Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHTH59G)

DOT Name	NADPH oxidase 5 (NOX5)
Synonyms	EC 1.6.3.-
Gene Name	NOX5
Related Disease	Adenocarcinoma ( ) Glomerulosclerosis ( ) Renal fibrosis ( ) Adult T-cell leukemia/lymphoma ( ) Arteriosclerosis ( ) Atherosclerosis ( ) Barrett esophagus ( ) Breast cancer ( ) Breast carcinoma ( ) Cardiac disease ( ) Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy ( ) Cerebral infarction ( ) Chronic granulomatous disease ( ) Colon cancer ( ) Colon carcinoma ( ) Diabetic kidney disease ( ) Ductal carcinoma ( ) Esophageal adenocarcinoma ( ) Esophagitis ( ) Essential hypertension ( ) High blood pressure ( ) leukaemia ( ) Leukemia ( ) Multiple sclerosis ( ) Myocardial infarction ( ) Nephropathy ( ) T-cell leukaemia ( ) Type-1/2 diabetes ( ) Cardiovascular disease ( ) Acute myocardial infarction ( ) Adult glioblastoma ( ) Advanced cancer ( ) Coronary atherosclerosis ( ) Coronary heart disease ( ) Glioblastoma multiforme ( ) Hirschsprung disease ( ) Hyperglycemia ( ) Melanoma ( ) Neoplasm ( ) Prostate cancer ( ) Prostate carcinoma ( ) Stroke ( ) Ventricular septal defect ( )
UniProt ID	NOX5_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	6SZ5
EC Number	1.6.3.-
Pfam ID	PF13202 ; PF13405 ; PF08022 ; PF01794 ; PF08030
Sequence	MNTSGDPAQTGPEGCRGTMSAEEDARWLRWVTQQFKTIAGEDGEISLQEFKAALHVKESF FAERFFALFDSDRSGTITLQELQEALTLLIHGSPMDKLKFLFQVYDIDVCARQGASAGTE WGAGAGPHWASSPLGTGSGSIDPDELRTVLQSCLRESAISLPDEKLDQLTLALFESADAD GNGAITFEELRDELQRFPGVMENLTISAAHWLTAPAPRPRPRRPRQLTRAYWHNHRSQLF CLATYAGLHVLLFGLAASAHRDLGASVMVAKGCGQCLNFDCSFIAVLMLRRCLTWLRATW LAQVLPLDQNIQFHQLMGYVVVGLSLVHTVAHTVNFVLQAQAEASPFQFWELLLTTRPGI GWVHGSASPTGVALLLLLLLMFICSSSCIRRSGHFEVFYWTHLSYLLVWLLLIFHGPNFW KWLLVPGILFFLEKAIGLAVSRMAAVCIMEVNLLPSKVTHLLIKRPPFFHYRPGDYLYLN IPTIARYEWHPFTISSAPEQKDTIWLHIRSQGQWTNRLYESFKASDPLGRGSKRLSRSVT MRKSQRSSKGSEILLEKHKFCNIKCYIDGPYGTPTRRIFASEHAVLIGAGIGITPFASIL QSIMYRHQKRKHTCPSCQHSWIEGVQDNMKLHKVDFIWINRDQRSFEWFVSLLTKLEMDQ AEEAQYGRFLELHMYMTSALGKNDMKAIGLQMALDLLANKEKKDSITGLQTRTQPGRPDW SKVFQKVAAEKKGKVQVFFCGSPALAKVLKGHCEKFGFRFFQENF
Function	Calcium-dependent NADPH oxidase that catalyzes the generation of superoxide from molecular oxygen utilizing NADPH as an electron donor. May play a role in cell growth and apoptosis ; [Isoform v2]: Calcium-dependent NADPH oxidase that catalyzes the generation of superoxide from molecular oxygen utilizing NADPH as an electron donor. Also functions as a calcium-dependent proton channel and may regulate redox-dependent processes in lymphocytes and spermatozoa. Involved in endothelial generation of reactive oxygen species (ROS), proliferation and angiogenesis and contribute to endothelial response to thrombin ; [Isoform v1]: Calcium-dependent NADPH oxidase that catalyzes the generation of superoxide from molecular oxygen utilizing NADPH as an electron donor; [Isoform v5]: Calcium-dependent NADPH oxidase that catalyzes the generation of superoxide from molecular oxygen utilizing NADPH as an electron donor. According to PubMed:22427510, lacks enzyme activity. Involved in endothelial generation of reactive oxygen species (ROS), proliferation and angiogenesis and contribute to endothelial response to thrombin ; [Isoform v4]: Lacks calcium-dependent NADPH oxidase activity; [Isoform v3]: Lacks calcium-dependent NADPH oxidase activity.
