NADPH oxidase, also known as Nox enzymes, represent a family of multi-component membrane enzymes composed of at least five proteincomponents, namely two transmembrane flavocytochrome b components (gp91phox and p22phox) and three cytosolic components (p47phox, p67phox, and p40phox). Then it has been demonstrated that angiotensin II stimulates NADPH oxidase activity in cultured vascular muscle cellsNADPH oxidase is the key enzyme that is involved in ROS production. Subsequently NADPH oxidase is demonstrated to exist in the other kinds of cells such as endothelial cells, phagocytic cells, fibroblasts, and adipocytes.
An overview of NADPH Oxidase
The nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, also known as NOX, are transmembrane proteins present in various cells in mammals, contributing to production of reactive oxygen species (ROS). ROS has an essential role in numerous cellular signaling processes, regulating cell proliferation, migration and differentiation. Besides, ROS is also implicated in innate immune response, extracellular matrix dynamics and inflammation. However, an excess of ROS will lead to oxidative stress, which is involved in the pathogenesis of different diseases including neurodegenerative disorders and cancer.
Major types of NADPH Oxidase
There are seven members in the NOX enzyme family: NOX1-5, DUOX1 and DUOX2, all of which are characterized by at least six trans-membrane helices. DUOX1 and DUOX2 were termed due to an additional trans-membrane domain and an extracellular N-terminus. The seven isoforms can be observed in different tissues and cell types. For example, NOX1 is mainly expressed in the colon, while NOX2 is widely distributed in thymus, small intestine, spleen, and pancreas.
Inhibition of NADPH Oxidase
The early NADPH oxidase inhibitors, such as diphenylene iodonium and apocynin, are still being applied into clinical use despite their non-selectivity and off-target effect. As more efforts have been put into the research on NADPH oxidase inhibitors, an increasing number of novel small-molecule NADPH oxidase inhibitors with more potency and higher selectivity have been reported. These novel inhibitors are able to inhibit the activity of NADPH oxidase without affecting upstream signaling pathways of NOX activation. In recent years, numerous new small-molecule NADPH oxidase inhibitors have been synthesized by researchers, such as GKT136901, ML171, S17834, and more.
NADPH Oxidase and diseases
It was found that during the pathogenesis of sclerosis, 7-ketocholesterol may promote the expression of NOX4 by activating IRE1/JNK/AP-1 signaling pathway, leading to increased ROS production and apoptosis of smooth muscle cells. The expression of NOX in tumor cells is different from that in normal tissues, indicating that the abnormal expression and regulation of NOX may be related to the development and progression of tumors.
1. Jiang, F., Liu, G. S., Dusting, G. J., & Chan, E. C. (2014). NADPH oxidase-dependent redox signaling in TGF-β-mediated fibrotic responses. Redox biology, 2, 267-272.
2. Altenhöfer, S., Radermacher, K. A., Kleikers, P. W., Wingler, K., & Schmidt, H. H. (2015). Evolution of NADPH oxidase inhibitors: selectivity and mechanisms for target engagement. Antioxidants & redox signaling, 23(5), 406-427.
3. Page, P. (2014). Advances and strategies in NADPH oxidase inhibitors and activators patents. Pharmaceutical patent analyst, 3(4), 387-409.