Natural Compounds as Modulators of NADPH Oxidases

Table 1

NOX isoforms and pathology [modified from [22, 23]].

Characteristic	Binding partners	Intracellular localization	Tissue distribution	Implication in pathology
NOX1	p22^phox, NOXO1, NoxA1, Rac1, PDI, TKS4/5*	Caveolae on the plasma membrane, redoxisomes	Colon epithelia VSMCs, endothelial cells, uterus, placenta, prostate, osteoclasts, retinal pericytes, neurons, astrocytes, microglia	Colon cancer, prostate cancer, gastrointestinal inflammation, hypertension, restenosis after angioplasty
NOX2	p22^phox, p67^phox, p40^phox, p47^phox, Rac1/2	Phagosomes, cytoskeleton, lamellipodia, redoxisomes	Phagocytes, CNS, endothelium, VSMCs, fibroblasts, cardiomyocytes, skeletal muscle, hepatocytes, hematopoietic stem cells	Gastrointestinal inflammation, hypertension, myocardial injury, restenosis after angioplasty, melanoma, diabetes, neurodegenerative diseases
NOX3	p22^phox, NOXO1	Plasma membrane	Inner ear, lung endothelial cells, fetal tissues	Hearing loss, pancreatic cancer
NOX4	p22^phox, PDI, TKS4/5, Poldip2*	Focal adhesions, nucleus, endoplasmic reticulum, mitochondria	Ubiquitously expressed but highly in the kidney	Pancreatic cancer, melanoma, diabetes
NOX5	Ca^2+, Hsp90, CaM^#	Internal membranes, plasma membrane	Lymphatic tissue, testis, VSMCs, endothelial cells, spleen, uterus, and prostate	Atherosclerosis prostate cancer, pancreatic cancer
Duox1	Ca^2+, DuoxA1	Plasma membrane	Thyroid, respiratory epithelium	Thyroid dysfunction, cystic fibrosis
Duox2	Ca^2+, DuoxA2	Plasma membrane	Airway epithelial, colon, salivary gland	Thyroid dysfunction, cystic fibrosis

∗Recently, the protein polymerase (DNA-directed) delta-interacting protein 2 (Poldip2) was identified to bind and to increase the activity of NOX4. Further, protein disulfide isomerase (PDI) and a p47phox analogue tyrosine kinase substrate with 4/5 SH3 domains (Tks4/5) have been reported to bind and activate NOX1 and NOX4. NOX4 is the only isoform that produces hydrogen peroxide instead of superoxide.
^#The NOX5 protein contains four N-terminal calcium-binding sites that regulate activation of the enzyme. Activity of NOX5 can be further supported by the binding of Hsp90 or Calmodulin to the C-terminus of the protein.