NADPH oxidases: Introduction

The NADPH oxidase (NOX) family are conserved transmembrane enzymes that are expressed in a number of human tissues [8]. Shared core structural elements include a heme-containing 6-transmembrane domain, a FAD cofactor binding site and a cytosolic NADPH binding domain. NOXs facilitate electron transfer across the plasma membrane and are important for redox homeostasis. The DUOX enzymes contain an extracellular peroxidase homology domain. NOX2 is found in phagocytic cells, whereas NOX1, 3, 4 and 5 are expressed by non-phagocytic cells [1-2].
NOX enzymes are a significant source of reactive oxygen species (ROS) in a large variety of diseases [5,7,9,13]. Accumulating evidence implicates the NOXs in the development and progression of inflammation-associated disorders (including atherosclerosis [10] and fibrosis [6]), and cancer [3,11]. Preclinical studies show that dual NOX1/4 inhibitors have broad potential across fibrotic and inflammatory diseases of the kidney, liver, lungs and skin. GKT137831 (Genkyotex) is the first NOX inhibitor to reach clinical evaluation and will serve as proof-of-principle for the clinical utility of NOX inhibitors in human diseases.

The DUOX enzymes are isoforms of phagocyte NOX2, but activation of these enzymes is mediated by the presence of calcium‐regulated EF‐hand domains rather than by protein cofactors that are required for NOX activation. They were first identified in thyroid tissues as enzymes critical for the production of the H2O2 that supports oxidative iodination by thyroperoxidase (TPO) in the generation of thyroid hormone. DUOX expression has sunsequently been identified in other tissues, including lung, placenta, testis, prostate, pancreas and heart (DUOX1), and colon, lung, kidney, liver, pancreas, prostate and testis (DUOX2) [4]. The DUOXs are expressed in epithelial cell types at mucosal surfaces, and play crucial roles in the innate host defence mechanism. As a result, these two enzymes are being investigated as novel targets in allergic disease, with experimental evidence suggesting that DUOX1 may be the more important of the two isozymes in allergic responses [14]. DUOX2 may be more relevant as an anti-cancer therapeutic target [12].


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11. Little AC, Sulovari A, Danyal K, Heppner DE, Seward DJ, van der Vliet A. (2017) Paradoxical roles of dual oxidases in cancer biology. Free Radic Biol Med, 110: 117-132. [PMID:28578013]

12. Lu J, Risbood P, Kane Jr CT, Hossain MT, Anderson L, Hill K, Monks A, Wu Y, Antony S, Juhasz A et al.. (2017) Characterization of potent and selective iodonium-class inhibitors of NADPH oxidases. Biochem Pharmacol, 143: 25-38. [PMID:28709950]

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14. van der Vliet A, Danyal K, Heppner DE. (2018) Dual oxidase: a novel therapeutic target in allergic disease. Br J Pharmacol, 175 (9): 1401-1418. [PMID:29405261]

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