INVESTIGADORES
GRAMAJO Hugo Cesar
congresos y reuniones científicas
Título:
ACYL-CoA CARBOXYLASES IN MYCOBACTERIA:
Autor/es:
GRAMAJO, H.C.; GAGO, G.; KURTH, D.H
Lugar:
Rosario
Reunión:
Congreso; SAIB XLII reunion anual; 2006
Resumen:
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.