Crystal structures of Mycobacterium tuberculosis KasA show mode of action within cell wall biosynthesis and its inhibition by thiolactomycin.
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.
Luckner
Sylvia R
SR
Rudolf Virchow Center for Experimental Biomedicine, Institute for Structural Biology, University of Würzburg, Würzburg, Germany.
Machutta
Carl A
CA
Tonge
Peter J
PJ
Kisker
Caroline
C
D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000737:chemistry* / Q000378:metabolism; D000995:Antitubercular Agents / Q000494:pharmacology*; D001665:Binding Sites; D002473:Cell Wall / Q000378:metabolism*; D018360:Crystallography, X-Ray; D005227:Fatty Acids / Q000096:biosynthesis; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000378:metabolism; D009171:Mycolic Acids / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013379:Substrate Specificity; D013876:Thiophenes / Q000494:pharmacology
D000995:Antitubercular Agents; D005227:Fatty Acids; D009171:Mycolic Acids; D013876:Thiophenes; C035068:thiolactomycin; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase