Review Article
Regulation of Nox and Duox enzymatic activity and expression

https://doi.org/10.1016/j.freeradbiomed.2007.03.028Get rights and content

Abstract

In 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 by-product 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.

Section snippets

The respiratory burst

The “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

Reactive oxygen in nonphagocytic cells

During the 1990s, probably as a result of more sensitive methods for detection of H2O2 and O2-, several groups reported the occurrence of ROS in a wide variety of cell types other than professional phagocytes [70], [71], [72], [73], [74], [75], [76]. Although frequently attributed to mitochondrial respiration, in many cases ROS generation was inhibited by diphenylene iodonium (DPI), an inhibitor of the phagocyte NADPH oxidase and some other flavoprotein dehydrogenases [77]. However, although

Regulation of the activity of nonphagocytic Nox/Duox enzymes

A summary of the known modes of regulation of Nox and Duox enzymes is shown in Table 1, and is detailed below.

Regulation of Nox/Duox expression

Although the activity of Nox and Duox enzymes is acutely regulated by subunits or calcium, the maximum capacity of a cell to generate ROS will be determined not only by the activation state, but also by the protein expression of Nox/Duox enzymes and their regulatory subunits. Misregulation of Nox protein expression is a component of certain disease states and stress responses, as discussed in the accompanying review. Therefore, the transcriptional and perhaps translational regulation of Nox

Conclusions

This review of the mechanism and regulation of ROS generation by Nox and Duox enzymes makes evident that ROS levels in cells and tissues are carefully controlled, both by tissue- and stimulus-specific expression of Nox and Duox proteins and their regulatory subunits, and by acute regulation via calcium, protein phosphorylation, guanine nucleotide exchange on Rac, and the assembly of regulatory subunits. Both the expression and the acute activation are regulated by complex mechanisms, and much

Acknowledgments

This work was supported by NIH Grants CA105116 and CA084138.

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