Acyl-coa carboxylases in mycobacteria: finding new targets for drug development.

GRAMAJO, H.; GABRIELA MARISA GAGO; KURTH, D.

Rosario

Congreso; XLII Reunión Anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2006

SAIB

The most relevant lipids present in Mycobacterium cell envelope are the mycolic acids, long-chain á-alkyl, â-hydroxy fatty acids, and the characteristic methyl-branched long-chain acids. These unusual fatty acids are essential for the survival, virulence and antibiotic resistance of M. tuberculosis. Acyl-CoA carboxylases (ACCases) commit acyl-CoAs to the biosynthesis of these unique fatty acids. Unlike other organisms, M. tuberculosis contains six ACCase carboxyltransferase (CT) domains, whose specific roles in the pathogen are not well defined. The biochemical characterization of ACCase5 of M. tuberculosis, led us to propose this complex as the propionyl-CoA carboxylase enzyme that produces methylmalonyl-CoA for the biosynthesis of the multimethyl-branched fatty acids. ACCase6, instead, appears to be the acetyl-CoA carboxylase complex that provides malonyl- CoA for the biosynthesis of mycolic acids. Crystal structures of the CT components, AccD5 and AccD6, of these two enzyme complexes showed a highly conserved active site and supported the biochemical roles of these enzymes. In silico screening of NCI database, resulted in the identification of inhibitors of the two CTs, that were also capable of inhibiting growth of M. smegmatis and M. bovis BCG. Our functional and structural studies provide a new structure-based drug design target for tuberculosis therapeutic development.