INVESTIGADORES
GRAMAJO Hugo Cesar
congresos y reuniones científicas
Título:
A NEW DRUG TARGET: ACCASE6, AN ESSENTIAL
Autor/es:
KURTH, D.; GAGO, G.; DIACOVICH, L.; GRAMAJO, H.C.
Lugar:
Rosario
Reunión:
Congreso; SAIB XLII reunion anual; 2006
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, 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