Molecular basis of NADPH oxidase activation

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Neutrophils and macrophages are types of white blood cell and are key components of the innate immune system. These cells are professional phagocytes and rapidly engulf and destroy microbes. One of the early events in this process is production of superoxide (02) by activated NADPH oxidase. Hereditary mutations in the NADPH oxidase complex in individuals with chronic granulomatous disease result in recurring life-threatening infections, underlining the importance of this enzyme. However, because of the potential tissue damage that can also be caused by the reactive oxygen species produced by NADPH oxidase, it is tightly regulated. Too much NADPH oxidase activity can be harmful. When neutrophil recruitment and activation by the immune system is abnormally high, life-threatening acute inflammatory tissue injury can result. This is especially prevalent in certain acute viral and bacterial lung infections.

The core catalytic machinery of the enzyme requires the association of four regulatory protein subunits to become fully active. The molecular organisation of the active NADPH oxidase has been the subject of many investigations, however, much remains unexplained about how signalling pathways activate NADPH oxidase. The goal of this research is to understand the structural basis of NADPH oxidase activation and to develop specific chemical inhibitors of this process.

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