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CYBB
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	3A1F
Identifiers
Aliases	CYBB, AMCBX2, CGD, GP91-1, GP91-PHOX, GP91PHOX, IMD34, NOX2, p91-PHOX, cytochrome b-245 beta chain, CGDX
External IDs	OMIM: 300481; MGI: 88574; HomoloGene: 68054; GeneCards: CYBB; OMA:CYBB - orthologs
Gene location (Human)
Chr.	X chromosome (human)
End	37,813,461 bp
Gene location (Mouse)
Chr.	X chromosome (mouse)
End	9,354,010 bp
RNA expression pattern
	Top expressed in
	monocyte; ; granulocyte; ; bone marrow; ; bone marrow cells; ; synovial joint; ; blood; ; trabecular bone; ; appendix; ; lymph node; ; decidua;
	Top expressed in
	granulocyte; ; stroma of bone marrow; ; mesenteric lymph nodes; ; right lung lobe; ; spleen; ; lumbar spinal ganglion; ; tibiofemoral joint; ; calvaria; ; blood; ; ankle;
	More reference expression data
	; ;
	More reference expression data
Gene ontology
Molecular function	flavin adenine dinucleotide binding; superoxide-generating NAD(P)H oxidase activity; metal ion binding; voltage-gated ion channel activity; protein binding; heme binding; protein heterodimerization activity; electron transfer activity; oxidoreductase activity;
Cellular component	cytoplasm; integral component of membrane; phagocytic vesicle membrane; membrane; plasma membrane; integral component of plasma membrane; NADPH oxidase complex; perinuclear region of cytoplasm; phagocytic vesicle; Golgi apparatus; endoplasmic reticulum; soma; intracellular anatomical structure; endoplasmic reticulum membrane; rough endoplasmic reticulum; dendrite; nuclear envelope; specific granule membrane; tertiary granule membrane; perinuclear endoplasmic reticulum;
Biological process	regulation of ion transmembrane transport; ion transport; superoxide anion generation; respiratory burst; vascular endothelial growth factor receptor signaling pathway; hydrogen peroxide biosynthetic process; innate immune response; inflammatory response; superoxide metabolic process; cellular response to L-glutamine; positive regulation of angiogenesis; response to angiotensin; response to nutrient; cellular response to hypoxia; hypoxia-inducible factor-1alpha signaling pathway; cellular response to cadmium ion; cellular response to ethanol; response to aldosterone; neutrophil degranulation; cellular response to oxidative stress; electron transport chain; ion transmembrane transport; antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent; defense response; cell redox homeostasis;
	Sources:Amigo / QuickGO
Orthologs
	1536
	13058
	ENSG00000165168
	ENSMUSG00000015340
	P04839
	Q61093
	NM_000397
	NM_007807
	NP_000388
	NP_031833
	Wikidata
View/Edit Human	View/Edit Mouse

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 (also called CYBB gene).^[5] The protein is a superoxide generating enzyme which forms reactive oxygen species (ROS).

Function

The CYBB gene encode cytochrome b-245, beta chain. This protein is subunit of a group of proteins that forms an enzyme complex called NADPH oxidase, which plays an essential role in the immune system. Within this complex, the cytochrome b-245, beta chain has an alpha chain partner (produced from the CYBA gene). Both alpha and beta chains are required for either to function and the NADPH oxidase complex requires both chains in order to be functional. It has been proposed as a primary component of the microbicidal oxidase system of phagocytes.

Nox2 is the catalytic, membrane-bound subunit of NADPH oxidase. It is inactive until it binds to the membrane-anchored p22phox, forming the heterodimer known as flavocytochrome b558.^[6] After activation, the regulatory subunits p67phox, p47phox, p40phox and a GTPase, typically Rac, are recruited to the complex to form NADPH oxidase on the plasma membrane or phagosomal membrane.^[7] Nox2 itself is composed of an N-terminal transmembrane domain that binds two heme groups, and a C-terminal domain that is able to bind to FAD and NADPH.^[8]

Evidence has shown that it plays an important role in atherosclerotic lesion development in the aortic arch, thoracic, and abdominal aorta. ^[9] ^[10]

It has also been shown to play a part in determining the size of a myocardial infarction due to its connection to ROS, which play a role in myocardial reperfusion injury. This was a result of the relation between Nox2 and signaling necessary for neutrophil recruitment.^[11] Furthermore, it increases global post-reperfusion oxidative stress, likely due to decreased STAT3 and Erk phosphorylation.^[11]

