Activation and modulation of 72kDa matrix metalloproteinase-2 by peroxynitrite and glutathione
| Autor: | Hernando Leon, Grzegorz Sawicki, Tyler van Mulligen, Adrian C. Nicolescu, Andrew Holt, Bryan D. Crawford, Serena Viappiani, Richard Schulz |
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| Rok vydání: | 2009 |
| Předmět: |
inorganic chemicals
Molecular Sequence Data Matrix metalloproteinase medicine.disease_cause Biochemistry Enzyme activator chemistry.chemical_compound Tandem Mass Spectrometry Peroxynitrous Acid Zymogen medicine Humans Amino Acid Sequence Pharmacology Chemistry Glutathione Enzyme Activation Oxidative Stress Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization cardiovascular system Matrix Metalloproteinase 2 Oxidative stress Intracellular Peroxynitrite Cysteine |
| Zdroj: | Biochemical Pharmacology. 77:826-834 |
| ISSN: | 0006-2952 |
| DOI: | 10.1016/j.bcp.2008.11.004 |
| Popis: | Matrix metalloproteinase-2 (MMP-2) has emerged as a key protease in various pathologies associated with oxidative stress, including myocardial ischemia-reperfusion, heart failure or inflammation. Peroxynitrite (ONOO(-)), an important effector of oxidative stress, was reported to activate some full length MMP zymogens, particularly in the presence of glutathione (GSH), but whether this occurs for MMP-2 is unknown. Treating MMP-2 zymogen with ONOO(-) resulted in a concentration-dependent regulation of MMP-2, with 0.3-1 microM ONOO(-) increasing and 30-100 microM ONOO(-) attenuating enzyme activity. The enzyme's V(max) was also significantly increased by 1 microM ONOO(-). Comparable responses to ONOO(-) treatment were observed using the intracellular target of MMP-2, troponin I (TnI). GSH at 100 microM attenuated the effects of ONOO(-) on MMP-2. Mass spectrometry revealed that ONOO(-) can oxidize and, in the presence of GSH, S-glutathiolate the MMP-2 zymogen or a synthetic peptide containing the cysteine-switch motif in the enzyme's autoinhibitory domain. These results suggest that ONOO(-) and GSH can modulate the activity of 72 kDa MMP-2 by modifying the cysteine residue in the autoinhibitory domain of the zymogen, a process that may be relevant to pathophysiological conditions associated with increased oxidative stress. |
| Databáze: | OpenAIRE |
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