5v3y
Crystal Structure of Mtb Pks13 Thioesterase domain in complex with inhibitor TAM16
Structural highlights
FunctionPKS13_MYCTU Involved in the biosynthesis of mycolic acids (PubMed:19436070, PubMed:23770708, PubMed:25467124). Forms, with FadD32, the initiation module of the mycolic condensation system (PubMed:19436070, PubMed:19477415, PubMed:25467124). Synthesizes, in coupled reaction with FadD32, the biosynthetic precursors of mycolic acids, alpha-alkyl beta-ketoacids, via the condensation of two long chain fatty acid derivatives, a very long meromycoloyl-AMP and a shorter 2-carboxyacyl-CoA (PubMed:19436070, PubMed:25467124). The acyl chain of the acyl-AMP produced by FadD32 is specifically transferred onto the N-terminal ACP domain of Pks13, and then transferred onto the KS domain. The extender unit carboxyacyl-CoA is specifically loaded onto the AT domain, which catalyzes the covalent attachment of the carboxyacyl chain to its active site, and its subsequent transfer onto the P-pant arm of the C-terminal ACP domain. The KS domain catalyzes the condensation between the two loaded fatty acyl chains to produce an alpha-alkyl beta-ketothioester linked to the C-ACP domain (PubMed:19436070). Then, the thioesterase-like domain acts as a transacylase and is responsible for both the release and the transfer of the alpha-alkyl beta-ketoacyl chain onto a polyol acceptor molecule, particularly trehalose, leading to the formation of the trehalose monomycolate precursor (PubMed:25467124).[1] [2] [3] [4] Publication Abstract from PubMedWidespread resistance to first-line TB drugs is a major problem that will likely only be resolved through the development of new drugs with novel mechanisms of action. We have used structure-guided methods to develop a lead molecule that targets the thioesterase activity of polyketide synthase Pks13, an essential enzyme that forms mycolic acids, required for the cell wall of Mycobacterium tuberculosis. Our lead, TAM16, is a benzofuran class inhibitor of Pks13 with highly potent in vitro bactericidal activity against drug-susceptible and drug-resistant clinical isolates of M. tuberculosis. In multiple mouse models of TB infection, TAM16 showed in vivo efficacy equal to the first-line TB drug isoniazid, both as a monotherapy and in combination therapy with rifampicin. TAM16 has excellent pharmacological and safety profiles, and the frequency of resistance for TAM16 is approximately 100-fold lower than INH, suggesting that it can be developed as a new antitubercular aimed at the acute infection. PAPERCLIP. Development of a Novel Lead that Targets M. tuberculosis Polyketide Synthase 13.,Aggarwal A, Parai MK, Shetty N, Wallis D, Woolhiser L, Hastings C, Dutta NK, Galaviz S, Dhakal RC, Shrestha R, Wakabayashi S, Walpole C, Matthews D, Floyd D, Scullion P, Riley J, Epemolu O, Norval S, Snavely T, Robertson GT, Rubin EJ, Ioerger TR, Sirgel FA, van der Merwe R, van Helden PD, Keller P, Bottger EC, Karakousis PC, Lenaerts AJ, Sacchettini JC Cell. 2017 Jul 13;170(2):249-259.e25. doi: 10.1016/j.cell.2017.06.025. Epub 2017 , Jun 29. PMID:28669536[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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