Regulation of Nox and Duox enzymatic activity and expression

Abstract

SummaryIn recent years, it has become clear that reactive oxygen species (ROS, which include superoxide, hydrogen peroxide and other metabolites) are produced in biological systems. Rather than being simply a byproduct of aerobic metabolism, it is now recognized that specific enzymes ---the Nox (NADPH-oxidase) and Duox (Dual oxidase) enzymes ----seem to have the sole function of generating ROS in a carefully regulated manner, and key roles in signal transduction, immune function, hormone biosynthesis and other normal biological functions are being uncovered. The prototypical Nox is the respiratory burst oxidase or phagocyte oxidase, which generates large amounts of superoxide and other reactive species in the phagosomes of neutrophils and macrophages, playing a central role in innate immunity by killing microbes. This enzyme system has been extensively studied over the past two decades, and provides a basis for comparison with the more recently described Nox and Duox enzymes, which generate ROS in a variety of cells and tissues. This review first considers the structure and regulation of the respiratory burst oxidase, and then reviews recent studies relating to the regulation of the activity of the novel Nox/Duox enzymes. The regulation of Nox and Duox expression in tissues and by specific stimuli is also considered here. An accompanying review considers biological and pathological roles of the Nox family of enzymes. The Respiratory Burst Oxidase of Phagocytes a. The respiratory burstThe "respiratory burst" refers to the early observation that when professional phagocytes such as neutrophils and macrophages are exposed to microbes, they consume large amounts of oxygen. Unexpectedly, this oxygen consumption was not inhibited by cyanide, an inhibitor of mitochondrial electron transport. This observation led to a more than 25 year search for the enzymatic origin of the respiratory burst and to the eventual discovery and molecular characterization of the phagocytic NADPH-oxidase or "respiratory burst oxidase". The phagocyte oxidase generates superoxide via the one electron-reduction of oxygen by NADPH, with secondary production of hydrogen peroxide, HOCl and other activated forms of oxygen. Together, these reactive oxygen species (ROS) participate in host defense by killing invading microbes. b. gp91 phox , the catalytic moiety of the respiratory burst oxidaseThe phagocytic NADPH-oxidase consists of a membrane-localized glycosylated, catalytic subunit, gp91 phox (which has also come to be known as Nox2, a terminology that will be used in this review), along with a second membrane-associated subunit, p22 phox , both depicted in Fig. 1. Nox2 and p22 phox stabilize one another in a tightly associated heterodimer which is referred to as flavocytochrome b 558 . The C-terminal half of Nox2 forms a domain that is Contact information: 148 Whitehead Biomedical Research Building, Department of Pathology and Laboratory Medicine, 615 Michael Street, Atlanta, GA 30322, U.S. A. Phone: 404-727-5875, Fax: 404-712-2979, e-mail: nox...

NADPH oxidases in lung biology and pathology: Host defense enzymes, and more

“…General features of NOX/DUOX and their regulators and activation mechanisms are summarized in Table I. Additional details regarding the molecular biology and regulation of the various NOX/DUOX enzymes are summarized in several excellent recent reviews (1,2,6,16).…”

“…In addition, NOX4 expression is also induced by other stimuli, including hypoxia/ischemia, shear stress, and ER stress, but to date no information appears to be available regarding the NOX4 promoter or its transcriptional regulators (6,16,81). NOX4 appears to be evolutionary more distant from NOX1-3, and only shares ~39% identity to NOX2.…”

Common and Diverging Integrin Signals Downstream of Adhesion and Mechanical Stimuli and Their Interplay with Reactive Oxygen Species

“…These variations, together with the complicated chemistry and fast reactivity of ROS, underlie the complexity of this research field and the experimental difficulties it is facing. More detailed information can be found in several comprehensive reviews on ROS chemistry and biology (41,(60)(61)(62)(63)(64)(65).…”

Regulation of smooth muscle by inducible nitric oxide synthase and NADPH oxidase in vascular proliferative diseases

“…The molecular mechanisms regulating Nox activity have been recently reviewed [20,96]. In general terms, Noxs are multimeric complexes composed of one or two membrane proteins (Nox and p22phox) as well as cytosolic components including p47phox, NOXO1, p40phox, p67phox, NOXOA1, Rac1 and Rac2.…”