Tissue Specificity	Mainly expressed in pachytene spermatocytes of testis and in lymphocyte-rich areas of spleen and lymph nodes. Also detected in ovary, placenta, pancreas, cardiac fibroblasts. Expressed in B-cells and prostate malignant cells.; [Isoform v1]: Expressed in spleen . Expressed in endothelial cells, pulmonary artery smooth muscle cells and epithelial colorectal adenocarcinoma cells .; [Isoform v2]: Expressed in microvascular endothelial cells (at protein level) . Expressed in testis . Expressed in endothelial cells and pulmonary artery smooth muscle cells .; [Isoform v3]: Expressed in pulmonary artery smooth muscle cells and epithelial colorectal adenocarcinoma cells.; [Isoform v4]: Expressed in endothelial cells and pulmonary artery smooth muscle cells.; [Isoform v5]: Expressed in microvascular endothelial cells (at protein level).
Reactome Pathway	Detoxification of Reactive Oxygen Species (R-HSA-3299685 )

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Adenocarcinoma	DIS3IHTY	Definitive	Altered Expression	[1]
Glomerulosclerosis	DISJF20Z	Definitive	Altered Expression	[2]
Renal fibrosis	DISMHI3I	Definitive	Altered Expression	[2]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Biomarker	[3]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[4]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[4]
Barrett esophagus	DIS416Y7	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Cardiac disease	DISVO1I5	Strong	Biomarker	[7]
Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy	DIS93Z3E	Strong	Biomarker	[8]
Cerebral infarction	DISR1WNP	Strong	Altered Expression	[9]
Chronic granulomatous disease	DIS9ZR24	Strong	Genetic Variation	[10]
Colon cancer	DISVC52G	Strong	Altered Expression	[11]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[11]
Diabetic kidney disease	DISJMWEY	Strong	Genetic Variation	[2]
Ductal carcinoma	DIS15EA5	Strong	Altered Expression	[12]
Esophageal adenocarcinoma	DISODWFP	Strong	Biomarker	[13]
Esophagitis	DISHVC9B	Strong	Altered Expression	[14]
Essential hypertension	DIS7WI98	Strong	Altered Expression	[15]
High blood pressure	DISY2OHH	Strong	Biomarker	[16]
leukaemia	DISS7D1V	Strong	Biomarker	[3]
Leukemia	DISNAKFL	Strong	Biomarker	[3]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[17]
Myocardial infarction	DIS655KI	Strong	Biomarker	[7]
Nephropathy	DISXWP4P	Strong	Altered Expression	[18]
T-cell leukaemia	DISJ6YIF	Strong	Biomarker	[3]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[2]
Cardiovascular disease	DIS2IQDX	moderate	Biomarker	[16]
Acute myocardial infarction	DISE3HTG	Limited	Biomarker	[19]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[20]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[21]
Coronary atherosclerosis	DISKNDYU	Limited	Biomarker	[19]
Coronary heart disease	DIS5OIP1	Limited	Biomarker	[19]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[20]
Hirschsprung disease	DISUUSM1	Limited	Genetic Variation	[22]
Hyperglycemia	DIS0BZB5	Limited	Posttranslational Modification	[23]
Melanoma	DIS1RRCY	Limited	Altered Expression	[24]
Neoplasm	DISZKGEW	Limited	Biomarker	[24]
