8E19
Crystal structure of TnmK1 complexed with TNM H
Summary for 8E19
| Entry DOI | 10.2210/pdb8e19/pdb |
| Related | 8E18 |
| Descriptor | 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) |
| Functional Keywords | biosynthesis, hydrolase |
| Biological source | Streptomyces sp. CB03234 |
| Total number of polymer chains | 1 |
| Total formula weight | 53035.79 |
| 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 Cited by 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: 36279548DOI: 10.1021/jacs.2c08957 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.03 Å) |
Structure validation
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