NADPH oxidase: Difference between revisions

==NADPH Oxidase==

<StructureSection load='6SZ5' size='340' side='right' caption='Calmodulin bonded to a NOX-5 peptide' scene=''>

NADPH oxidase in its entirety leads to the release of reactive oxygen species; this process is called oxidative burst, where the eradication of invading microorganisms in macrophages and neutrophils ensues.  NADPH oxidase is important in the maintenance of immune function, apoptosis, and cell growth. In previous times it was believed that NADPH oxidase generation of superoxides was only to happen in phagocytes, but inconsequent research studies, there are many enzymes that are responsible for reactive oxygen species production. For example, in kidneys, reactive oxygen species are produced from NOX3, and those molecules monitor renal function through sodium transport and oxygenation. Adding on, oxygen radicals increase sodium chloride absorption in the loop of Henle, which results in the regulation of sodium and hydrogen ion exchange. NADPH oxidase is known to function itself as a bacteria killer from the production of bacterial oxygen species by using oxygen and NADPH as substrates. In general, NADPH oxidase generates superoxides by moving electrons from NADPH inside of a cell and conjugating the oxygen atom to make superoxides

The structure of NADPH oxidase is classified as a multiplex enzyme where it has more than one integral membrane proteins; glycoprotein gp9 1 Phox and adaptor protein p22(phox); the two integral membrane proteins can combine and form a heterodimeric flavocytochrome b558 that takes in the inner part of the enzyme. Furthermore, the C-terminal is a cytoplasmic domain that is similar to ferredoxin-NADP+ reductase, which holds the NADPH binding and FAD-binding sites. The N-terminal has six alpha-helical transmembrane segments, and this segment is common to all NADPH oxidase family enzymes. These transmembrane segments are also found in fungal ferric reductase, where Fre enzymes are activated to reduce Fe3+ and Cu2+ for iron and copper upregulation, however, they do not use oxygen as a substrate as NADPH oxidase would. The third and fifth helices of NADPH oxidase have two His residues that are used to give ligands for the binding of iron from two non-similar hemes. This action results in one heme facing the cytoplasmic side and the other heme facing the outer membrane side. The hemes themselves are set up perpendicular to the surface of the membrane. This allows electrons to be transferred from the cytosolic NADPH through FAD and across the cellular membrane from the hemes to reach oxygen, this is how it produces the superoxides. Again, this all happens in the N-terminal heme-containing region. The third alpha helix contains 13 amino acids, notably His101 and His115, the fifth alpha-helix on the other hand contains 12 amino acids which are His209 and His222. In any of the alpha helices, if there is any substitution in any of the four His residues (His101,His115,His209, or His222) then there is an imbalance in the attached hemes into gp91. Nox1 is normally found in the endothelium, fibroblasts, and smooth muscle cells. Nox1 contains an activator called Noxa1 and an organizer called p45phox, p47phox needs activation in order to regulate the enzyme activity. Nox2 is found in vascular cells, except in large arteries, it is also a 58 kDa protein. Nox2 is the best enzyme of the Nox family, it serves as a superoxide producer and a signaling module. Nox2 has a separate gp91 system that is found in white blood cells such as neutrophils and macrophages. Nox2 makes intracellular and extracellular superoxides. Nox2 just like Nox1 is activated with the assistance of p47phox phosphorylation. Nox4 is found in all vascular cells and is also more abundant compared to all of the other Nox subtypes.  It can be specifically found in perinuclear space or the endoplasmic reticulum. Nox4 uses p22phox as its subunit. Nox5 is different than all the other Nox subtypes because it contains an added N-terminal domain that is meant for regulation. Nox4 is highly present in the kidney, but in other human tissues it is not usually found. Nox4 is commonly encoded on chromosome eleven. Nox5 also does not need any additional subunits, and is activated by Ca2+ binding to its N-terminal. The sensitivity to Ca2+ is increased due to calmodulin and phosphorylation. Nox5 can primarily be found in cytoskeletal components, plasma membranes, or the endoplasmic reticulum.