Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMDA97Z)

• DOT Name: Ecto-NOX disulfide-thiol exchanger 2 (ENOX2)
• Synonyms: APK1 antigen; Cytosolic ovarian carcinoma antigen 1; Tumor-associated hydroquinone oxidase; tNOX) oxidase (EC 1.-.-.-); Protein disulfide-thiol oxidoreductase (EC 1.-.-.-)]
• Gene Name: ENOX2
• UniProt ID: ENOX2_HUMAN
• EC Number: 1.-.-.-
• Pfam ID: PF00076
• Sequence:
  MQRDFRWLWVYEIGYAADNSRTLNVDSTAMTLPMSDPTAWATAMNNLGMAPLGIAGQPIL
  PDFDPALGMMTGIPPITPMMPGLGIVPPPIPPDMPVVKEIIHCKSCTLFPPNPNLPPPAT
  RERPPGCKTVFVGGLPENGTEQIIVEVFEQCGEIIAIRKSKKNFCHIRFAEEYMVDKALY
  LSGYRIRLGSSTDKKDTGRLHVDFAQARDDLYEWECKQRMLAREERHRRRMEEERLRPPS
  PPPVVHYSDHECSIVAEKLKDDSKFSEAVQTLLTWIERGEVNRRSANNFYSMIQSANSHV
  RRLVNEKAAHEKDMEEAKEKFKQALSGILIQFEQIVAVYHSASKQKAWDHFTKAQRKNIS
  VWCKQAEEIRNIHNDELMGIRREEEMEMSDDEIEEMTETKETEESALVSQAEALKEENDS
  LRWQLDAYRNEVELLKQEQGKVHREDDPNKEQQLKLLQQALQGMQQHLLKVQEEYKKKEA
  ELEKLKDDKLQVEKMLENLKEKESCASRLCASNQDSEYPLEKTMNSSPIKSEREALLVGI
  ISTFLHVHPFGASIEYICSYLHRLDNKICTSDVECLMGRLQHTFKQEMTGVGASLEKRWK
  FCGFEGLKLT
• Function: May be involved in cell growth. 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 22 minutes and play a role in control of the ultradian cellular biological clock.
• Tissue Specificity: Found in the sera of cancer patients with a wide variety of cancers including breast, prostate, lung and ovarian cancers, leukemias, and lymphomas. Not found in the serum of healthy volunteers or patients with disorders other than cancer. Probably shed into serum by cancer cells. Found on the cell borders of renal, kidney and ovarian carcinomas but not on the borders of surrounding non-cancerous stromal cells.

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Capsaicin	DMGMF6V	Approved	Ecto-NOX disulfide-thiol exchanger 2 (ENOX2) increases the response to substance of Capsaicin.	[11]

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 2 (ENOX2).	[1]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ecto-NOX disulfide-thiol exchanger 2 (ENOX2).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ecto-NOX disulfide-thiol exchanger 2 (ENOX2).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ecto-NOX disulfide-thiol exchanger 2 (ENOX2).	[3]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Ecto-NOX disulfide-thiol exchanger 2 (ENOX2).	[4]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ecto-NOX disulfide-thiol exchanger 2 (ENOX2).	[5]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the activity of Ecto-NOX disulfide-thiol exchanger 2 (ENOX2).	[6]
Phenoxodiol	DMBUJVX	Phase 1/2	Phenoxodiol decreases the activity of Ecto-NOX disulfide-thiol exchanger 2 (ENOX2).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ecto-NOX disulfide-thiol exchanger 2 (ENOX2).	[7]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Ecto-NOX disulfide-thiol exchanger 2 (ENOX2).	[9]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of Ecto-NOX disulfide-thiol exchanger 2 (ENOX2).	[10]

References

• [1] 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.
• [2] 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.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [5] 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.
• [6] Reciprocal relationship between cytosolic NADH and ENOX2 inhibition triggers sphingolipid-induced apoptosis in HeLa cells. J Cell Biochem. 2010 Aug 15;110(6):1504-11. doi: 10.1002/jcb.22724.
• [7] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [8] 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.
• [9] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [10] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [11] 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. 2004;20(4):235-49.