8E18

Crystal structure of apo TnmK1

Summary for 8E18

• Entry DOI: 10.2210/pdb8e18/pdb
• Descriptor: Secreted hydrolase, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID (3 entities in total)
• Functional Keywords: biosynthesis, hydrolase
• Biological source: Streptomyces sp. CB03234
• Total number of polymer chains: 1
• Total formula weight: 52678.50

Authors

Liu, Y.-C.,Gui, C.,Shen, B. (deposition date: 2022-08-10, release date: 2022-11-09, Last modification date: 2023-10-18)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.14 Å)