Antioxidant Defence

Characterisation of a family of enzymes as peroxidases almost automatically triggers the idea that they are in charge of defence against oxidative stress. This is not necessarily justified, and many examples of better known peroxidase families may be quoted to highlight that the ability to reduce hydroperoxides is used physiologically for different purposes. In fact, most of the known heme-type peroxidases just use the substrate H2O2 to achieve specific syntheses that require oxidation equivalents, and similarly the phospholipid hydroperoxide glutathione peroxidase (GPx4) makes use of hydroperoxides to cross-link proteins, which is a process indispensable for sperm maturation in mammals (Ursini et al., 1999).

However, ever since the production of an oxygen-rich atmosphere early in biological evolution, living organisms have of necessity developed protective systems to combat the powerful damaging effects of oxidation. Peroxides (hydrogen peroxide, alkyl hydroperoxides and peroxynitrite) and oxygen- and nitrogen-centred radicals derived there from (ROS or NOS, respectively) have the potential to chemically damage carbohydrates, proteins, lipids and nucleic acids. Being a kind of unavoidable hazard in aerobic life, ROS and NOS are further "misused" to build up the armamentarium of the steady battle between pathogenic micro-organisms and their victims. In this context, the formation of the superoxide radical is often complicated by generation of NO and lipid hydroperoxides by NO synthases and lipoxygenases, respectively. Inevitably, this scenario affords efficient systems of self-protection and defence against the chemical attack from outside. The required efficiency is best achieved by catalysis, and accordingly the biological defence systems are commonly composed of enzymes.

The first line of defence appears to be common to all organisms with the exception of some anaerobes (Jenney et al., 1999). One or the other type of superoxide dismutase (SOD) eliminates the superoxide radical anion that arises from autoxidation processes, leakage of the respiratory chain or the respiratory burst during the innate immune response. One of the products of the SOD reaction, H2O2, has to be removed by peroxidases, since it is cytotoxic as such and may generate even more drastic oxidants such as hypochloric acid or the hydroxyl radical which destroys most of the cellular components with diffusion-limited rate constants. Nature has invented at least three distinct families of proteins for this job: the heme-type peroxidases, the glutathione peroxidases (Flohe and Brigelius-Flohe, 2006), and the peroxiredoxins (Hofmann et al., 2002), and such proteins and their supply devices have been combined during evolution, with considerable complexity, to provide species-specific antioxidant defence systems (see Chapters 6-8 and 10-12). The peroxidase family known best, the heme proteins, appears to be least suited to cope with the demand, since they typically reduce only H2O2 at sufficient rates; the glutathione peroxidases act on a large variety of hydroperoxides and do so with extreme velocity when they contain selenocysteine in their active site; the peroxiredoxins, which almost exclusively work with sulphur catalysis, are less efficient, but share with glutathione peroxidases the broad substrate specificity that may cover hydroperoxides of complex lipids and even peroxynitrite (Bryk et al., 2000; Hofmann et al, 2002; Jaeger et al., 2004; Trujillo et al, 2004). In many micro-organisms, which often lack the more efficient heme- and selenoperoxidases, peroxiredoxins appear to be the predominant, if not the only peroxide-detoxifying enzymes. In vertebrates, where the peroxiredoxins have to compete with a variety of faster peroxidases, more specific biological roles than defence against generalized oxidative stress are likely to be involved (Hofmann et al., 2002). In some mammalian tissues, however, peroxiredoxins are sufficiently abundant to contribute to defence against oxidative stress (Lee et al., 2003).

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