One- and Two-Electron Oxidations of beta-Amyloid 25-35 by Carbonate Radical Anion (CO 3o-) 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-beta25-35 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 (CO3o-). PMC efficiently oxidizes thioether sulfur of the Met residue to sulfoxide. Interestingly, such oxidation hampers the tendency of A-beta to aggregate. Conversely, CO3o- causes the one-electron oxidation of methionine residue to sulfur radical cation (MetSo+). 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.