ENOX2

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) ([https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=10495 map]). The gene is conserved in chimpanzee, Rhesus monkey, dog, mouse, rat, chicken, and zebrafish.

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.{{Cite journal|last1=Morré|first1=D. James|last2=Morré|first2=Dorothy M.|date=1998-11-01|title=NADH oxidase activity of soybean plasma membranes oscillates with a temperature compensated period of 24 min|journal=The Plant Journal|language=en|volume=16|issue=3|pages=277–284|doi=10.1046/j.1365-313x.1998.00293.x|issn=1365-313X|doi-access=free}}{{Cite journal|last1=Morré|first1=D. J.|last2=Chueh|first2=P. J.|last3=Lawler|first3=J.|last4=Morré|first4=D. M.|date=1998-10-01|title=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|pmid=9932650|journal=Journal of Bioenergetics and Biomembranes|volume=30|issue=5|pages=477–487|issn=0145-479X|doi=10.1023/A:1020594214379|s2cid=20415997}}{{Cite journal|last1=Sun|first1=Peichuan|last2=Morré|first2=D. James|last3=Morré|first3=Dorothy M.|date=2000-10-20|title=Periodic NADH oxidase activity associated with an endoplasmic reticulum fraction from pig liver. Response to micromolar concentrations of retinol|journal=Biochimica et Biophysica Acta (BBA) - Molecular Cell Research|volume=1498|issue=1|pages=52–63|doi=10.1016/S0167-4889(00)00079-3|pmid=11042350|doi-access=}} Regarding NADH oxidation, the protein has a specific activity of 10-20μmol/min/mg of protein with a turnover number of 200-500.{{Cite journal|last1=Yantiri|first1=F.|last2=Morré|first2=D. J.|date=2001-07-15|title=Isolation and characterization of a tumor-associated NADH oxidase (tNOX) from the HeLa cell surface|pmid=11437345|journal=Archives of Biochemistry and Biophysics|volume=391|issue=2|pages=149–159|doi=10.1006/abbi.2001.2404|issn=0003-9861}}{{Cite journal|last1=del Castillo-Olivares|first1=A.|last2=Yantiri|first2=F.|last3=Chueh|first3=P. J.|last4=Wang|first4=S.|last5=Sweeting|first5=M.|last6=Sedlak|first6=D.|last7=Morré|first7=D. M.|last8=Burgess|first8=J.|last9=Morré|first9=D. J.|date=1998-10-01|title=A drug-responsive and protease-resistant peripheral NADH oxidase complex from the surface of HeLa S cells|pmid=9750173|journal=Archives of Biochemistry and Biophysics|volume=358|issue=1|pages=125–140|doi=10.1006/abbi.1998.0823|issn=0003-9861}} The oscillations are independent of temperature, with a period of 24 minutes, completing 60 cycles in a 24-hour day. The period of oscillation changes to 22 and 26 minutes in the cancer related (tNOX) and age-related (arNOX) forms respectively. This regular oscillation is attributed to the maintenance of biological clock{{Cite journal|last1=Morré|first1=D. James|last2=Chueh|first2=Pin-Ju|last3=Pletcher|first3=Jake|last4=Tang|first4=Xiaoyu|last5=Wu|first5=Lian-Ying|last6=Morré|first6=Dorothy M.|date=2002-10-08|title=Biochemical basis for the biological clock|pmid=12356293|journal=Biochemistry|volume=41|issue=40|pages=11941–11945|issn=0006-2960|doi=10.1021/bi020392h}}

NADH activity of ENOX2 has been shown to be stimulated by various hormones and growth factors, including insulin, EGF, transferrin, lactoferrin, vasopressin and glucagon.{{Cite journal|last1=Bruno|first1=M|last2=Brightman|first2=A O|last3=Lawrence|first3=J|last4=Werderitsh|first4=D|last5=Morré|first5=D M|last6=Morre|first6=D J|date=1992-06-15|title=Stimulation of NADH oxidase activity from rat liver plasma membranes by growth factors and hormones is decreased or absent with hepatoma plasma membranes.|pmc=1132580|journal=Biochemical Journal|volume=284|issue=Pt 3|pages=625–628|issn=0264-6021|doi=10.1042/bj2840625|pmid=1622384}} This stimulation is not seen in protein samples recovered from cancer cells, suggesting the regular NADH oxidase activity of ENOX2 is decoupled in cancer. ENOX2 also has a number of protein-protein interactions, with ENOX1 and SOX2, among others.{{Cite web|url=https://thebiogrid.org/115758|title=ENOX2 (RP5-875H3.1) Result Summary {{!}} BioGRID|last=Lab|first=Mike Tyers|website=thebiogrid.org|access-date=2016-10-16}}

Numerous studies in the 1990s correlated NADH oxidase activity with cell growth. 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.{{Cite journal|last1=Wang|first1=S.|last2=Pogue|first2=R.|last3=Morré|first3=D. M.|last4=Morré|first4=D. J.|date=2001-06-20|title=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|journal=Biochimica et Biophysica Acta (BBA) - Molecular Cell Research|pmid=11420117|volume=1539|issue=3|pages=192–204|issn=0006-3002|doi=10.1016/s0167-4889(01)00107-0|doi-access=free}} Maximum cell growth rates correspond to the portion of the ENOX cycle involved in protein dulsulfide bridge formation.{{Cite journal|last1=Morré|first1=D. James|last2=Pogue|first2=Rhea|last3=Morré|first3=Dorothy M.|title=Soybean cell enlargement oscillates with a temperature-compensated period length of CA. 24 min|journal=In Vitro Cellular & Developmental Biology - Plant|language=en|volume=37|issue=1|pages=19–23|doi=10.1007/s11627-001-0004-3|issn=1054-5476|year=2001|pmid=12026936|s2cid=1724211}} 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.

The cancer associated, drug responsive variant of ENOX, tNOX, arises as a splice variant and is found on the cell surface of human cancers.{{Cite journal|title=Monoclonal antibody to a cancer-specific and drug-responsive hydroquinone (NADH) oxidase from the sera of cancer patients|journal=Cancer Immunol Immunother|volume=51}} 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. These properties of tNOX are being used to develop early detection and intervention mechanisms for human cancers.{{Cite book|title=Early Detection: An Opportunity for Cancer Prevention Through Early Intervention|last1=James|first1=D.|last2=M.|first2=Dorothy|date=2012-04-20|publisher=InTech|isbn=9789535105473|language=en|doi=10.5772/32415}}

Ecto-nox disulfide-thiol exchanger 1

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