C.,Kalkreuter, E.,Liu, Y.C.,Adhikari, A.,Teijaro, C.N.,Yang, D.,Chang, C.,Shen, B.
Intramolecular C-C Bond Formation Links Anthraquinone and Enediyne Scaffolds in Tiancimycin Biosynthesis.
J.Am.Chem.Soc., 144:20452-20462, 2022

PubMed 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.

PubMed: 36279548
DOI: 10.1021/jacs.2c08957

実験手法

X-RAY DIFFRACTION (2.03 Å)