Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ2PKPM)

• DOT Name: Ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2)
• Synonyms: NTPDase 2; EC 3.6.1.-; CD39 antigen-like 1; Ecto-ATP diphosphohydrolase 2; Ecto-ATPDase 2; Ecto-ATPase 2
• Gene Name: ENTPD2
• Related Disease:
  Pancreatic cancer
  Primary biliary cholangitis
  Advanced cancer
  Hepatocellular carcinoma
  Neoplasm
  High blood pressure
  Nervous system inflammation
• UniProt ID: ENTP2_HUMAN
• EC Number: 3.6.1.-
• Pfam ID: PF01150
• Sequence:
  MAGKVRSLLPPLLLAAAGLAGLLLLCVPTRDVREPPALKYGIVLDAGSSHTSMFIYKWPA
  DKENDTGIVGQHSSCDVPGGGISSYADNPSGASQSLVGCLEQALQDVPKERHAGTPLYLG
  ATAGMRLLNLTNPEASTSVLMAVTHTLTQYPFDFRGARILSGQEEGVFGWVTANYLLENF
  IKYGWVGRWFRPRKGTLGAMDLGGASTQITFETTSPAEDRASEVQLHLYGQHYRVYTHSF
  LCYGRDQVLQRLLASALQTHGFHPCWPRGFSTQVLLGDVYQSPCTMAQRPQNFNSSARVS
  LSGSSDPHLCRDLVSGLFSFSSCPFSRCSFNGVFQPPVAGNFVAFSAFFYTVDFLRTSMG
  LPVATLQQLEAAAVNVCNQTWAQLQARVPGQRARLADYCAGAMFVQQLLSRGYGFDERAF
  GGVIFQKKAADTAVGWALGYMLNLTNLIPADPPGLRKGTDFSSWVVLLLLFASALLAALV
  LLLRQVHSAKLPSTI
• Function: In the nervous system, could hydrolyze ATP and other nucleotides to regulate purinergic neurotransmission. Hydrolyzes ADP only to a marginal extent. The order of activity with different substrates is ATP > GTP > CTP = ITP > UTP >> ADP = UDP.
• Tissue Specificity: Brain, placenta, skeletal muscle, kidney, pancreas, heart, ovary, testis, colon, small intestine, prostate and pancreas. No expression in adult thymus, spleen, lung, liver and peripheral blood leukocytes.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
  Taste transduction (hsa04742)
• Reactome Pathway: Phosphate bond hydrolysis by NTPDase proteins (R-HSA-8850843)
• BioCyc Pathway: MetaCyc:ENSG00000054179-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pancreatic cancer	DISJC981	Strong	Biomarker	[1]
Primary biliary cholangitis	DIS43E0O	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[3]
Neoplasm	DISZKGEW	moderate	Biomarker	[3]
High blood pressure	DISY2OHH	Disputed	Biomarker	[4]
Nervous system inflammation	DISB3X5A	Limited	Biomarker	[5]

1 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 Ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2).	[7]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2).	[9]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2).	[10]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2).	[11]

References

• [1] Upregulation of CD39/NTPDases and P2 receptors in human pancreatic disease.Am J Physiol Gastrointest Liver Physiol. 2007 Jan;292(1):G223-30. doi: 10.1152/ajpgi.00259.2006. Epub 2006 Aug 17.
• [2] Ectonucleotidase NTPDase2 is selectively down-regulated in biliary cirrhosis.J Investig Med. 2004 Nov;52(7):475-82. doi: 10.1136/jim-52-07-42.
• [3] Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma.Nat Commun. 2017 Sep 11;8(1):517. doi: 10.1038/s41467-017-00530-7.
• [4] L-NAME-treatment alters ectonucleotidase activities in kidney membranes of rats.Life Sci. 2010 Aug 28;87(9-10):325-32. doi: 10.1016/j.lfs.2010.07.008. Epub 2010 Jul 23.
• [5] Down-regulation of NTPDase2 and ADP-sensitive P2 Purinoceptors Correlate with Severity of Symptoms during Experimental Autoimmune Encephalomyelitis.Front Cell Neurosci. 2017 Oct 30;11:333. doi: 10.3389/fncel.2017.00333. eCollection 2017.
• [6] 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.
• [7] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [9] 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.
• [10] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [11] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.