Abstract
This chapter focusses on the biological formation and reactions of the superoxide radical, with emphasis on production by NADPH oxidases (NOXes). There are seven members of the NOX family, all of which catalyze the oxidation of NADPH and the transfer of electrons to oxygen. NOXes 1-3 and 5 transfer a single electron to generate superoxide radicals as their primary product whereas the others transfer two electrons to give hydrogen peroxide. The topology of the NOX enzyme complex is such that electron transfer occurs across a membrane, to generate superoxide in phagosomes, endosomes or extracellularly. Superoxide production by NOX2 in neutrophils and other phagocytic cells is important for their antimicrobial activity whereas NOX activity in other cells has more of a signaling role. Most biologically generated superoxide undergoes either spontaneous or superoxide dismutase-catalyzed dismutation to oxygen and hydrogen peroxide. However, superoxide does react with other biological molecules, notably iron-sulfur centres in proteins, nitric oxide, other radicals and transition metal centres. These reactions can be deleterious but also have a regulatory function. The widely held view is that the antimicrobial activity associated with NOX activation in phagocytes and the signalling functions in other cells are due to hydrogen peroxide and other downstream products. However, this begs the question as to why NOXes are designed to produce superoxide and there are grounds for considering whether superoxide itself plays a more direct role.