Mitochondrial creatine kinase is a prime target of peroxynitrite-induced modification and inactivation.
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Stachowiak O, Dolder M, Wallimann T, Richter C
Mitochondrial creatine kinase is a prime target of peroxynitrite-induced modification and inactivation.
J Biol Chem. 1998 Jul 3;273(27):16694-9.
- PubMed ID
- 9642223 [ View in PubMed]
- Abstract
The reaction of peroxynitrite (PN) with sarcomeric mitochondrial creatine kinase (Mib-CK; EC 2.7.3.2) was observed at different stages of complexity (i) with purified Mi-CK, (ii) with enzyme bound on isolated mitoplasts, and (iii) within intact respiring mitochondria. Creatine-stimulated respiration was abolished by PN concentrations likely to be physiological and far before the respiratory chain itself was affected, thus demonstrating that Mi-CK is a prime target for inactivation by PN in intact mitochondria. The inactivation by PN of Mi-CK was reversed by 22% with 2-mercaptoethanol. More remarkable protective effects were noticed with the full set of CK substrates, e.g. 30 and 50% protection with MgATP plus creatine and MgADP plus phosphocreatine, respectively, but not with each substrate alone. These data indicate an involvement of the active-site Cys-278 residue of Mi-CK in this process. Furthermore, changes in endogenous tryptophan fluorescence intensity and spectral changes after reaction of Mi-CK with PN suggest additional modifications of Trp and Tyr residues. PN-inactivated Mi-CK can no longer be efficiently converted into dimers by incubation with reagents inducing a transition state analog complex at the active site. Thus, obviously, upon reaction of octameric Mi-CK with PN, the octamer-dimer equilibrium of Mi-CK is also affected. The consequences for cellular energy homeostasis and calcium handling are discussed.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Creatine Creatine kinase S-type, mitochondrial Protein Humans YesLigandDetails Phosphocreatine Creatine kinase B-type Protein Humans YesLigandDetails Phosphocreatine Creatine kinase S-type, mitochondrial Protein Humans YesLigandDetails