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J. Biol. Chem., Vol. 280, Issue 29, 27402-27411, July 22, 2005

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Copper-catalyzed Protein Oxidation and Its Modulation by Carbon Dioxide

ENHANCEMENT OF PROTEIN RADICALS IN CELLS^*

Dario C. Ramirez, Sandra E. Gomez Mejiba, and Ronald P. Mason

From the Laboratory of Pharmacology and Chemistry, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709

It is well known that hydrogen peroxide (H₂O₂)-induced copper-catalyzed fragmentation of proteins follows a site-specific oxidative mechanism mediated by hydroxyl radical-like species (i.e. Cu(I)O, Cu(II)/^.OH or Cu(III)) that ends in increased carbonyl formation and protein fragmentation. We have found that the nitrone spin trap DMPO (5,5-dimethyl-1-pyrroline N-oxide) prevented such processes by trapping human serum albumin (HSA)-centered radicals, in situ and in real time, before they reacted with oxygen. When (bi)carbonate (CO₂, H₂CO₃, and ) was added to the reaction mixture, it blocked fragmentation mediated by hydroxyl radical-like species but enhanced DMPO-trappable radical sites in HSA. In the past, this effect would have been explained by oxidation of (bi)carbonate to a carbonate radical anion () by a bound hydroxyl radical-like species. We now propose that the radical is formed by the reduction of (a complex of H₂O₂ with CO₂) by the protein-Cu(I) complex. diffuses and produces more DMPO-trappable radical sites but does not fragment HSA. We were also able, for the first time, to detect discrete but highly specific H₂O₂-induced copper-catalyzed -mediated induction of DMPO-trappable protein radicals in functioning RAW 264.7 macrophages. We conclude that carbon dioxide modulates H₂O₂-induced copper-catalyzed oxidative damage to proteins by preventing site-specific fragmentation and enhancing DMPO-trappable protein radicals in functioning cells. The pathophysiological significance of our findings is discussed.

Received for publication, April 19, 2005

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Laboratory of Pharmacology and Chemistry, NIEHS, National Institutes of Health, 111 T. W. Alexander Dr., Bldg. 101, MD F0-02, Research Triangle Park, NC 27709. Tel.: 919-541-3866; Fax: 919-541-1043; E-mail: ramirez1{at}niehs.nih.gov.

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