P22phox

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p22phox Protein, also known as the human neutrophil cytochrome b light chain (CYBA), is an essential component of the membrane-associated enzyme phagocyte NADPH-oxidase [1] 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 (ROS), [2] and a functionally important step for the antimicrobial activity of phagocytic cells. [3] p22phox is also expressed in many other human cells such as endothelial and vascular smooth muscle cells, including those within the coronary arteries. [4] Specific polymorphisms of the CYBA gene have been identified that are associated with a decreased risk of coronary artery disease (CAD). [4]

Cytochrome b A mitochondrial protein involved in the respiratory chain

Cytochrome b 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.

Reactive oxygen species chemical compound

Reactive oxygen species (ROS) are chemically reactive chemical species containing oxygen. Examples include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.

Gene polymorphism

A gene is said to be polymorphic if more than one allele occupies that gene’s locus within a population. In addition to having more than one allele at a specific locus, each allele must also occur in the population at a rate of at least 1% to generally be considered polymorphic.

Contents

Protein structure and gene function

Cytochrome b is a heterodimer of two glycoproteins, 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 [1] and is able to function as a component of NAD(P)H oxidases. [2] 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. [1]

Oxidative stress in the vasculature induced by ROS (particularly the superoxide anion) 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 and CAD. [5] Genetic alterations in the CYBA gene have been reported that interrupt this pathway in the vasculature, including the C242T and A640G polymorphisms. [2]

Atherosclerosis form of arteriosclerosis

Atherosclerosis is a disease in which the inside of an artery narrows due to the build up of plaque. Initially, there are generally no symptoms. When severe, it can result in coronary artery disease, stroke, peripheral artery disease, or kidney problems, depending on which arteries are affected. Symptoms, if they occur, generally do not begin until middle age.

The C242T polymorphism occurs in exon 4 and results in a histidine to tyrosine amino acid substitution [1] 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. [6] 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. [2]

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. [7] Although this variation has been less extensively studied, it has also been linked to a decreased risk of CAD, [2] possibly due to decreased translational activity of the CYBA gene. [7] Specific mechanisms of this particular polymorphism are currently under investigation. [2]

Related Research Articles

Electron transport chain A process in which a series of electron carriers operate together to transfer electrons from donors to any of several different terminal electron acceptors to generate a transmembrane electrochemical gradient.

An electron transport chain (ETC) is a series of complexes that transfer electrons from electron donors to electron acceptors via redox (both reduction and oxidation occurring simultaneously) reactions, and couples this electron transfer with the transfer of protons (H+ ions) across a membrane. This creates an electrochemical proton gradient that drives the synthesis of adenosine triphosphate (ATP), a molecule that stores energy chemically in the form of highly strained bonds. The molecules of the chain include peptides, enzymes (which are proteins or protein complexes), and others. The final acceptor of electrons in the electron transport chain during aerobic respiration is molecular oxygen although a variety of acceptors other than oxygen such as sulfate exist in anaerobic respiration.

Chronic granulomatous disease diverse group of hereditary diseases in which certain cells of the immune system have difficulty forming the reactive oxygen compounds used to kill certain ingested pathogens.

Chronic granulomatous disease (CGD) is a diverse group of hereditary diseases in which certain cells of the immune system have difficulty forming the reactive oxygen compounds used to kill certain ingested pathogens. This leads to the formation of granulomata in many organs. CGD affects about 1 in 200,000 people in the United States, with about 20 new cases diagnosed each year.

Nicotinamide adenine dinucleotide phosphate coenzyme

Nicotinamide adenine dinucleotide phosphate, abbreviated NADP+ or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NADPH as a reducing agent. It is used by all forms of cellular life.

Respiratory burst is the rapid release of reactive oxygen species from different types of cells.

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. Human isoforms of the catalytic component of the complex include NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1, and DUOX2.

NOX2 protein-coding gene in the species Homo sapiens

NADPH oxidase 2 (Nox2), also known as cytochrome b(558) subunit beta or Cytochrome b-245 heavy chain, is a protein that in humans is encoded by the NOX2 gene. The protein is a super-oxide generating enzyme which forms reactive oxygen species (ROS).

Reactive nitrogen species

Reactive nitrogen species (RNS) are a family of antimicrobial molecules derived from nitric oxide (•NO) and superoxide (O2•−) produced via the enzymatic activity of inducible nitric oxide synthase 2 (NOS2) and NADPH oxidase respectively. NOS2 is expressed primarily in macrophages after induction by cytokines and microbial products, notably interferon-gamma (IFN-γ) and lipopolysaccharide (LPS).

