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| Reference : Thiomandelic acid, a broad spectrum inhibitor of zinc beta-lactamases: kinetic and spect... |
| Scientific journals : Article | |||
| Life sciences : Biochemistry, biophysics & molecular biology | |||
| http://hdl.handle.net/2268/77927 | |||
| Thiomandelic acid, a broad spectrum inhibitor of zinc beta-lactamases: kinetic and spectroscopic studies. | |
| English | |
| Mollard, C. [> > > >] | |
| Moali, C. [> > > >] | |
| Papamicael, C. [> > > >] | |
Damblon, Christian  [Université de Liège - ULg > Département de chimie (sciences) > Chimie biologique structurale >] | |
| Vessilier, S. [> > > >] | |
| Amicosante, G. [> > > >] | |
| Schofield, C. J. [> > > >] | |
| Galleni, Moreno [Université de Liège - ULg > Département des sciences de la vie > Macromolécules biologiques >] | |
| Frère, Jean-Marie [Université de Liège - ULg > > Centre d'ingénierie des protéines >] | |
| Roberts, G. C. [> > > >] | |
| 2001 | |
| Journal of Biological Chemistry | |
| American Society for Biochemistry and Molecular Biology | |
| 276 | |
| 48 | |
| 45015-23 | |
| International | |
| 0021-9258 | |
| 1083-351X | |
| Baltimore | |
| MD | |
| [en] Arginine/chemistry ; Binding Sites ; Enzyme Inhibitors/pharmacology ; Kinetics ; Magnetic Resonance Spectroscopy ; Mandelic Acids/chemical synthesis/chemistry/metabolism ; Models, Chemical ; Models, Molecular ; Protein Binding ; Spectrophotometry ; Structure-Activity Relationship ; Sulfhydryl Compounds/chemical synthesis/chemistry/metabolism ; Zinc/chemistry/metabolism ; beta-Lactamases/antagonists & inhibitors | |
| [en] Resistance to beta-lactam antibiotics mediated by metallo-beta-lactamases is an increasingly worrying clinical problem. Candidate inhibitors include mercaptocarboxylic acids, and we report studies of a simple such compound, thiomandelic acid. A series of 35 analogues were synthesized and examined as metallo-beta-lactamase inhibitors. The K(i) values (Bacillus cereus enzyme) are 0.09 microm for R-thiomandelic acid and 1.28 microm for the S-isomer. Structure-activity relationships show that the thiol is essential for activity and the carboxylate increases potency; the affinity is greatest when these groups are close together. Thioesters of thiomandelic acid are substrates for the enzyme, liberating thiomandelic acid, suggesting a starting point for the design of "pro-drugs." Importantly, thiomandelic acid is a broad spectrum inhibitor of metallo-beta-lactamases, with a submicromolar K(i) value for all nine enzymes tested, except the Aeromonas hydrophila enzyme; such a wide spectrum of activity is unprecedented. The binding of thiomandelic acid to the B. cereus enzyme was studied by NMR; the results are consistent with the idea that the inhibitor thiol binds to both zinc ions, while its carboxylate binds to Arg(91). Amide chemical shift perturbations for residues 30-40 (the beta(3)-beta(4) loop) suggest that this small inhibitor induces a movement of this loop of the kind seen for other larger inhibitors. | |
| http://hdl.handle.net/2268/77927 | |
| 10.1074/jbc.M107054200 |
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