Crystal structures of Mycobacterium tuberculosis KasA show mode of action within cell wall biosynthesis and its inhibition by thiolactomycin.
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Luckner SR, Machutta CA, Tonge PJ, Kisker C
Crystal structures of Mycobacterium tuberculosis KasA show mode of action within cell wall biosynthesis and its inhibition by thiolactomycin.
Structure. 2009 Jul 15;17(7):1004-13. doi: 10.1016/j.str.2009.04.012.
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- 19604480 [ View in PubMed]
- Abstract
Mycobacteria have a unique cell wall consisting of mycolic acids, very-long-chain lipids that provide protection and allow the bacteria to persist within human macrophages. Inhibition of cell wall biosynthesis is fatal for the organism and a starting point for the discovery and development of novel antibiotics. We determined the crystal structures of KasA, a key enzyme involved in the biosynthesis of long-chain fatty acids, in its apo-form and bound to the natural product inhibitor thiolactomycin. Detailed insights into the interaction of the inhibitor with KasA and the identification of a polyethylene glycol molecule that mimics a fatty acid substrate of approximately 40 carbon atoms length, represent the first atomic view of a mycobacterial enzyme involved in the synthesis of long-chain fatty acids and provide a robust platform for the development of novel thiolactomycin analogs with high affinity for KasA.