In addition, it appears that hippocampal oxidative stress is increased in septic animals due to the actions of Nox2. This connection also came about through the actions of the chemically active ROS, which work as one of the main components that help in the development of neuroinflammation associated with sepsis-associated encephalopathy (SAE).^[12] Endothelial Nox2 limits NF-κB activation and TLR4 expression, which in turn attenuates the severity of hypotension and systemic inflammation induced by lipopolysaccharides (LPS).^[13]

It seems that Nox2 also plays an important role in angiotensin II-mediated inward remodelling in cerebral arterioles due to the emittance of superoxides from Nox2-containing NADPH oxidases.^[14]

Clinical significance

CYBB deficiency is one of five described biochemical defects associated with chronic granulomatous disease (CGD).^[15] CGD is characterized by recurrent, severe infections to pathogens that are normally harmless to humans, such as the common mold Aspergillus niger, and can result from point mutations in the gene encoding Nox2. ^[8] In this disorder, there is decreased activity of phagocyte NADPH oxidase; neutrophils are able to phagocytize bacteria but cannot kill them in the phagocytic vacuoles. The cause of the killing defect is an inability to increase the cell's respiration and consequent failure to deliver activated oxygen into the phagocytic vacuole.^[5] At least 34 disease-causing mutations in this gene have been discovered.^[16]

Since Nox2 was shown to play an essential role in determining the size of a myocardial infarction, the protein can be a potential target for drug medication due to its negative effect on myocardial reperfusion.^[10]

Recent evidence highly suggests that Nox2 generates ROS which contribute to reduce flow-mediated dilation (FMD) in patients with periphery artery disease (PAD). Scientists have gone to conclude that administering an antioxidant helps with inhibiting Nox2 activity and allowing in the improvement of arterial dilation.^[17]

Lastly, targeting Nox2 in the bone marrow could be a great therapeutic attempt at treating vascular injury during diabetic retinopathy (damage to the retina), because the Nox2-generated ROS which are produced by the bone-marrow derived cells & local retinal cells are accumulating the vascular injury in the diabetic retina area.^[18]

CYBB transcript levels are upregulated in the lung parenchyma of smokers. ^[19]