Prostate cancer	DISF190Y	Limited	Altered Expression	[24]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[24]
Stroke	DISX6UHX	Limited	Biomarker	[25]
Ventricular septal defect	DISICO41	Limited	Biomarker	[19]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of NADPH oxidase 5 (NOX5).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of NADPH oxidase 5 (NOX5).	[30]
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6 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of NADPH oxidase 5 (NOX5).	[27]
Isoflavone	DM7U58J	Phase 4	Isoflavone affects the expression of NADPH oxidase 5 (NOX5).	[28]
Dalcetrapib	DMKNCVM	Phase 3	Dalcetrapib increases the expression of NADPH oxidase 5 (NOX5).	[29]
Anacetrapib	DMP2BFG	Phase 3	Anacetrapib decreases the expression of NADPH oxidase 5 (NOX5).	[29]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of NADPH oxidase 5 (NOX5).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of NADPH oxidase 5 (NOX5).	[31]
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⏷ Show the Full List of 6 Drug(s)

References

1	NADPH oxidases and cancer.Clin Sci (Lond). 2015 Jun;128(12):863-75. doi: 10.1042/CS20140542.
2	Endothelial or vascular smooth muscle cell-specific expression of human NOX5 exacerbates renal inflammation, fibrosis and albuminuria in the Akita mouse.Diabetologia. 2019 Sep;62(9):1712-1726. doi: 10.1007/s00125-019-4924-z. Epub 2019 Jun 20.
3	Superoxide-Generating Nox5 Is Functionally Required for the Human T-Cell Leukemia Virus Type 1-Induced Cell Transformation Phenotype.J Virol. 2015 Sep;89(17):9080-9. doi: 10.1128/JVI.00983-15. Epub 2015 Jun 24.
4	Histone Acetyltransferase-Dependent Pathways Mediate Upregulation of NADPH Oxidase 5 in Human Macrophages under Inflammatory Conditions: A Potential Mechanism of Reactive Oxygen Species Overproduction in Atherosclerosis.Oxid Med Cell Longev. 2019 Sep 2;2019:3201062. doi: 10.1155/2019/3201062. eCollection 2019.
5	Effect of Proton Pump Inhibitor Therapy on NOX5, mPGES1 and iNOS expression in Barrett's Esophagus.Sci Rep. 2019 Nov 7;9(1):16242. doi: 10.1038/s41598-019-52800-7.
6	Dihydrotanshinone-Induced NOX5 Activation Inhibits Breast Cancer Stem Cell through the ROS/Stat3 Signaling Pathway.Oxid Med Cell Longev. 2019 Mar 24;2019:9296439. doi: 10.1155/2019/9296439. eCollection 2019.
7	NOX5 expression is increased in intramyocardial blood vessels and cardiomyocytes after acute myocardial infarction in humans.Am J Pathol. 2012 Jun;180(6):2222-9. doi: 10.1016/j.ajpath.2012.02.018. Epub 2012 Apr 10.
8	ER stress and Rho kinase activation underlie the vasculopathy of CADASIL.JCI Insight. 2019 Dec 5;4(23):e131344. doi: 10.1172/jci.insight.131344.
9	NOX5 as a therapeutic target in cerebral ischemic injury.J Clin Invest. 2019 Mar 18;129(4):1530-1532. doi: 10.1172/JCI127682. eCollection 2019 Mar 18.
10	Severe X-linked chronic granulomatous disease in two unrelated females.Eur J Pediatr. 2007 Feb;166(2):153-9. doi: 10.1007/s00431-006-0211-3. Epub 2006 Nov 3.
11	Clinical Significance of NADPH Oxidase 5 in Human Colon Cancer.Anticancer Res. 2019 Aug;39(8):4405-4410. doi: 10.21873/anticanres.13611.
