One- and Two-Electron Oxidations of β-Amyloid 25-35 by Carbonate Radical Anion (CO 3 •- ) and Peroxymonocarbonate (HCO 4 - ): Role of Sulfur in Radical Reactions and Peptide Aggregation.

The beta-amyloid (A beta) peptide plays a key role in the pathogenesis of Alzheimer's disease. The methionine (Met) residue at position 35 in A beta C-terminal domain is critical for neurotoxicity, aggregation, and free radical formation initiated by the peptide. The role of Met in modulating toxicological properties of A beta most likely involves an oxidative event at the sulfur atom. We therefore investigated the one- or two-electron oxidation of the Met residue of A beta(25-35) fragment and the effect of such oxidation on the behavior of the peptide. Bicarbonate promotes two-electron oxidations mediated by hydrogen peroxide after generation of peroxymonocarbonate (HCO4-, PMC). The bicarbonate/carbon dioxide pair stimulates one-electron oxidations mediated by carbonate radical anion (CO3 center dot-). PMC efficiently oxidizes thioether sulfur of the Met residue to sulfoxide. Interestingly, such oxidation hampers the tendency of A beta to aggregate. Conversely, CO3 center dot- causes the one-electron oxidation of methionine residue to sulfur radical cation (MetS(center dot+)). The formation of this transient reactive intermediate during A beta oxidation may play an important role in the process underlying amyloid neurotoxicity and free radical generation.