A new drug target: ACCase6, an essential acetyl-CoA carboxylase of Mycobacterium tuberculosis

KURTH, D; GAGO, G; DIACOVICH, L; GRAMAJO, H

Rosario, Santa Fe, Argentina

Congreso; XLII Annual Meeting of the Argentinean Society for Biochemistry and Molecular Biology (SAIB); 2006

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 informationis available regarding the biosynthesis of the precursors for this complex molecules. Our working hypothesis is that the alphacarboxy acyl-CoAs utilized in the biosynthesis of the membraneand cell-wall fatty acids are the product of the Acyl-CoA Carboxylase complexes (ACCase) present in M. tuberculosis. These enzymes, whose gene structure appears to be uniquewithin actinomycetes, are an attractive target for the development of new and specific anti-mycobacterial agents. We successfully reconstituted the essential ACCase6, whose main role appears to be the synthesis of malonyl-CoA. The kinetic properties of this enzyme showed a clear substrate preference for acetyl-CoA, suggesting that ACCase6 could provide the substrate, malonyl-CoA, for the biosynthesis of straight chain fatty acids in this microorganism. The ligand NCI 170233 inhibited ACCase6 at low μM concentrations. Moreover, this compound inhibited growth of M. smegmatis at μM concentrations. 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 therapeutic development.