Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4WOLA8)

• DOT Name: Ecto-NOX disulfide-thiol exchanger 1 (ENOX1)
• Synonyms: Candidate growth-related and time keeping constitutive hydroquinone oxidase; cCNOX; Cell proliferation-inducing gene 38 protein; Constitutive Ecto-NOX; cNOX) oxidase (EC 1.-.-.-); Protein disulfide-thiol oxidoreductase (EC 1.-.-.-)]
• Gene Name: ENOX1
• Related Disease:
  Diabetic kidney disease
  Advanced cancer
  Hepatocellular carcinoma
  Major depressive disorder
  Rheumatoid arthritis
  Diabetic retinopathy
  Non-insulin dependent diabetes
  Retinopathy
• UniProt ID: ENOX1_HUMAN
• EC Number: 1.-.-.-
• Pfam ID: PF00076
• Sequence:
  MVDAGGVENITQLPQELPQMMAAAADGLGSIAIDTTQLNMSVTDPTAWATAMNNLGMVPV
  GLPGQQLVSDSICVPGFDPSLNMMTGITPINPMIPGLGLVPPPPPTEVAVVKEIIHCKSC
  TLFPQNPNLPPPSTRERPPGCKTVFVGGLPENATEEIIQEVFEQCGDITAIRKSKKNFCH
  IRFAEEFMVDKAIYLSGYRMRLGSSTDKKDSGRLHVDFAQARDDFYEWECKQRMRAREER
  HRRKLEEDRLRPPSPPAIMHYSEHEAALLAEKLKDDSKFSEAITVLLSWIERGEVNRRSA
  NQFYSMVQSANSHVRRLMNEKATHEQEMEEAKENFKNALTGILTQFEQIVAVFNASTRQK
  AWDHFSKAQRKNIDIWRKHSEELRNAQSEQLMGIRREEEMEMSDDENCDSPTKKMRVDES
  ALAAQAYALKEENDSLRWQLDAYRNEVELLKQEKEQLFRTEENLTKDQQLQFLQQTMQGM
  QQQLLTIQEELNNKKSELEQAKEEQSHTQALLKVLQEQLKGTKELVETNGHSHEDSNEIN
  VLTVALVNQDRENNIEKRSQGLKSEKEALLIGIISTFLHVHPFGANIEYLWSYMQQLDSK
  ISANEIEMLLMRLPRMFKQEFTGVGATLEKRWKLCAFEGIKTT
• Function: Probably acts as a terminal oxidase of plasma electron transport from cytosolic NAD(P)H via hydroquinones to acceptors at the cell surface. Hydroquinone oxidase activity alternates with a protein disulfide-thiol interchange/oxidoreductase activity which may control physical membrane displacements associated with vesicle budding or cell enlargement. The activities oscillate with a period length of 24 minutes and play a role in control of the ultradian cellular biological clock.
• Tissue Specificity: Expressed in lymphocyte cells, breast and breast cancer (at protein level). Found in the sera of cancer patients with a wide variety of cancers including breast, prostate, lung and ovarian cancers, leukemias, and lymphomas. Found also in the serum of healthy volunteers or patients with disorders other than cancer. Probably shed into serum by cancer cells.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Diabetic kidney disease	DISJMWEY	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[4]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[5]
Diabetic retinopathy	DISHGUJM	Limited	Biomarker	[6]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Altered Expression	[6]
Retinopathy	DISB4B0F	Limited	Altered Expression	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Ecto-NOX disulfide-thiol exchanger 1 (ENOX1).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ecto-NOX disulfide-thiol exchanger 1 (ENOX1).	[16]

9 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ecto-NOX disulfide-thiol exchanger 1 (ENOX1).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ecto-NOX disulfide-thiol exchanger 1 (ENOX1).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ecto-NOX disulfide-thiol exchanger 1 (ENOX1).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Ecto-NOX disulfide-thiol exchanger 1 (ENOX1).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Ecto-NOX disulfide-thiol exchanger 1 (ENOX1).	[12]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Ecto-NOX disulfide-thiol exchanger 1 (ENOX1).	[13]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Ecto-NOX disulfide-thiol exchanger 1 (ENOX1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ecto-NOX disulfide-thiol exchanger 1 (ENOX1).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Ecto-NOX disulfide-thiol exchanger 1 (ENOX1).	[17]

References

• [1] A genome-wide association study for diabetic nephropathy genes in African Americans.Kidney Int. 2011 Mar;79(5):563-72. doi: 10.1038/ki.2010.467. Epub 2010 Dec 8.
• [2] Cancer type-specific tNOX isoforms: A putative family of redox protein splice variants with cancer diagnostic and prognostic potential.Biofactors. 2008;34(3):201-7. doi: 10.3233/BIO-2009-1073.
• [3] Update on a tumor-associated NADH oxidase in gastric cancer cell growth. World J Gastroenterol. 2016 Mar 14;22(10):2900-5.
• [4] Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.Nat Genet. 2018 May;50(5):668-681. doi: 10.1038/s41588-018-0090-3. Epub 2018 Apr 26.
• [5] Genome-wide association analysis implicates the involvement of eight loci with response to tocilizumab for the treatment of rheumatoid arthritis.Pharmacogenomics J. 2013 Jun;13(3):235-41. doi: 10.1038/tpj.2012.8. Epub 2012 Apr 10.
• [6] Increased Expression of Ecto-NOX Disulfide-thiol Exchanger 1 (ENOX1) in Diabetic Mice Retina and its Involvement in Diabetic Retinopathy Development.In Vivo. 2019 Nov-Dec;33(6):1801-1806. doi: 10.21873/invivo.11671.
• [7] 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.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [10] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [11] DNA methylation inhibits p53-mediated survivin repression. Oncogene. 2009 May 14;28(19):2046-50. doi: 10.1038/onc.2009.62. Epub 2009 Apr 13.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [15] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [16] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [17] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.