Speaker
Prof.
Michael J. Davies
(The Heart Research Institute)
Description
Proteins are major targets for oxidative damage in biological systems due to their high abundance and rapid rates of reaction with radicals and other reactive species (e.g. UV-induced 1O2). Exposure of proteins to radicals generated by radiation, metal ion/hydroperoxide systems, peroxyl radicals, peroxynitrite, and activated white cells, results in the formation of protein-derived radicals. Subsequent reaction of these species in the presence of O2 yields new reactive groups on proteins including hydroperoxides and 3,4-dihydroxyphenylalanine (TIBS, 1993, 18, 437-441; Biochim Biophys Acta 2005, 1703, 93-109). These protein-derived species are long-lived, can diffuse from their site of generation due to slow enzymatic detoxification, and can be detected in intact cells. Subsequent reactions of these intermediates can result in secondary damage, with this occurring via at least two mechanisms: metal-ion mediated reduction of the hydroperoxide to alkoxyl radicals (Biochem J, 1995, 305, 643-649; Arch Biochem Biophys, 1996, 336, 163-172), and direct 2-electron reaction with readily oxidised materials (thiols and thioethers).
Reaction of peptide and protein hydroperoxides with thiol (Cys) groups appears to be of particular biological importance, as this can result in inactivation of critical thiol-dependent enzymes. Thus enzymes involved in protein turnover (cathepsins and the proteasome; Free Radic Biol Med, 2006, 40, 1539-1548; 2011, 50, 389-399), metabolism (GAPDH), signalling (protein tyrosine phosphatases; Free Radic Biol Med, 42, 1543-1551), ion homeostasis (Ca2+-ATPases), redox maintenance Free Radic Biol Med, 2010, 48, 1071-1078; 49, 1505-151) and apoptosis are all readily inactivated by peptide- and protein hydroperoxides. Inactivation occurs in a concentration-, time- and structure-dependent manner with hydroperoxide consumption and thiol oxidation occurring in parallel; in some cases sulfenic acid intermediates are detected. Some protein hydroperoxides are more effective than H2O2, probably as a result of the longer biological lifetime.
Overall, these data support the hypothesis that hydroperoxides formed on oxidized proteins may contribute to cellular dysfunction and altered redox signalling in systems subject to oxidative stress by inducing strand breaks and mutagenic lesions in DNA (Biochem J, 1998, 330, 1059-1067; 1999, 344, 125-134, inhibiting key cellular enzymes, altering cellular redox status and signalling, and depleting antioxidants.
Primary author
Prof.
Michael J. Davies
(The Heart Research Institute)
Co-authors
Dr
Aldwin Suryo Rahmanto
(The Heart Research Institute)
Dr
Philip Morgan
(The Heart Research Institute)
