Nox5: Molecular regulation and pathophysiology

Nox5 is considered to be the precursor NADPH oxidase in the evolution of the Noxs and is the most ancient member of the Nox family. It is widely conserved across species and five splice variants have been identified. Nox5 shares structural homology with other isoforms, specifically the catalytic core comprising six transmembrane helices chelating two hemes and a dehydrogenase domain that binds FAD and NADPH. Nox5 is distinct from Nox1–4 in that it has a calcium-binding region with EF-hand domains and is the only isoform that does not require NADPH oxidase subunits for its activation. Nox5 is activated by an increase in intracellular free calcium concentration and undergoes conformational change with consequent superoxide (O2^•-) production. It is also regulated by postranslational modifications and interaction with regulatory partners. While there have been advances in the molecular biology of Nox5, there is a paucity of information on the pathophysiological role of this isoform. Nox5 may be important in sperm function and smooth muscle contraction and it has been implicated in various pathologies including cardiovascular disease, kidney disease and cancer. This chapter provides a comprehensive review of the discovery, regulation and function of Nox5 and the putative role in human health and disease.