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Originally published In Press as doi:10.1074/jbc.M208572200 on October 24, 2002

J. Biol. Chem., Vol. 278, Issue 2, 1125-1130, January 10, 2003
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Differential Effects of Peroxynitrite on Human Mitochondrial Creatine Kinase Isoenzymes
INACTIVATION, OCTAMER DESTABILIZATION, AND IDENTIFICATION OF INVOLVED RESIDUES*

Silke Wendt, Uwe SchlattnerDagger , and Theo Wallimann

From the Institute of Cell Biology, Swiss Federal Institute of Technology, Hönggerberg HPM, CH-8093 Zürich, Switzerland

Creatine kinase isoenzymes are very susceptible to free radical damage and are inactivated by superoxide radicals and peroxynitrite. In this study, we have analyzed the effects of peroxynitrite on enzymatic activity and octamer stability of the two human mitochondrial isoenzymes (ubiquitous mitochondrial creatine kinase (uMtCK) and sarcomeric mitochondrial creatine kinase (sMtCK)), as well as of chicken sMtCK, and identified the involved residues. Inactivation by peroxynitrite was concentration-dependent and similar for both types of MtCK isoenzymes. Because peroxynitrite did not lower the residual activity of a sMtCK mutant missing the active site cysteine (C278G), oxidation of this residue is sufficient to explain MtCK inactivation. Mass spectrometric analysis confirmed oxidation of Cys-278 and further revealed oxidation of the C-terminal Cys-358, possibly involved in MtCK/membrane interaction. Peroxynitrite also led to concentration-dependent dissociation of MtCK octamers into dimers. In this study, ubiquitous uMtCK was much more stable than sarcomeric sMtCK. Mass spectrometric analysis revealed chemical modifications in peptide Gly-263-Arg-271 located at the dimer/dimer interface, including oxidation of Met-267 and nitration of Trp-268 and/or Trp-264, the latter being a very critical residue for octamer stability. These data demonstrate that peroxynitrite affects the octameric state of MtCK and confirms human sMtCK as the generally more susceptible isoenzyme. The results provide a molecular explanation of how oxidative damage can lead to inactivation and decreased octamer/dimer ratio of MtCK, as seen in neurodegenerative diseases and heart pathology, respectively.

* This work was supported by a Swiss Federal Institute of Technology graduate training stipend (to S. W.) and grants of the Swiss Society for Research of Muscle Diseases (to T. W.), the Novartis Foundation (to T. W.), the Swiss National Science Foundation (Grant 31-62024.00 to T. W. and U. S.), the Schweizer Krebsliga, and the Zentralschweizer Krebsliga (to U. S. and T. W.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed. Tel.: 41-1-633-33-91; Fax: 41-1-633-10-69; E-mail: schlattn@cell.biol.ethz.ch.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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