Role of AccD6 in fatty acid and mycolic acid biosynthesis

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

San Miguel de Tucumán

Congreso; XLV Annual Meeting of the Argentinean Society for Biochemistry and Molecular Biology (SAIB); 2009

SAIB

Mycolic acids are essential for the survival, virulence and antibiotic resistance of the human pathogen M. tuberculosis. Their structure and biosynthetic pathways are well studied, however, little information is available regarding the biosynthesis of the precursors for these complex molecules. In Mycobacteria, Acyl-CoA Carboxylases (ACCase) are meant to provide the building blocks for de novo fatty acid biosynthesis. Unlike other organisms, Mycobacteria contain several ACCase complexes, whose specific roles are not well defined. It has been proposed that the M. smegmatis ACCase 6 complex is the essential ACCase that provides the malonyl-CoA for the elongation steps of both fatty acid and mycolic acid biosynthesis. By generating a conditional mutant in the M. smegmatis accD6 gene, we 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 have also characterized a potent AccD6 inhibitor with anti-mycobacterial properties, highlighting the relevance of AccD6 as a target of novel anti-mycobacterial agents. Finally, we studied the effect of malonate supplementation in the accD6 conditional mutant and found that it could help to overcome the lack of ACCase 6 and therefore of malonyl-CoA deficiency. These experiments constitute the first evidences of a link between malonate metabolism and fatty acid biosynthesis.