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Papers In Press, published online ahead of print April 9, 2003
Biophysics Research Institute, Medical College of Wisconsin, Milwaukee, WI 53226
Corresponding Author: balarama{at}mcw.edu
This study adresses the mechanism of covalent aggregation of human Cu, Zn SOD (hSOD1WT) induced by bicarbonate (HCO3¯)-mediated peroxidase activity. Higher molecular weight species (apparent dimers and trimers) of hSOD1WT were formed from incubation mixtures containing hSOD1WT, H2O2, and HCO3¯. HCO3¯-dependent peroxidase activity and covalent aggregation of hSOD1WT were mimicked by UV photolysis of hSOD1-WT in the presence of a [Co(NH3)5CO3]+ complex that generates the carbonate radical anion (CO3.- ). Human SOD1WT has but one aromatic residue—a tryptophan residue (Trp-32) on the surface of the protein. Substitution of Trp-32 with phenylalanine produced a mutant (hSOD1W32F) which exhibits HCO3¯-dependent peroxidase activity similar to wild-type enzyme. However, unlike hSOD1WT, incubations containing hSOD1W32F, H2O2, and HCO3¯ did not result in covalent aggregation of SOD1. These findings indicate that Trp-32 is crucial for CO3.--induced covalent aggregation of hSOD1WT. Spin-trapping results revealed the formation of the Trp-32 radical from hSOD1WT, but not from hSOD1W32F. Spin traps also inhibited the covalent aggregation of hSOD1WT. Fluorescence experiments revealed that Trp-32 was further oxidized by CO3.-, forming kynurenine-type products in the presence of oxygen. Molecular oxygen was needed for HCO3¯/H2O2-dependent aggregation of hSOD1WT, implicating a role for a Trp-32-dependent peroxidative reaction in the covalent aggregation of hSOD1WT. Taken together, these results indicate that Trp-32 oxidation is crucial for covalent aggregation of hSOD1. Implications of HCO3¯-dependent SOD1 peroxidase activity in ALS disease are discussed.
J. Biol. Chem, 10.1074/jbc.M302051200
Submitted on February 26, 2003
Revised on April 5, 2003
Accepted on April 9, 2003
Bicarbonate dependent peroxidase activity of human copper, zinc superoxide dismutase induces covalent aggregation of protein- intermediacy of tryptophan-derived oxidation products
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