Interactions

Nox2 has been shown to interact directly with podocyte TRPC6 channels.^[20]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000165168 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000015340 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ ^a ^b "Entrez Gene: CYBB cytochrome b-245, beta polypeptide (chronic granulomatous disease)".
^ Hervé C, Tonon T, Collén J, Corre E, Boyen C (March 2006). "NADPH oxidases in Eukaryotes: red algae provide new hints!". Current Genetics. 49 (3): 190–204. doi:10.1007/s00294-005-0044-z. PMID 16344959. S2CID 19791715.
^ Kawahara T, Lambeth JD (September 2007). "Molecular evolution of Phox-related regulatory subunits for NADPH oxidase enzymes". BMC Evolutionary Biology. 7 (1): 178. Bibcode:2007BMCEE...7..178K. doi:10.1186/1471-2148-7-178. PMC 2121648. PMID 17900370.
^ ^a ^b Aguirre J, Lambeth JD (November 2010). "Nox enzymes from fungus to fly to fish and what they tell us about Nox function in mammals". Free Radical Biology & Medicine. 49 (9): 1342–1353. doi:10.1016/j.freeradbiomed.2010.07.027. PMC 2981133. PMID 20696238.
^ Sorescu D, Weiss D, Lassègue B, Clempus RE, Szöcs K, Sorescu GP, et al. (March 2002). "Superoxide production and expression of nox family proteins in human atherosclerosis". Circulation. 105 (12): 1429–1435. doi:10.1161/01.cir.0000012917.74432.66. PMID 11914250.
^ ^a ^b Chaubey S, Jones GE, Shah AM, Cave AC, Wells CM (2013). "Nox2 is required for macrophage chemotaxis towards CSF-1". PLOS ONE. 8 (2): e54869. Bibcode:2013PLoSO...854869C. doi:10.1371/journal.pone.0054869. PMC 3562318. PMID 23383302.
^ ^a ^b Braunersreuther V, Montecucco F, Asrih M, Ashri M, Pelli G, Galan K, et al. (November 2013). "Role of NADPH oxidase isoforms NOX1, NOX2 and NOX4 in myocardial ischemia/reperfusion injury". Journal of Molecular and Cellular Cardiology. 64: 99–107. doi:10.1016/j.yjmcc.2013.09.007. PMID 24051369. S2CID 20225141.
^ Hernandes MS, D'Avila JC, Trevelin SC, Reis PA, Kinjo ER, Lopes LR, et al. (February 2014). "The role of Nox2-derived ROS in the development of cognitive impairment after sepsis". Journal of Neuroinflammation. 11 (1): 36. doi:10.1186/1742-2094-11-36. PMC 3974031. PMID 24571599.
^ Trevelin SC, Sag CM, Zhang M, Alves-Filho JC, Cunha TM, Santos CX, et al. (August 2021). "Endothelial Nox2 Limits Systemic Inflammation and Hypotension in Endotoxemia by Controlling Expression of Toll-Like Receptor 4". Shock. 56 (2): 268–277. doi:10.1097/SHK.0000000000001706. PMC 8284354. PMID 34276040.
^ Chan SL, Baumbach GL (26 June 2013). "Deficiency of Nox2 prevents angiotensin II-induced inward remodeling in cerebral arterioles". Frontiers in Physiology. 4: 133. doi:10.3389/fphys.2013.00133. PMC 3693079. PMID 23805104.
^ "CYBB cytochrome b-245 beta chain [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-05-10.
^ Šimčíková D, Heneberg P (December 2019). "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases". Scientific Reports. 9 (1): 18577. Bibcode:2019NatSR...918577S. doi:10.1038/s41598-019-54976-4. PMC 6901466. PMID 31819097.
^ Loffredo L, Carnevale R, Cangemi R, Angelico F, Augelletti T, Di Santo S, et al. (April 2013). "NOX2 up-regulation is associated with artery dysfunction in patients with peripheral artery disease". International Journal of Cardiology. 165 (1): 184–192. doi:10.1016/j.ijcard.2012.01.069. PMID 22336250.
^ Rojas M, Zhang W, Xu Z, Lemtalsi T, Chandler P, Toque HA, et al. (2013). "Requirement of NOX2 expression in both retina and bone marrow for diabetes-induced retinal vascular injury". PLOS ONE. 8 (12): e84357. Bibcode:2013PLoSO...884357R. doi:10.1371/journal.pone.0084357. PMC 3866146. PMID 24358357.
^ Pintarelli G, Noci S, Maspero D, Pettinicchio A, Dugo M, De Cecco L, et al. (September 2019). "Cigarette smoke alters the transcriptome of non-involved lung tissue in lung adenocarcinoma patients". Scientific Reports. 9 (1): 13039. Bibcode:2019NatSR...913039P. doi:10.1038/s41598-019-49648-2. PMC 6736939. PMID 31506599.
^ Kim EY, Anderson M, Wilson C, Hagmann H, Benzing T, Dryer SE (November 2013). "NOX2 interacts with podocyte TRPC6 channels and contributes to their activation by diacylglycerol: essential role of podocin in formation of this complex". American Journal of Physiology. Cell Physiology. 305 (9): C960 – C971. doi:10.1152/ajpcell.00191.2013. PMID 23948707.

External links

gp91phox+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Human CYBB genome location and CYBB gene details page in the UCSC Genome Browser.
Overview of all the structural information available in the PDB for UniProt: P04839 (Cytochrome b-245 heavy chain) at the PDBe-KB.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000165168 – Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000015340 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[entrez-5] "Entrez Gene: CYBB cytochrome b-245, beta polypeptide (chronic granulomatous disease)".

[6] Hervé C, Tonon T, Collén J, Corre E, Boyen C (March 2006). "NADPH oxidases in Eukaryotes: red algae provide new hints!". Current Genetics. 49 (3): 190–204. doi:10.1007/s00294-005-0044-z. PMID 16344959. S2CID 19791715.

[7] Kawahara T, Lambeth JD (September 2007). "Molecular evolution of Phox-related regulatory subunits for NADPH oxidase enzymes". BMC Evolutionary Biology. 7 (1): 178. Bibcode:2007BMCEE...7..178K. doi:10.1186/1471-2148-7-178. PMC 2121648. PMID 17900370.

[:0-8] Aguirre J, Lambeth JD (November 2010). "Nox enzymes from fungus to fly to fish and what they tell us about Nox function in mammals". Free Radical Biology & Medicine. 49 (9): 1342–1353. doi:10.1016/j.freeradbiomed.2010.07.027. PMC 2981133. PMID 20696238.

