OP46 - Superoxide-mediated post-translational modification of tyrosine residues

Abstract

Superoxide is a byproduct of aerobic respiration. Its in vivo formation is associated with many inflammatory diseases, oxidative stress and aging. Regardless of the rapid spontaneous disproportion of superoxide to give hydrogen peroxide and oxygen, aerobic organisms cannot survive without further catalyzing the rate of this reaction by superoxide dismutase. Therefore, chemical reactions, which contribute to the detrimental effects of superoxide, have to be fast enough to compete with the catalytic dismutation process. The reaction of superoxide with tyrosyl radicals fulfills this criterion and we have shown in a series of publications (see below) that radical addition reactions to tyrosine residues may represent a possible mechanism for superoxide toxicity. Tyr residues are major sites of radical attack on proteins and they also form at active sites of pivotal enzymes (such as cyclo-oxygenase or ribonucleotide reductase) during turnover. This presentation will focus on the mechanisms of the reaction of superoxide with tyrosyl radicals in peptides and proteins in a wide range of model systems. We will present that addition of superoxide to tyrosyl radicals result in the formation of novel Tyr-hydroperoxide species, which can further react with 1) Met residues via intramolecular oxygen transfer to form Met sulfoxide or 2) Cys residues to generate the corresponding disulfide species. These reactions produce a modified bicyclic Tyr monoxide species, which favorably undergo a Michael addition reaction with thiols (such as glutathione) to form novel Tyr-Cys cross-linked adducts.