12	STAT5A-mediated NOX5-L expression promotes the proliferation and metastasis of breast cancer cells.Exp Cell Res. 2017 Feb 1;351(1):51-58. doi: 10.1016/j.yexcr.2016.12.020. Epub 2016 Dec 26.
13	Rho Kinase ROCK2 Mediates Acid-Induced NADPH Oxidase NOX5-S Expression in Human Esophageal Adenocarcinoma Cells.PLoS One. 2016 Feb 22;11(2):e0149735. doi: 10.1371/journal.pone.0149735. eCollection 2016.
14	Hydrogen peroxide reduces lower esophageal sphincter tone in human esophagitis.Gastroenterology. 2005 Nov;129(5):1675-85. doi: 10.1053/j.gastro.2005.09.008.
15	Unique role of NADPH oxidase 5 in oxidative stress in human renal proximal tubule cells.Redox Biol. 2014 Feb 22;2:570-9. doi: 10.1016/j.redox.2014.01.020. eCollection 2014.
16	Vascular Biology of Superoxide-Generating NADPH Oxidase 5-Implications in Hypertension and Cardiovascular Disease.Antioxid Redox Signal. 2019 Mar 1;30(7):1027-1040. doi: 10.1089/ars.2018.7583. Epub 2018 Nov 15.
17	Serum NADPH oxidase concentrations and the associations with iron metabolism in relapsing remitting multiple sclerosis.J Trace Elem Med Biol. 2019 Sep;55:39-43. doi: 10.1016/j.jtemb.2019.05.011. Epub 2019 May 25.
18	NADPH oxidase 5 and renal disease.Curr Opin Nephrol Hypertens. 2015 Jan;24(1):81-7. doi: 10.1097/MNH.0000000000000081.
19	Regulation of NADPH oxidase 5 by protein kinase C isoforms.PLoS One. 2014 Feb 5;9(2):e88405. doi: 10.1371/journal.pone.0088405. eCollection 2014.
20	NADPH Oxidases NOXs and DUOXs as putative targets for cancer therapy.Anticancer Agents Med Chem. 2013 Mar;13(3):502-14.
21	NOX5: Molecular biology and pathophysiology.Exp Physiol. 2019 May;104(5):605-616. doi: 10.1113/EP086204. Epub 2019 Mar 18.
22	Association analysis of NOX5 polymorphisms with Hirschsprung disease.J Pediatr Surg. 2019 Sep;54(9):1815-1819. doi: 10.1016/j.jpedsurg.2018.12.017. Epub 2019 Jan 3.
23	NADPH Oxidase Nox5 Accelerates Renal Injury in Diabetic Nephropathy.Diabetes. 2017 Oct;66(10):2691-2703. doi: 10.2337/db16-1585. Epub 2017 Jul 26.
24	NADPH oxidase 5 (NOX5)-induced reactive oxygen signaling modulates normoxic HIF-1 and p27(Kip1) expression in malignant melanoma and other human tumors.Mol Carcinog. 2017 Dec;56(12):2643-2662. doi: 10.1002/mc.22708. Epub 2017 Aug 30.
25	Calcium-dependent blood-brain barrier breakdown by NOX5 limits postreperfusion benefit in stroke.J Clin Invest. 2019 Mar 18;129(4):1772-1778. doi: 10.1172/JCI124283. eCollection 2019 Mar 18.
26	Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
27	Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013 May;169(1):167-78.
28	Soy isoflavones alter expression of genes associated with cancer progression, including interleukin-8, in androgen-independent PC-3 human prostate cancer cells. J Nutr. 2006 Jan;136(1):75-82.
29	Cholesteryl ester-transfer protein inhibitors stimulate aldosterone biosynthesis in adipocytes through Nox-dependent processes. J Pharmacol Exp Ther. 2015 Apr;353(1):27-34.
30	Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
31	Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.