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

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NADPH Oxidases Revisited: From Function to Structure

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Abstract

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 p22phox; 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 p47phox and p67phox; involvement of Rac and RhoGDI, and solving the mechanism of the assembly of the functionally active NADPH oxidase complex.

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Notes

  1. 1.

    In this chapter, I used the general term “NADPH oxidase” and the abbreviated form “Nox”, approved by the Human Genome Organization (HUGO) Human Gene Nomenclature Committee (HGNC) (https://www.genenames.org) in 2000. This applies to the Nox homologs (also termed Nox isoforms) Nox1, Nox2, Nox3, Nox4, and Nox5, the “numbered” forms referring to the catalytic subunits, only. The approved abbreviated term for “dual oxidase” is “Duox” and the catalytic subunits are known as Duox1 and Duox2. I used “Noxs” as the plural of “Nox”, for lack of a better term.

  2. 2.

    This chapter discusses principally the history of research focused on the phagocyte NADPH oxidase (phagocyte Nox). This is also known as cytochrome b558, flavocytochrome b558, or cytochrome b-245 and is a heterodimer consisting of two subunits, known since 1991, as gp91phox and p22phox. In accordance to the rules of HGNC, the catalytic subunit gp91phox is also known as Nox2 (somewhat unjustly, considering the fact that it was the first to be discovered and characterized). The cytosolic components, p47phox, p67phox, p40phox, and Rac (1 or 2) are not integral parts of the phagocyte NADPH oxidase but assemble with cytochrome b558, to form the phagocyte NADPH oxidase complex.

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Acknowledgements

I am using this opportunity to thank the colleagues, postdoctoral fellows, students, and research associates, with whom I had the privilege to work and collaborate in the course of five decades, for their key role in solving some of the mysteries of Nox2. Here is the list in alphabetical order: Arie Abo, Iris Aharoni, Natalie Alloul, Maya Amichay, Edna Bechor, Yevgeny Berdichevsky, Yael Bromberg, Iris Dahan, Valery Diatchuk, Iris Dotan, Sharon Engel, Aya Federman, Tanya Fradin, Maya Freund, Rahamim Gadba, Yara Gorzalczany, Miriam Hirshberg, Irina Issaieva, Michal Itan, Gili Joseph, Yona Keisari, Pablo Kiselstein, Sarah Knoller, Vasilij Koshkin, Taly Kroizman, Ofra Lotan, Ariel Mizrahi, Shahar Molshanski-Mor, Igor Morozov, Yael Nakash, Eyal Ozeri, Nimrod Pik, Meirav Rafalowski, Rive Sarfstein, Doron Sha’ag, Sally Shpungin, Natalia Sigal, Amir Toporik, Yelena Ugolev, and Anat Zahavi. They are, to paraphrase Churchill, “the few to whom I owe so much”. I thank Dr. Sigrid Noreng for most valuable advice on the structural aspects of Nox2 and for help in conceiving the model illustrated in Fig. 1.7.

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  1. Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Edgar Pick

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    Edgar Pick

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Pick, E. (2023). Paradigm Shifts in the History of Nox2 and Its Regulators: An Appreciative Critique. In: Pick, E. (eds) NADPH Oxidases Revisited: From Function to Structure. Springer, Cham. https://doi.org/10.1007/978-3-031-23752-2_1

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