L-4 - Protein oxidation: Beyond the cell

Abstract

Proteins are major targets for oxidants due to their abundance and high rate constants for reaction. For isolated proteins, we now have a reasonable understanding of both the chemistry that occurs, and its structural and functional consequences. With highly-reactive oxidants both side-chain and backbone damage can be detected, whereas with less reactive species more selective damage is observed, primarily at the side-chains of Cys, Met, Trp, Tyr and His. For cellular proteins, a similar pattern can be observed. Much of this damage is repaired, or removed rapidly via protein catabolism. Outside the cell, the situation is somewhat different. Extracellular proteins, and particularly matrix protein, are often highly abundant (e.g. elastin comprises ~50% of arteries by dry mass) and are relatively poorly protected against damage. Many of these proteins are long-lived and can accumulate high levels of modification during ageing and disease. Most of these proteins have low levels of Cys and Met residues resulting in altered extents and types of damage. Of particular note are the high levels of cystine (i.e. disulfides) present in some structural proteins. Recent data indicate that some of these are particularly susceptible to oxidation, with this resulting in structural, functional and mechanical changes, with consequences for tissue integrity and the function of adherent cells.