Mechanism of action of pyridazine analogues on protein tyrosine phosphatase 1B (PTP1B)
| Autor: | Agneta Tjernberg, Johan Weigelt, Johan Schultz, Stephen James, Kurt Benkestock, Styrbjörn Byström, Dan Hallén |
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| Rok vydání: | 2004 |
| Předmět: |
Reducing agent
Stereochemistry Clinical Biochemistry Pharmaceutical Science Biochemistry Catalysis Pyridazine chemistry.chemical_compound Drug Discovery medicine Hydrogen peroxide Molecular Biology Protein Tyrosine Phosphatase Non-Receptor Type 1 Molecular Structure biology Organic Chemistry Active site Isothermal titration calorimetry Hydrogen Peroxide Pyridazines chemistry Mechanism of action Enzyme inhibitor Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization biology.protein Molecular Medicine Protein Tyrosine Phosphatases medicine.symptom Oxidation-Reduction |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 14:891-895 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2003.12.014 |
| Popis: | The inhibitory effect on PTP1B caused by the addition of pyridazine analogues has been investigated. Biophysical techniques, that is, mass spectrometry (MS), nuclear magnetic resonance (NMR), and isothermal titration calorimetry (ITC) were used for the characterization. Pyridazine analogues cause catalytic oxidation of the reducing agent, generating hydrogen peroxide that oxidizes the active site cysteine on the enzyme, leading to enzyme inactivation. Two additional compound classes show the same effect. We found one common structural feature in these molecules that allows the reaction with triplet molecular oxygen to be less endothermic. A proposed mechanism for the catalytic redox cycle is described. |
| Databáze: | OpenAIRE |
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