Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ2O8BW)

• DOT Name: Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4)
• Synonyms: NTPDase 4; EC 3.6.1.15; EC 3.6.1.6; Golgi UDPase; Lysosomal apyrase-like protein of 70 kDa; Uridine-diphosphatase; UDPase; EC 3.6.1.42
• Gene Name: ENTPD4
• Related Disease:
  Acquired immune deficiency syndrome
  Advanced cancer
• UniProt ID: ENTP4_HUMAN
• PDB ID: 6WG5
• EC Number: 3.6.1.15; 3.6.1.42; 3.6.1.6
• Pfam ID: PF01150
• Sequence:
  MGRIGISCLFPASWHFSISPVGCPRILNTNLRQIMVISVLAAAVSLLYFSVVIIRNKYGR
  LTRDKKFQRYLARVTDIEATDTNNPNVNYGIVVDCGSSGSRVFVYCWPRHNGNPHDLLDI
  RQMRDKNRKPVVMKIKPGISEFATSPEKVSDYISPLLNFAAEHVPRAKHKETPLYILCTA
  GMRILPESQQKAILEDLLTDIPVHFDFLFSDSHAEVISGKQEGVYAWIGINFVLGRFEHI
  EDDDEAVVEVNIPGSESSEAIVRKRTAGILDMGGVSTQIAYEVPKTVSFASSQQEEVAKN
  LLAEFNLGCDVHQTEHVYRVYVATFLGFGGNAARQRYEDRIFANTIQKNRLLGKQTGLTP
  DMPYLDPCLPLDIKDEIQQNGQTIYLRGTGDFDLCRETIQPFMNKTNETQTSLNGVYQPP
  IHFQNSEFYGFSEFYYCTEDVLRMGGDYNAAKFTKAAKDYCATKWSILRERFDRGLYASH
  ADLHRLKYQCFKSAWMFEVFHRGFSFPVNYKSLKTALQVYDKEVQWTLGAILYRTRFLPL
  RDIQQEAFRASHTHWRGVSFVYNHYLFSGCFLVVLLAILLYLLRLRRIHRRTPRSSSAAA
  LWMEEGLPAQNAPGTL
• Function: [Isoform 1]: Catalyzes the hydrolysis of nucleoside triphosphates and diphosphates in a calcium- or magnesium-dependent manner, with a preference for pyrimidines. Preferentially hydrolyzes UTP and TTP. AMP, ADP, ATP and UMP are not substrates. Preferentially activated by Ca(2+) over Mg(2+) ; [Isoform 2]: Has a broad substrate specificity with the ability of cleaving all nucleotide di- and triphosphates with the exception of adenosine di- and triphosphate (ADP and ATP). Preferentially hydrolyzes CTP, UDP, CDP, GTP and GDP. Can use either Ca(2+) or Mg(2+) equally.
• Tissue Specificity: Ubiquitous. Highest expression in testis and lowest in bladder.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Pyrimidine metabolism (hsa00240)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
  Lysosome (hsa04142)
• Reactome Pathway: Phosphate bond hydrolysis by NTPDase proteins (R-HSA-8850843)
• BioCyc Pathway: MetaCyc:HS09501-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acquired immune deficiency syndrome	DISL5UOX	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4).	[7]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4).	[10]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4).	[11]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4).	[12]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4).	[13]
PP-242	DM2348V	Investigative	PP-242 decreases the expression of Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4).	[8]

References

• [1] Identification of Genes Whose Expression Profile Is Associated with Non-Progression towards AIDS Using eQTLs.PLoS One. 2015 Sep 14;10(9):e0136989. doi: 10.1371/journal.pone.0136989. eCollection 2015.
• [2] ENTPD5-mediated modulation of ATP results in altered metabolism and decreased survival in gliomablastoma multiforme.Tumour Biol. 2012 Dec;33(6):2411-21. doi: 10.1007/s13277-012-0505-1. Epub 2012 Sep 20.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [7] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [8] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [9] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [10] 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.
• [11] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [12] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [13] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [14] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.