Oxidative Damage to Proteins

Abstract Proteins are a major target for biological oxidants as a result of their abundance and high rate constants for reaction with many species. Protein damage is therefore a major consequence of oxidant formation both external to and within cells. Reaction can occur with both the side chains and backbone, with the extent of attack at particular sites dependent on multiple factors. In some cases, damage is limited to specific residues, whereas with other species (e.g., hydroxyl radicals), damage is widespread and nonspecific. These pathways, and the resulting products, are reviewed here. The latter include reactive hydroperoxides, which can induce further oxidation and chain reactions (both within proteins and to other molecules) and stable products that can be employed as biomarkers for protein oxidation in vitro and in vivo . The product profile can yield data on the oxidants involved. As most protein damage is nonrepairable, oxidation can have deleterious effects, including loss (or sometimes gain) of function (e.g., enzymatic, structural, or signaling), fragmentation, aggregation, unfolding, altered interactions with other proteins, and modified turnover. The major fate of oxidized proteins is catabolism by proteasomal and lysosomal pathways, but in some cases, these altered materials are poorly degraded and accumulate within cells; this may contribute to multiple human pathologies.