5v40

Structural highlights

Function

PKS13_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]}

References

1. ↑ Gavalda S, Léger M, van der Rest B, Stella A, Bardou F, Montrozier H, Chalut C, Burlet-Schiltz O, Marrakchi H, Daffé M, Quémard A. The Pks13/FadD32 crosstalk for the biosynthesis of mycolic acids in Mycobacterium tuberculosis. J Biol Chem. 2009 Jul 17;284(29):19255-64. PMID:19436070 doi:10.1074/jbc.M109.006940
2. ↑ Léger M, Gavalda S, Guillet V, van der Rest B, Slama N, Montrozier H, Mourey L, Quémard A, Daffé M, Marrakchi H. The dual function of the Mycobacterium tuberculosis FadD32 required for mycolic acid biosynthesis. Chem Biol. 2009 May 29;16(5):510-9. PMID:19477415 doi:10.1016/j.chembiol.2009.03.012
3. ↑ Wilson R, Kumar P, Parashar V, Vilchèze C, Veyron-Churlet R, Freundlich JS, Barnes SW, Walker JR, Szymonifka MJ, Marchiano E, Shenai S, Colangeli R, Jacobs WR Jr, Neiditch MB, Kremer L, Alland D. Antituberculosis thiophenes define a requirement for Pks13 in mycolic acid biosynthesis. Nat Chem Biol. 2013 Aug;9(8):499-506. PMID:23770708 doi:10.1038/nchembio.1277
4. ↑ Gavalda S, Bardou F, Laval F, Bon C, Malaga W, Chalut C, Guilhot C, Mourey L, Daffé M, Quémard A. The polyketide synthase Pks13 catalyzes a novel mechanism of lipid transfer in mycobacteria. Chem Biol. 2014 Dec 18;21(12):1660-9. PMID:25467124 doi:10.1016/j.chembiol.2014.10.011
5. ↑ 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. Development of a Novel Lead that Targets M. tuberculosis Polyketide Synthase 13. Cell. 2017 Jul 13;170(2):249-259.e25. doi: 10.1016/j.cell.2017.06.025. Epub 2017 , Jun 29. PMID:28669536 doi:http://dx.doi.org/10.1016/j.cell.2017.06.025