دورية أكاديمية
Thiomandelic acid, a broad spectrum inhibitor of zinc beta-lactamases: kinetic and spectroscopic studies.
| العنوان: | Thiomandelic acid, a broad spectrum inhibitor of zinc beta-lactamases: kinetic and spectroscopic studies. |
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| المؤلفون: | Mollard, C., Moali, C., Papamicael, C., Damblon, Christian, Vessilier, S., Amicosante, G., Schofield, C. J., Galleni, Moreno, Frère, Jean-Marie, Roberts, G. C. |
| المصدر: | Journal of Biological Chemistry, 276 (48), 45015-23 (2001) |
| بيانات النشر: | American Society for Biochemistry and Molecular Biology, 2001. |
| سنة النشر: | 2001 |
| مصطلحات موضوعية: | 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, Life sciences, Biochemistry, biophysics & molecular biology, Sciences du vivant, Biochimie, biophysique & biologie moléculaire |
| الوصف: | 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. |
| نوع الوثيقة: | journal article http://purl.org/coar/resource_type/c_6501Test article |
| اللغة: | English |
| العلاقة: | urn:issn:0021-9258; urn:issn:1083-351X |
| DOI: | 10.1074/jbc.M107054200 |
| الوصول الحر: | https://orbi.uliege.be/handle/2268/77927Test |
| رقم الانضمام: | edsorb.77927 |
| قاعدة البيانات: | ORBi |
| DOI: | 10.1074/jbc.M107054200 |
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