NADPH Oxidases (NOX): An Overview from Discovery, Molecular Mechanisms to Physiology and Pathology

Abstract

The reactive oxygen species (ROS)-producing enzyme NADPH oxidase (NOX) was first identified in the membrane of phagocytic cells. For many years, its only known role was in immune defense, where its ROS production leads to the destruction of pathogens by the immune cells. NOX from phagocytes catalyzes, via one-electron trans-membrane transfer to molecular oxygen, the production of the superoxide anion. Over the years, six human homologs of the catalytic subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the NOX2/gp91phox component present in the phagocyte NADPH oxidase assembly itself, the homologs are now referred to as the NOX family of NADPH oxidases. NOX are complex multidomain proteins with varying requirements for assembly with combinations of other proteins for activity. The recent structural insights acquired on both prokaryotic and eukaryotic NOX open new perspectives for the understanding of the molecular mechanisms inherent to NOX regulation and ROS production (superoxide or hydrogen peroxide). This new structural information will certainly inform new investigations of human disease. As specialized ROS producers, NOX enzymes participate in numerous crucial physiological processes, including host defense, the post-translational processing of proteins, cellular signaling, regulation of gene expression, and cell differentiation. These diversities of physiological context will be discussed in this review. We also discuss NOX misregulation, which can contribute to a wide range of severe pathologies, such as atherosclerosis, hypertension, diabetic nephropathy, lung fibrosis, cancer, or neurodegenerative diseases, giving this family of membrane proteins a strong therapeutic interest.

The Active Compounds and Therapeutic Target of Tripterygium wilfordii Hook. f. in Attenuating Proteinuria in Diabetic Nephropathy: A Review

“…Oxidative stress is associated with inflammation in DN progression. The presence and severity of systemic inflammation contribute to kidney injury-related oxidative stress (73). Oxidative stress caused by the overaccumulation of reactive oxygen species (ROS) induces protein and nucleic acid damage, thereby leading to impaired cellular damage and tissue pathology (74).…”

The Role of the BH4 Cofactor in Nitric Oxide Synthase Activity and Cancer Progression: Two Sides of the Same Coin

“…Dysfunctional NOS is a source of superoxide anion (O 2 •− ), which is associated with the development of cardiovascular diseases, diabetes, neurodegenerative disorders, and more recently, its role in cancer has been reported [13,[35][36][37]. The role of ROS in malignant transformation and tumor progression depends on its concentration and cancer stage, contributing to carcinogenesis or tumor cell death [13,16,33].…”

“…Moreover, nitric oxide (NO) and reactive nitrogen species (RNS) metabolism are also altered in inflammation [11]. High reactive oxygen species (ROS) levels found in tumors are caused by different mechanisms, including increased NADPH oxidase expression and activity, mitochondrial damage, endoplasmic reticulum stress, and nitric oxide synthase dysfunction (NOS) [12][13][14][15][16].…”

Diabetes Mellitus and Cardiovascular Diseases: Nutraceutical Interventions Related to Caloric Restriction

“…Even if accumulating data have pointed out that diets rich in green leafy vegetables represent an important source of NO [51], the endothelial nitric oxide synthase (eNOS) enzyme is primary involved in NO production from the amino acid L-arginine [52]. It is well established that excessive oxidative stress impairs eNOS activity while NOX (Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase) enzymes, which are mainly responsible for ROS cellular generation, are upregulated [48,53]. In obesity or in a hyperglycemic state, ROS rapidly reacts with NO, forming secondary reactive nitrogen species, including peroxynitrite, thus decreasing NO bioavailability.…”