ENOX2

ENOX2
Identifiers
Aliases	ENOX2 , APK1, COVA1, tNOX, ecto-NOX disulfide-thiol exchanger 2
External IDs	OMIM: 300282; MGI: 2384799; HomoloGene: 17120; GeneCards: ENOX2; OMA:ENOX2 - orthologs
Gene location (Human) Chr. X chromosome (human) [1] Band Xq26.1 Start 130,622,325 bp [1] End 130,903,234 bp [1]
Gene location (Mouse) Chr. X chromosome (mouse) [2] Band X|X A5 Start 48,098,584 bp [2] End 48,377,136 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Achilles tendon gonad tendon of biceps brachii popliteal artery tibial arteries right coronary artery left coronary artery testicle thoracic aorta monocyte Top expressed in habenula interventricular septum Paneth cell otic vesicle muscle of thigh trigeminal ganglion sciatic nerve saccule substantia nigra ventricular zone More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein-disulfide reductase activity oxidoreductase activity protein binding nucleic acid binding RNA binding Cellular component extracellular region cytosol plasma membrane membrane external side of plasma membrane extracellular space Biological process cell growth regulation of growth ultradian rhythm rhythmic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10495 209224 Ensembl ENSG00000165675 ENSMUSG00000031109 UniProt Q16206 Q8R0Z2 RefSeq (mRNA) NM_001281736 NM_006375 NM_182314 NM_001382516 NM_001382517 NM_001382518 NM_001382519 NM_001382520 NM_001382521 NM_001382522 NM_001271447 NM_001271448 NM_001271449 NM_001271450 NM_001271451 NM_145951 RefSeq (protein) NP_001268665 NP_006366 NP_872114 NP_001369445 NP_001369446 NP_001369447 NP_001369448 NP_001369449 NP_001369450 NP_001369451 NP_001258376 NP_001258377 NP_001258378 NP_001258379 NP_001258380 NP_666063 Location (UCSC) Chr X: 130.62 – 130.9 Mb Chr X: 48.1 – 48.38 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

ENOX2 is a gene located on the long arm of the X chromosome in humans. ^[5] The gene encodes the protein Ecto-NOX disulfide-thiol exchanger 2, a member of the NOX family of NADPH oxidases. ^{[6] [7] [8]}

Ecto-NOX disulfide-thiol exchanger 2 is a growth-related cell surface protein. It was identified because it reacts with the monoclonal antibody K1 in cells, such as the ovarian carcinoma line OVCAR-3, also expressing the CAKI surface glycoprotein. ^[6] The encoded protein has two enzymatic activities: catalysis of hydroquinone or NADH oxidation, and protein disulfide interchange. The two activities alternate with a period length of about 24 minutes. The encoded protein also displays prion-like properties. Two transcript variants encoding different isoforms have been found for this gene. ^[9]

Gene Location

The human ENOX2 gene is located on the long (q) arm of the X chromosome in humans, at region 2 band 6 sub band 1, from base pair 130,622,330 to 130,903,317 (build GRCh38.p7) (map). The gene is conserved in chimpanzee, Rhesus monkey, dog, mouse, rat, chicken, and zebrafish. ^[5]

Function

ENOX2 and related NOX proteins exhibit two distinct oscillating functions: the oxidation of NADH to NAD+ and a protein disulfide isomerase-like activity, unprecedented in the biochemical literature. ^{[8] [10] [11] [12]} Regarding NADH oxidation, the protein has a specific activity of 10-20μmol/min/mg of protein with a turnover number of 200-500. ^{[13] [14]} The oscillations are independent of temperature, with a period of 24 minutes, completing 60 cycles in a 24-hour day. ^{[10] [12]} The period of oscillation changes to 22 and 26 minutes in the cancer related (tNOX) and age-related (arNOX) forms respectively. ^[8] This regular oscillation is attributed to the maintenance of biological clock ^{[8] [15]}

Interactions

NADH activity of ENOX2 has been shown to be stimulated by various hormones and growth factors, including insulin, EGF, transferrin, lactoferrin, vasopressin and glucagon. ^[16] This stimulation is not seen in protein samples recovered from cancer cells, suggesting the regular NADH oxidase activity of ENOX2 is decoupled in cancer. ^[16] ENOX2 also has a number of protein-protein interactions, with ENOX1 and SOX2, among others. ^[17]

Cell Growth

Numerous studies in the 1990s correlated NADH oxidase activity with cell growth. ^[8] Conditions which stimulated cell growth also stimulated NADH oxidase activity and conditions that inhibited cell growth inhibited NADH oxidase activity. Further experimental evidence showed that the rate of cell enlargement oscillates within the 24 minute oscillation of ENOX function. ^[18] Maximum cell growth rates correspond to the portion of the ENOX cycle involved in protein dulsulfide bridge formation. ^[19] Theories suggest that ENOX is responsible for the breakup and formation of disulfide bonds in membrane proteins, thus maximum cell growth coincides with maximum protein disulfide interchange activity. ^[8]

Role In Disease

Cancer

The cancer associated, drug responsive variant of ENOX, tNOX, arises as a splice variant and is found on the cell surface of human cancers. ^{[8] [20]} tNOX exhibits a periodicity of 22 minutes, compared to the native 24 minutes and can be inhibited by a number of anticancer drugs, without affecting the native ENOX. ^[8] These properties of tNOX are being used to develop early detection and intervention mechanisms for human cancers. ^[21]

See also

Ecto-nox disulfide-thiol exchanger 1

References

1. GRCh38: Ensembl release 89: ENSG00000165675 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000031109 – 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.
5. "ENOX2 ecto-NOX disulfide-thiol exchanger 2 [ Homo sapiens (human) ]". NCBI. Retrieved 2016-10-16.
6. Chang K, Pastan I (May 1994). "Molecular cloning and expression of a cDNA encoding a protein detected by the K1 antibody from an ovarian carcinoma (OVCAR-3) cell line". Int J Cancer. 57 (1): 90–7. doi:10.1002/ijc.2910570117. PMID   8150545. S2CID   1970834.
7. Chueh PJ, Kim C, Cho N, Morre DM, Morre DJ (Mar 2002). "Molecular cloning and characterization of a tumor-associated, growth-related, and time-keeping hydroquinone (NADH) oxidase (tNOX) of the HeLa cell surface". Biochemistry. 41 (11): 3732–41. doi:10.1021/bi012041t. PMID   11888291.
8. Morré, D. James; Morré, Dorothy M. (2003-08-01). "Cell surface NADH oxidases (ECTO-NOX proteins) with roles in cancer, cellular time-keeping, growth, aging and neurodegenerative diseases". Free Radical Research. 37 (8): 795–808. doi:10.1080/1071576031000083107. ISSN   1071-5762. PMID   14567438. S2CID   28452870.
9. "Entrez Gene: COVA1 cytosolic ovarian carcinoma antigen 1".
10. Morré, D. James; Morré, Dorothy M. (1998-11-01). "NADH oxidase activity of soybean plasma membranes oscillates with a temperature compensated period of 24 min". The Plant Journal. 16 (3): 277–284. doi: 10.1046/j.1365-313x.1998.00293.x . ISSN   1365-313X.
11. Morré, D. J.; Chueh, P. J.; Lawler, J.; Morré, D. M. (1998-10-01). "The sulfonylurea-inhibited NADH oxidase activity of HeLa cell plasma membranes has properties of a protein disulfide-thiol oxidoreductase with protein disulfide-thiol interchange activity". Journal of Bioenergetics and Biomembranes. 30 (5): 477–487. doi:10.1023/A:1020594214379. ISSN   0145-479X. PMID   9932650. S2CID   20415997.
12. Sun, Peichuan; Morré, D. James; Morré, Dorothy M. (2000-10-20). "Periodic NADH oxidase activity associated with an endoplasmic reticulum fraction from pig liver. Response to micromolar concentrations of retinol". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1498 (1): 52–63. doi:10.1016/S0167-4889(00)00079-3. PMID   11042350.
13. Yantiri, F.; Morré, D. J. (2001-07-15). "Isolation and characterization of a tumor-associated NADH oxidase (tNOX) from the HeLa cell surface". Archives of Biochemistry and Biophysics. 391 (2): 149–159. doi:10.1006/abbi.2001.2404. ISSN   0003-9861. PMID   11437345.
14. del Castillo-Olivares, A.; Yantiri, F.; Chueh, P. J.; Wang, S.; Sweeting, M.; Sedlak, D.; Morré, D. M.; Burgess, J.; Morré, D. J. (1998-10-01). "A drug-responsive and protease-resistant peripheral NADH oxidase complex from the surface of HeLa S cells". Archives of Biochemistry and Biophysics. 358 (1): 125–140. doi:10.1006/abbi.1998.0823. ISSN   0003-9861. PMID   9750173.
15. Morré, D. James; Chueh, Pin-Ju; Pletcher, Jake; Tang, Xiaoyu; Wu, Lian-Ying; Morré, Dorothy M. (2002-10-08). "Biochemical basis for the biological clock". Biochemistry. 41 (40): 11941–11945. doi:10.1021/bi020392h. ISSN   0006-2960. PMID   12356293.
16. Bruno, M; Brightman, A O; Lawrence, J; Werderitsh, D; Morré, D M; Morre, D J (1992-06-15). "Stimulation of NADH oxidase activity from rat liver plasma membranes by growth factors and hormones is decreased or absent with hepatoma plasma membranes". Biochemical Journal. 284 (Pt 3): 625–628. doi:10.1042/bj2840625. ISSN   0264-6021. PMC   1132580 . PMID   1622384.
17. Lab, Mike Tyers. "ENOX2 (RP5-875H3.1) Result Summary | BioGRID". thebiogrid.org. Retrieved 2016-10-16.
18. Wang, S.; Pogue, R.; Morré, D. M.; Morré, D. J. (2001-06-20). "NADH oxidase activity (NOX) and enlargement of HeLa cells oscillate with two different temperature-compensated period lengths of 22 and 24 minutes corresponding to different NOX forms". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1539 (3): 192–204. doi: 10.1016/s0167-4889(01)00107-0 . ISSN   0006-3002. PMID   11420117.
19. Morré, D. James; Pogue, Rhea; Morré, Dorothy M. (2001). "Soybean cell enlargement oscillates with a temperature-compensated period length of CA. 24 min". In Vitro Cellular & Developmental Biology - Plant. 37 (1): 19–23. doi:10.1007/s11627-001-0004-3. ISSN   1054-5476. PMID   12026936. S2CID   1724211.
20. "Monoclonal antibody to a cancer-specific and drug-responsive hydroquinone (NADH) oxidase from the sera of cancer patients". Cancer Immunol Immunother. 51.
21. James, D.; M., Dorothy (2012-04-20). Early Detection: An Opportunity for Cancer Prevention Through Early Intervention. InTech. doi:10.5772/32415. ISBN   9789535105473.

Further reading

• Tarasoutchi F, Grinberg M, de Figueiredo Neto JA, et al. (1991). "[Mitral valve aneurysm associated with mitral insufficiency in absence of aortic insufficiency]". Arq. Bras. Cardiol. 56 (3): 231–4. PMID   1888291.
• Dai S, Morré DJ, Geilen CC, et al. (1997). "Inhibition of plasma membrane NADH oxidase activity and growth of HeLa cells by natural and synthetic retinoids". Mol. Cell. Biochem. 166 (1–2): 101–9. doi:10.1023/A:1006866726050. PMID   9046026. S2CID   25814254.
• Morré DJ, Chueh PJ, Lawler J, Morré DM (1999). "The sulfonylurea-inhibited NADH oxidase activity of HeLa cell plasma membranes has properties of a protein disulfide-thiol oxidoreductase with protein disulfide-thiol interchange activity". J. Bioenerg. Biomembr. 30 (5): 477–87. doi:10.1023/A:1020594214379. PMID   9932650. S2CID   20415997.
• Kishi T, Morré DM, Morré DJ (1999). "The plasma membrane NADH oxidase of HeLa cells has hydroquinone oxidase activity". Biochim. Biophys. Acta. 1412 (1): 66–77. doi: 10.1016/S0005-2728(99)00049-3 . PMID   10354495.
• Kelker M, Kim C, Chueh PJ, et al. (2001). "Cancer isoform of a tumor-associated cell surface NADH oxidase (tNOX) has properties of a prion". Biochemistry. 40 (25): 7351–4. doi:10.1021/bi010596i. PMID   11412089.
• Yantiri F, Morré DJ (2001). "Isolation and characterization of a tumor-associated NADH oxidase (tNOX) from the HeLa cell surface". Arch. Biochem. Biophys. 391 (2): 149–59. doi:10.1006/abbi.2001.2404. PMID   11437345.
• Morré DJ, Sedlak D, Tang X, et al. (2001). "Surface NADH oxidase of HeLa cells lacks intrinsic membrane binding motifs". Arch. Biochem. Biophys. 392 (2): 251–6. doi:10.1006/abbi.2001.2436. PMID   11488599.
• Chueh PJ, Morré DM, Morré DJ (2002). "A site-directed mutagenesis analysis of tNOX functional domains". Biochim. Biophys. Acta. 1594 (1): 74–83. doi:10.1016/s0167-4838(01)00286-2. PMID   11825610.
• Cho N, Chueh PJ, Kim C, et al. (2002). "Monoclonal antibody to a cancer-specific and drug-responsive hydroquinone (NADH) oxidase from the sera of cancer patients". Cancer Immunol. Immunother. 51 (3): 121–9. doi:10.1007/s00262-001-0262-2. PMC   11032947 . PMID   11941450. S2CID   22275635.
• Morré DJ, Chueh PJ, Pletcher J, et al. (2002). "Biochemical basis for the biological clock". Biochemistry. 41 (40): 11941–5. doi:10.1021/bi020392h. PMID   12356293.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi: 10.1073/pnas.242603899 . PMC   139241 . PMID   12477932.
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi: 10.1038/ng1285 . PMID   14702039.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC   528928 . PMID   15489334.
• Chueh PJ, Wu LY, Morré DM, Morré DJ (2005). "tNOX is both necessary and sufficient as a cellular target for the anticancer actions of capsaicin and the green tea catechin (-)-epigallocatechin-3-gallate". BioFactors. 20 (4): 235–49. PMID   15706060.
• Ross MT, Grafham DV, Coffey AJ, et al. (2005). "The DNA sequence of the human X chromosome". Nature. 434 (7031): 325–37. Bibcode:2005Natur.434..325R. doi:10.1038/nature03440. PMC   2665286 . PMID   15772651.
• Rual JF, Venkatesan K, Hao T, et al. (2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID   16189514. S2CID   4427026.