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.

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“…Rather, oxidized proteins are catabolised (i.e. degraded into amino acids), while new replacement proteins are synthesised de novo [24,29]. There are, however, enzyme systems that can repair damaged proteins [24].…”

“…mycosporine-like amino acids and melanin) [26]. Antioxidants include non-enzymatic and enzymatic scavengers that remove either oxidant precursors or the oxidants themselves thereby delaying or preventing oxidative damage [24]. Finally, heat shock proteins are molecular chaperones that prevent damage to proteins that can be caused by exposure to environmental stress factors such as UVR [27].…”

“…These DNA lesions and strand breaks can impede DNA transcription and replication, and thus compromise the functional integrity and viability of cells [21]. Oxidation of lipids and proteins by ROS similarly disrupts cellular functioning by disrupting membrane function and causing structural alterations to proteins that lead to a loss of function, modified turnover and altered interactions with other molecules [23,24]. Depending on the extent of the damage to DNA, protein and lipids, and the capacity for repair (see the section "Defences against UVR damage"), UVR exposure can ultimately lead to mutations and cell death [21] (Fig.…”

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“…ROS may attack both the side chains and backbone, and the extent of the insult depends on multiple factors. In some cases, the damage is limited to specific residues, whereas in case of other ROS, the damage is widespread and nonspecific [78].…”

“…As protein damage is usually non-repairable, oxidation may have deleterious consequences, including the loss (or sometimes gain) of enzymatic, structural or signaling function, fragmentation, unfolding, altered interactions with other proteins and modified turnovers. Generally, oxidized proteins are degraded by proteasomal and lysosomal pathways; however, in some cases, such altered material is poorly degraded and may accumulate within cells contributing to multiple mammalian pathologies [78,79].…”