p22phox Protein, also known as the human neutrophil

cytochrome b Cytochrome b within both molecular and cell biology, is a protein found in the mitochondria of eukaryotic cells. It functions as part of the electron transport chain and is the main subunit of transmembrane cytochrome bc1 and b6f complexes. F ...

light chain (CYBA), is an essential component of the membrane-associated enzyme phagocyte NADPH-oxidaseDinauer MC, Pierce EA, Bruns GA, Curnutte JT, Orkin SH. "Human neutrophil cytochrome b light chain (p22-phox). Gene structure, chromosomal location, and mutations in cytochrome-negative autosomal recessive chronic granulomatous disease." ''J Clin Invest.'' November 1990; 86(5): 1729-37. This enzyme uses NADH or NADPH as the electron donor for the one electron reduction of oxygen to produce superoxide anion, a

reactive oxygen species In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen () p ...

(ROS),Xu Q, Yuan F, Wu J. "Polymorphisms of C242T and A640G in CYBA Gene and the risk of coronary artery disease: A meta-analysis." ''PLoS One''. 2014; 9(1): e84251 and a functionally important step for the antimicrobial activity of

phagocytic cells Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek ', "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek '' ...

. p22phox is also expressed in many other human cells such as endothelial and vascular smooth muscle cells, including those within the coronary arteries.Azumi H et al. "Expression of NADH/NADPH oxidase p22phox in human coronary arteries." ''Circulation''. October 5, 1999; 100(14): 1494-8. Specific polymorphisms of the CYBA gene have been identified that are associated with a decreased risk of

coronary artery disease Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pla ...

(CAD).

Protein structure and gene function

Cytochrome b is a heterodimer of two

glycoproteins Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...

, gp91phox (also known as the heavy or β chain) and p22phox (the light or α chain). The heavy and light chains are closely associated in phagocytic cells, but while the expression of gp91phox is restricted to these cells, p22phox has been detected in many other cell types and is able to function as a component of NAD(P)H oxidases. The alpha chain CYBA gene is located on chromosome 16q24 and consists of 6 exons and 5 introns, with a total length of 8.5kb.

Genetic polymorphisms and link to coronary artery disease

Oxidative stress in the vasculature induced by ROS (particularly the

superoxide anion In chemistry, a superoxide is a Chemical compound, compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen species, reactive oxygen ion superoxide is p ...

) via the NAD(P)H oxidase pathway causes vascular wall remodeling and endothelial dysfunction, consistent with the initial pathogenesis of vascular diseases such as

atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...

and CAD. Genetic alterations in the CYBA gene have been reported that interrupt this pathway in the vasculature, including the C242T and A640G polymorphisms. The C242T polymorphism occurs in exon 4 and results in a histidine to tyrosine amino acid substitution in the p22phox protein. This leads to reduced NAD(P)H oxidase activity in human blood vessels and therefore a decreased production of ROS and vascular oxidative stress.Tomasz J, et al. "Functional effect of the C242T polymorphism in the NAD(P)H oxidase p22phox gene on vascular superoxide production in atherosclerosis." ''Circulation''. 2000; 102: 1744 – 1747. A 2014 meta-analysis indicated a protective role of this polymorphism for CAD in an Asian population due to reduced NAD(P)H oxidase activity. The A640G polymorphism is located in the 3’ untranslated region (UTR) of the CYBA gene and does not cause an amino acid substitution, however it has still been shown to have an effect on ROS generation.Bedard K, Attar H, Bonnefont J, Jaquet V, Borel C, Plastre O, Stasia MJ, Antonarakis S, Krause KH. "Three common polymorphisms in the CYBA gene form a haplotype associated with decreased ROS generation." ''Hum. Mutat.'' July 2009; 30(7): 1123-1133 Although this variation has been less extensively studied, it has also been linked to a decreased risk of CAD, possibly due to decreased translational activity of the CYBA gene. Specific mechanisms of this particular polymorphism are currently under investigation.

References

Transmembrane proteins