IBR   13079
INSTITUTO DE BIOLOGIA MOLECULAR Y CELULAR DE ROSARIO
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Acyl-CoA carboxylases as new antimycobacterial drug targets
Autor/es:
KURTH, D; GAGO, G; LIN, T; TSAI, S.,; GRAMAJO, H
Lugar:
Vancouver, Canada
Reunión:
Congreso; Tuberculosis: From Lab Resaerch to Field Trials; 2007
Institución organizadora:
Keystone Symposia
Resumen:
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 this 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 M. tuberculosis. These enzymes, whose gene structure appears to be unique within actinomycetes, are an attractive target for the development of new and specific anti-mycobacterial agents. We successfully reconstituted the essential ACCase6, and demonstrated that this enzyme was able to carboxylate both acetyl-CoA and propionyl-CoA with similar efficiency, resembling the essential acetyl-CoA carboxylase from Streptomyces coelicolor. ACCase6 could then 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. We have also seen inhibition of 14C-acetate incorporation at sub-lethal concentrations of NCI 172033. 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.