The essential carboxyltransferase AccD6 as a target for novel anti-mycobacterial agents

KURTH, D; GAGO, G; DE LA IGLESIA, A; MORBIDONI, HR; TSAI, SC; GRAMAJO, H

Villa Carlos Paz

Congreso; XLIV Annual Meeting of the Argentinean Society for Biochemistry and Molecular Biology (SAIB); 2008

The hallmark of mycobacteria is their lipid-rich cell wall. Much work has been done solving the structures of these unique lipids and their biosynthetic pathways. However, almost no information is available regarding the biosynthesis of the precursors for these complex molecules. Our working hypothesis is that the alphacarboxy acyl-CoAs utilized in the biosynthesis of the membrane and cell-wall fatty acids are the product of the Acyl-CoA Carboxylase complexes (ACCase) present in Mycobacterium tuberculosis. The ACCase 6 complex, formed by the carboxyltransferase AccD6 and the biotinylated protein AccA3, has been proposed to be the essential ACCase that provides the malonyl-CoA for the elongation steps of both fatty acid and mycolic acid biosynthesis, although this has not been demonstrated experimentally so far. We generated a conditional mutant in the accD6 gene of M. smegmatis. Our analysis of this mutant demonstrated that AccD6 is the essential carboxyltransferase component of the ACCase 6 enzyme complex, and that this complex is implicated in the biosynthesis of malonyl-CoA for both fatty and mycolic acids. Our results shed light on the biological roles of the key ACCases in the biosynthesis of cell wall fatty acids, as well as providing a new target for tuberculosis drug-development.