[one-9] Sorescu D, Weiss D, Lassègue B, Clempus RE, Szöcs K, Sorescu GP, et al. (March 2002). "Superoxide production and expression of nox family proteins in human atherosclerosis". Circulation. 105 (12): 1429–1435. doi:10.1161/01.cir.0000012917.74432.66. PMID 11914250.

[two-10] Chaubey S, Jones GE, Shah AM, Cave AC, Wells CM (2013). "Nox2 is required for macrophage chemotaxis towards CSF-1". PLOS ONE. 8 (2): e54869. Bibcode:2013PLoSO...854869C. doi:10.1371/journal.pone.0054869. PMC 3562318. PMID 23383302.

[three-11] Braunersreuther V, Montecucco F, Asrih M, Ashri M, Pelli G, Galan K, et al. (November 2013). "Role of NADPH oxidase isoforms NOX1, NOX2 and NOX4 in myocardial ischemia/reperfusion injury". Journal of Molecular and Cellular Cardiology. 64: 99–107. doi:10.1016/j.yjmcc.2013.09.007. PMID 24051369. S2CID 20225141.

[four-12] Hernandes MS, D'Avila JC, Trevelin SC, Reis PA, Kinjo ER, Lopes LR, et al. (February 2014). "The role of Nox2-derived ROS in the development of cognitive impairment after sepsis". Journal of Neuroinflammation. 11 (1): 36. doi:10.1186/1742-2094-11-36. PMC 3974031. PMID 24571599.

[13] Trevelin SC, Sag CM, Zhang M, Alves-Filho JC, Cunha TM, Santos CX, et al. (August 2021). "Endothelial Nox2 Limits Systemic Inflammation and Hypotension in Endotoxemia by Controlling Expression of Toll-Like Receptor 4". Shock. 56 (2): 268–277. doi:10.1097/SHK.0000000000001706. PMC 8284354. PMID 34276040.

[five-14] Chan SL, Baumbach GL (26 June 2013). "Deficiency of Nox2 prevents angiotensin II-induced inward remodeling in cerebral arterioles". Frontiers in Physiology. 4: 133. doi:10.3389/fphys.2013.00133. PMC 3693079. PMID 23805104.

[15] "CYBB cytochrome b-245 beta chain [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-05-10.

[Šimčíková_2019_-_supplementary_table_S7-16] Šimčíková D, Heneberg P (December 2019). "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases". Scientific Reports. 9 (1): 18577. Bibcode:2019NatSR...918577S. doi:10.1038/s41598-019-54976-4. PMC 6901466. PMID 31819097.

[LoffredoCarnevale2013-17] Loffredo L, Carnevale R, Cangemi R, Angelico F, Augelletti T, Di Santo S, et al. (April 2013). "NOX2 up-regulation is associated with artery dysfunction in patients with peripheral artery disease". International Journal of Cardiology. 165 (1): 184–192. doi:10.1016/j.ijcard.2012.01.069. PMID 22336250.

[five2-18] Rojas M, Zhang W, Xu Z, Lemtalsi T, Chandler P, Toque HA, et al. (2013). "Requirement of NOX2 expression in both retina and bone marrow for diabetes-induced retinal vascular injury". PLOS ONE. 8 (12): e84357. Bibcode:2013PLoSO...884357R. doi:10.1371/journal.pone.0084357. PMC 3866146. PMID 24358357.

[pmid31506599-19] Pintarelli G, Noci S, Maspero D, Pettinicchio A, Dugo M, De Cecco L, et al. (September 2019). "Cigarette smoke alters the transcriptome of non-involved lung tissue in lung adenocarcinoma patients". Scientific Reports. 9 (1): 13039. Bibcode:2019NatSR...913039P. doi:10.1038/s41598-019-49648-2. PMC 6736939. PMID 31506599.

[six-20] Kim EY, Anderson M, Wilson C, Hagmann H, Benzing T, Dryer SE (November 2013). "NOX2 interacts with podocyte TRPC6 channels and contributes to their activation by diacylglycerol: essential role of podocin in formation of this complex". American Journal of Physiology. Cell Physiology. 305 (9): C960 – C971. doi:10.1152/ajpcell.00191.2013. PMID 23948707.

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PROFILPELAJAR.COM

NOX2

Function

Clinical significance

Interactions

References

Further reading

External links

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