Role of the essential carboxyltransferase AccD6

KURTH, D; BAZET LYONNET, B; GAGO, G; GRAMAJO, H

Rosario, Santa Fe, Argentina

Congreso; IV SLAMTB Meeting; 2009

SLAMTB

The hallmark of mycobacteria is their lipid-rich cell wall, where mycolic acids are one of the fundamental components. Their structure and biosynthetic pathways are well studied. However, almost no information is available regarding the biosynthesis of the precursors for these complex molecules. In most organisms, the alphacarboxy acyl-CoAs utilized in the biosynthesis of the membrane and cell-wall fatty acids are the product of the Acyl-CoA Carboxylases (ACCase). Several ACCase complexes are present in Mycobacteria, and only a few of them have been characterized. The M. smegmatis 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. To study this enzyme as a promising target for new drugs, and to confirm its role in vivo, 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. We also characterized an inhibitor of AccD6 with antimycobacterial properties highlighting the relevance of AccD6 as a new drug target. Finally, we found evidences that malonate suplementation could help to overcome the lack of ACCase 6 in M. smegmatis, suggesting a link between malonate metabolism and fatty acid biosynthesis.