Protein peroxides - key intermediates in oxidative damage?

Proteins comprise a major target for reactive radicals and other oxidants in biological systems as a result of their abundance and high rate constants for reaction. Kinetic data suggest that proteins consume > 75% of the hydroxyl radicals generated by gamma radiation. Hydrogen atom abstraction from protein side-chains or the backbone gives rise to carbon-centred radicals, which react at diffusion-controlled rates to give peroxyl radicals. Current data suggests that the major decay route for these peroxyl radicals is via hydrogen atom- or electron-abstraction from neighbouring residues with resultant formation of a further protein radical (thereby initiating chain reactions) and a protein peroxide. These peroxides are major products of protein oxidation induced by a range of species including hydroxyl, alkoxyl and peroxyl radicals, metal ion-catalysed systems, peroxynitrite, activated white cells and singlet oxygen. The yield of these materials, based on the amount of initial oxidant, can be as high as 95%, though this depends on the species involved and the conditions used. These species can be formed in an essentially random manner on both side-chains and the backbone (e.g with hydroxyl radicals) or with great specificity (e.g. with singlet oxygen, where His, Trp and Tyr are the major targets). Some of these peroxides have been characterised. Protein peroxides have half-lives of minutes to days at 4 deg C but can decay rapidly at 37 deg C, or on exposure to UV light or metal ions. Peroxide decomposition can give further radicals, identified by EPR spin trapping, via cleavage of the peroxide bond. Evidence has been obtained for reaction of these protein peroxides, via both radical and non-radical pathways, with other cellular targets including other proteins (e.g. to give enzymatic inactivation), with lipids (thereby initiating peroxidation) and with DNA (to give 8-oxodG, strand breaks and DNA-protein cross-links)