INVESTIGADORES
VILA Alejandro Jose
artículos
Título:
Probing the role of Met221 in the unusual metallo-lactamase GOB-18
Autor/es:
LISA, M N; J. MORÁN-BARRIO; GUINDÓN, MF; A. J. VILA
Revista:
INORGANIC CHEMISTRY
Editorial:
AMER CHEMICAL SOC
Referencias:
Lugar: Washington; Año: 2012 vol. 51 p. 12419 - 12425
ISSN:
0020-1669
Resumen:
Metallo-beta-lactamases (MbetaLs) are the main mechanism of bacterial
resistance against last generation β-lactam antibiotics such as
carbapenems. Most M beta Ls display unusual structural features in their
active sites, such as binuclear zinc centers without carboxylate
bridging ligands and/or a Cys ligand in a catalytic zinc site. Cys221 is
an essential residue for catalysis conserved in B1 and B2 lactamases,
while most B3 enzymes present a Ser in this position. GOB lactamases
stand as an exception within this picture, with a Met residue in
position 221. Then, we obtained a series of GOB-18 point mutants in
order to analyze the role of this unusual Met221 residue. We found that
Met221 is essential for the protein stability, most likely due to its
involvement in a hydrophobic core. In contrast to other known MbetaLs,
residue 221 is not involved in metal binding or in catalysis in GOB
enzymes, according to spectroscopic and kinetic studies. Our findings
show that the essential catalytic features are maintained despite the
structural heterogeneity among MbetaLs and suggest that a strategy to
design general inhibitors should be undertaken on the basis of
mechanistic rather than structural information.