The NADPH oxidase is a membrane-bound enzyme complex that faces the
extracellular space. It can be found in the plasma membrane as well as in the
membranes of phagosomes used by neutrophil white blood cells to engulf
microorganisms. Isoforms are designated NOX1, NOX2, NOX3, and NOX4.
Subunits It is made up of six subunits. These
subunits are: a Rho guanosine triphosphatase, usually
Rac1 or Rac2 Five "phox" units.
gp91-PHOX(Nox2) p22phox
p40phox p47phox
p67phox Function
Under normal circumstances, the complex is latent in neutrophils and is
activated to assemble in the membranes during respiratory burst.
NADPH oxidase generates superoxide by transferring electrons from NADPH inside
the cell across the membrane and coupling these to molecular oxygen to
produce superoxide anion, a reactive free-radical. Superoxide can be produced
in phagosomes, which contain ingested bacteria and fungi, or it can be
produced outside of the cell. In a phagosome, superoxide can spontaneously
form hydrogen peroxide that will undergo further reactions to generate reactive
oxygen species. Superoxide kills bacteria and fungi by
mechanisms that are not yet fully understood, but may inactivate critical
metabolic enzymes, initiate lipid peroxidation, and liberate redox-active
iron, which allows the generation of indiscriminate oxidants such as the
hydroxyl radical. It is presumed that superoxide kills bacteria directly, as
the virulence of many pathogens is dramatically attenuated when their
superoxide dismutase genes are deleted. However, downstream products of
superoxide also include hydrogen peroxide and hypochlorous acid, the
reactive agent in bleach. Role in pathology
NADPH oxidase is a major cause of atherosclerosis, and NADPH oxidase
inhibitors may reverse atherosclerosis. Atherosclerosis is caused by the
accumulation of macrophages containing cholesterol in artery walls. NADPH
oxidase produces ROSs. These ROSs activate an enzyme that makes the
macrophages adhere to the artery wall. This process is counterbalanced by NADPH
oxidase inhibitors, and by antioxidants. An imbalance in favor of ROS produces
atherosclerosis. In vitro studies have found that the NADPH oxidase inhibitors
apocynin and diphenyleneiodonium, along with the antioxidants N-acetyl-cysteine
and resveratrol, depolymerized the actin, broke the adhesions, and allowed
foam cells to migrate out of the intima. Mutations in the NADPH oxidase subunit
genes cause several Chronic Granulomatous Diseases, such as
X-linked chronic granulomatous disease autosomal recessive cytochrome
b-negative CGD autosomal recessive cytochrome
b-positive CGD type I autosomal recessive cytochrome
b-positive CGD type II. In these diseases, cells have a low
capacity for phagocytosis, and persistent bacterial infections occur.
Areas of infected cells are common, granulomas. A similar disorder called
neutrophil immunodeficiency syndrome is linked to a mutation in the RAC2, also a
part of the complex. One study suggests a role for NADPH
oxidase in ketamine-induced loss of neuronal parvalbumin and GAD67
expression. Similar loss is observed in schizophrenia, and the results may point
at the NADPH oxidase as a possible player in the pathophysiology of the
disease. Nitro blue tetrazolium is used in a diagnostic test, in particular, for
chronic granulomatous disease, a disease in which there is a defect in NADPH
oxidase; therefore, the phagocyte is unable to make the reactive oxygen
species or radicals required for bacterial killing, resulting in bacteria
thriving within the phagocyte. The higher the blue score the better the
cell is at producing reactive oxygen species.
Chemical reaction NADPH + 2O2 ↔ NADP+ + 2O2− + H+
Inhibition NADPH oxidase can be inhibited by
apocynin and DPI. Apocynin prevents the assembly of the NADPH oxidase subunits.
Using apocynin to inhibit NADPH oxidase may have clinical benefits in the
treatment of influenza as it lessens influenza-induced lung inflammation in
mice in vivo. See also
NOX1 NOX2
NOX3 NOX4
References External links
NADPH Oxidase at the US National Library of Medicine Medical Subject Headings
EC 1.6.3.1