Neutrophil cytosolic factor 2 protein-coding gene in the species Homo sapiens

Neutrophil cytosol factor 2 is a protein that in humans is encoded by the NCF2 gene.

Neutrophil cytosolic factor 1 protein-coding gene in the species Homo sapiens

Neutrophil cytosol factor 1, also known as p47phox, is a protein that in humans is encoded by the NCF1 gene.

NOX1 protein-coding gene in the species Homo sapiens

NADPH oxidase 1 is an enzyme that in humans is encoded by the NOX1 gene.

NOX4 protein-coding gene in the species Homo sapiens

NADPH oxidase 4 is an enzyme that in humans is encoded by the NOX4 gene, and is a member of the NOX family of NADPH oxidases.

Cytochrome b-245, alpha polypeptide protein-coding gene in the species Homo sapiens

Cytochrome b-245 light chain is a protein that in humans is encoded by the CYBA gene involved in superoxide production and phagocytosis.

Neutrophil cytosolic factor 4 protein-coding gene in the species Homo sapiens

Neutrophil cytosol factor 4 is a protein that in humans is encoded by the NCF4 gene.

Dual oxidase 2 protein-coding gene in the species Homo sapiens

Dual oxidase 2, also known as DUOX2 or ThOX2, is an enzyme that in humans is encoded by the DUOX2 gene. Dual oxidase is an enzyme that was first identified in the mammalian thyroid gland. In humans, two isoforms are found; hDUOX1 and hDUOX2. The protein location is not exclusive to thyroid tissue; hDUOX1 is prominent in airway epithelial cells and hDUOX2 in the salivary glands and gastrointestinal tract.

Dual oxidase 1 protein-coding gene in the species Homo sapiens

Dual oxidase 1, also known as DUOX1 or ThOX1, is an enzyme which in humans is encoded by the DUOX1 gene. DUOX1 was first identified in the mammalian thyroid gland. In humans, two isoforms are found; hDUOX1 and hDUOX2. Human DUOX protein localization is not exclusive to thyroid tissue; hDUOX1 is prominent in airway epithelial cells and hDUOX2 in the salivary glands and gastrointestinal tract.

NOX5 protein-coding gene in the species Homo sapiens

NADPH oxidase, EF-hand calcium binding domain 5, also known as NOX5, is a protein which in humans is encoded by the NOX5 gene.

NOXO1 protein-coding gene in the species Homo sapiens

NADPH oxidase organizer 1 is an enzyme that in humans is encoded by the NOXO1 gene.

NOX3 protein-coding gene in the species Homo sapiens

NADPH oxidase 3 is an enzyme that in humans is encoded by the NOX3 gene.

NOXA1 protein-coding gene in the species Homo sapiens

NADPH oxidase activator 1 is an enzyme that in humans is encoded by the NOXA1 gene.

Neutrophil oxidative burst test is a measure of neutrophil oxidation and is a useful assay in the diagnosis of chronic granulomatous disease and is also a useful means to determine the overall metabolic integrity of phagocytosing neutrophils. The NADPH oxidase enzyme is missing in CGD. From total blood, neutrophils can be purified and the NADPH oxidase activity can be measured with different methods in these cells after activation. Phagocytosis by polymorphonuclear neutrophils and monocytes constitutes an essential arm of host defense against bacterial or fungal infections. The phagocytic process can be separated into several major stages: chemotaxis, attachment of particles to the cell surface of phagocytes, ingestion (phagocytosis) and intracellular killing by oxygen-dependent and oxygen-independent mechanisms.

References

  1. 1 2 3 4 Dinauer 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.
  2. 1 2 3 4 5 6 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
  3. ↑ Ushio-Fukai M, Zafari A, Fukui T, Ishizaka N, Griendling K. "p22phox is a critical component of the superoxide-generating NADH/NADPH oxidase system and regulates angiotensin II induced hypertrophy in vascular smooth muscle cells." J Bio Chem. September 20, 1996; 271: 23317-21.
  4. 1 2 Azumi H et al. "Expression of NADH/NADPH oxidase p22phox in human coronary arteries." Circulation. October 5, 1999; 100(14): 1494-8.
  5. ↑ Fortuna A, San Jose G, Moreno MU, Diez J, Zalba G. "Oxidative stress and vascular remodeling." Exp. Physiol. July 2005; 90(4): 457-62.
  6. ↑ 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.
  7. 1 2 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
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