Paradigm Shifts in the History of Nox2 and Its Regulators: An Appreciative Critique

This chapter narrates the history of the almost a century-long work on the phagocyte NADPH oxidase, from the first report on the “respiration” of dog leukocytes phagocytizing bacteria (1932) to the contemporary efforts to predict and solve the structure of the enzyme. The main stations on this stellar road are discussed within their historical context, not omitting the occasional wrong turns and dead ends. The first pivotal findings were that the enzyme used NADPH as reducing power and that the primary product was superoxide, a radical differing from molecular oxygen by the mere addition of a single electron. Solving the intricacies of this “modest” chemical reaction rested on basic discoveries made at the laboratory bench, combined with work on the genetic basis and clinical aspects of chronic granulomatous disease. The most significant discoveries were: the flavoprotein nature of the enzyme; identification and purification of cytochrome b₅₅₈; cloning of Nox2 and p22^phox; the bis-heme motif; presence of all redox centers in Nox2; design of the cell-free system; discovery and identification of the cytosolic components; cloning of p47^phox and p67^phox; involvement of Rac and RhoGDI, and solving the mechanism of the assembly of the functionally active NADPH oxidase complex.