Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6E2OW6)

• DOT Name: Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1)
• Synonyms: EC 3.6.1.5; ATP diphosphohydrolase; ATP-DPH; ATPDase; Ecto-ATP diphosphohydrolase 1; Ecto-ATPDase 1; Ecto-ATPase 1; Ecto-apyrase; Lymphoid cell activation antigen; Nucleoside triphosphate diphosphohydrolase 1; NTPDase1; CD antigen CD39
• Gene Name: ENTPD1
• Related Disease:
  Complex hereditary spastic paraplegia
  Hereditary spastic paraplegia 64
• UniProt ID: ENTP1_HUMAN
• EC Number: 3.6.1.5
• Pfam ID: PF01150
• Sequence:
  MEDTKESNVKTFCSKNILAILGFSSIIAVIALLAVGLTQNKALPENVKYGIVLDAGSSHT
  SLYIYKWPAEKENDTGVVHQVEECRVKGPGISKFVQKVNEIGIYLTDCMERAREVIPRSQ
  HQETPVYLGATAGMRLLRMESEELADRVLDVVERSLSNYPFDFQGARIITGQEEGAYGWI
  TINYLLGKFSQKTRWFSIVPYETNNQETFGALDLGGASTQVTFVPQNQTIESPDNALQFR
  LYGKDYNVYTHSFLCYGKDQALWQKLAKDIQVASNEILRDPCFHPGYKKVVNVSDLYKTP
  CTKRFEMTLPFQQFEIQGIGNYQQCHQSILELFNTSYCPYSQCAFNGIFLPPLQGDFGAF
  SAFYFVMKFLNLTSEKVSQEKVTEMMKKFCAQPWEEIKTSYAGVKEKYLSEYCFSGTYIL
  SLLLQGYHFTADSWEHIHFIGKIQGSDAGWTLGYMLNLTNMIPAEQPLSTPLSHSTYVFL
  MVLFSLVLFTVAIIGLLIFHKPSYFWKDMV
• Function: Catalyzes the hydrolysis of both di- and triphosphate nucleotides (NDPs and NTPs) and hydrolyze NTPs to nucleotide monophosphates (NMPs) in two distinct successive phosphate-releasing steps, with NDPs as intermediates and participates in the regulation of extracellular levels of nucleotides (Probable). By hydrolyzing proinflammatory ATP and platelet-activating ADP to AMP, it blocks platelet aggregation and supports blood flow.
• Tissue Specificity: Expressed primarily on activated lymphoid cells . Also expressed in endothelial tissues . Highly expressed in placenta, lung, skeletal muscle, kidney .
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Pyrimidine metabolism (hsa00240)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
  Epstein-Barr virus infection (hsa05169)
• Reactome Pathway:
  Purinergic signaling in leishmaniasis infection (R-HSA-9660826)
  Phosphate bond hydrolysis by NTPDase proteins (R-HSA-8850843)
• BioCyc Pathway: MetaCyc:HS06471-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
Complex hereditary spastic paraplegia	DIS9KXQY	Definitive	Autosomal recessive	[1]
Hereditary spastic paraplegia 64	DISDPDCR	Strong	Autosomal recessive	[2]

11 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 1 (ENTPD1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1).	[6]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1).	[8]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1).	[9]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1).	[10]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1).	[15]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science. 2014 Jan 31;343(6170):506-511. doi: 10.1126/science.1247363.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] Expression profiling of nucleotide metabolism-related genes in human breast cancer cells after treatment with 5-fluorouracil. Cancer Invest. 2009 Jun;27(5):561-7.
• [9] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [10] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [11] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [12] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [13] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [14] 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.
• [15] 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.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.