The adventures of superoxide dismutase in health and disease: Superoxide in the balance

Abstract

This chapter focuses on superoxide dismutases (SOD), a group of enzymes important for removing biologically generated superoxide anion radical (O 2.-). These enzymes function by catalyzing the dismutation of superoxide radicals to hydrogen peroxide and oxygen, and their action helps to protect cells from oxidation of lipids, proteins and DNA. These enzymes are crucial in maintaining a proper balance of superoxide within specific cellular compartments that is essential for normal cellular signaling and stress responses. Three forms of SOD exist in humans: copper and zinc containing SOD (CuZnSOD), manganese containing SOD (MnSOD) and extracellular SOD (ecSOD). Each of the three SOD proteins plays a unique physiological role based in part on its tissue distribution and sub cellular localization. For example CuZnSOD is generally found in the cytosol, but can also be localized in the nucleus under certain conditions. CuZnSOD protects proteins, lipids and nuclear DNA from oxidation. In contrast, MnSOD, an enzyme required for life in an oxygen atmosphere, is located specifically in the mitochondrial matrix and protects the respiratory machinery and mitochondrial DNA from oxidative damage. ecSOD is found both extracellularly and on the plasma membrane. Its expression is greatest in endothelial cells of blood vessels where its key role appears to be regulating superoxide interactions with nitric oxide. Superoxide and nitric oxide react to form peroxynitrite, a toxic species. This reaction decreases the bioavailability of nitric oxide so it can no longer function to maintain vascular tone and health. The balance of superoxide and nitric oxide is therefore vital for proper vasculature function. In disease processes, dysregulation of SODs results in a pathogenic imbalance of superoxide, leading to profound effects on cells and tissue. For example, aberrant structure or activity of CuZnSOD has been linked to the neurological disease amyotrophic lateral sclerosis (ALS) and developmental abnormalities seen in Down's syndrome. Similarly, decreases in the function of MnSOD have been shown to play a role in carcinogenesis. Finally, cardiovascular disease is associated with poor vascular tone following lowered nitric oxide bioavailability. Decreased ecSOD function results in increased peroxynitrite formation that causes damage to the vasculature, thus accelerating cardiovascular disease. In summary, SODs are an essential group of enzymes that must be present at appropriate levels, structure, and locations to maintain a healthy balance of superoxide, necessary for development and disease prevention. © 2008 Springer Netherlands.