Reactive oxygen species: toxic molecules or spark of life?

Abstract

Increases in reactive oxygen species (ROS) and tissue evidence of oxidative injury are common in patients with inflammatory processes or tissue injury. This has led to many clinical attempts to scavenge ROS and reduce oxidative injury. However, we live in an oxygen rich environment and ROS and their chemical reactions are part of the basic chemical processes of normal metabolism. Accordingly, organisms have evolved sophisticated mechanisms to control these reactive molecules. Recently, it has become increasingly evident that ROS also play a role in the regulation of many intracellular signaling pathways that are important for normal cell growth and inflammatory responses that are essential for host defense. Thus, simply trying to scavenge ROS is likely not possible and potentially harmful. The 'normal' level of ROS will also likely vary in different tissues and even in different parts of cells. In this paper, the terminology and basic chemistry of reactive species are reviewed. Examples and mechanisms of tissue injury by ROS as well as their positive role as signaling molecules are discussed. Hopefully, a better understanding of the nature of ROS will lead to better planned therapeutic attempts to manipulate the concentrations of these important molecules. We need to regulate ROS, not eradicate them.

Figure 1

The change from thiols (-SH) to disulfide bonds (-S-S-) can produce a conformational change that may allow better protein-protein or protein-DNA interactions. Adapted from Droge et al. [11].

Figure 2

Oxidation of thioredoxin (Trx) by hydrogen peroxide (H₂O₂) leads to a change in shape of the molecule and the release of the transcriptional factor ASK1. Trx is then reduced again by Trx reductase, which allows it to again bind to ASK1 and inactivate this transcriptional factor. Through this mechanism the redox state of the cell can regulate the activity of the transcriptional factor ASK1.

Figure 3

Regulation of phosphatase by the redox state. Cysteine molecules have sulfur atoms (S) that are protonated and not reactive in most proteins. However, on some molecules, such as phosphatases, S can form thiolates (S-) at normal pH and these can be reversibly oxidized. The top of the figure shows the balance between phosphatase activity (which dephosphorylates molecules) and kinase activity (which phosphorylates and activates molecules). Phosphatase activity is regulated by the redox state as shown in the cycle below the bracket. Oxidation to sulfenic acid (-S-OH) is reversible. This can occur by glutathiolation (GSH) or by the formation of disulfides. However, excessive oxidation leads to sulfinic acid, which cannot easily be converted back to reduced forms of sulfur.