Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB6YLFT)

• DOT Name: Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3)
• Synonyms: E-NPP 3; NPP3; Phosphodiesterase I beta; PD-Ibeta; Phosphodiesterase I/nucleotide pyrophosphatase 3; CD antigen CD203c
• Gene Name: ENPP3
• UniProt ID: ENPP3_HUMAN
• PDB ID: 6C01; 6C02
• EC Number: 3.1.4.1; 3.6.1.9
• Pfam ID: PF01663 ; PF01033
• Sequence:
  MESTLTLATEQPVKKNTLKKYKIACIVLLALLVIMSLGLGLGLGLRKLEKQGSCRKKCFD
  ASFRGLENCRCDVACKDRGDCCWDFEDTCVESTRIWMCNKFRCGETRLEASLCSCSDDCL
  QRKDCCADYKSVCQGETSWLEENCDTAQQSQCPEGFDLPPVILFSMDGFRAEYLYTWDTL
  MPNINKLKTCGIHSKYMRAMYPTKTFPNHYTIVTGLYPESHGIIDNNMYDVNLNKNFSLS
  SKEQNNPAWWHGQPMWLTAMYQGLKAATYFWPGSEVAINGSFPSIYMPYNGSVPFEERIS
  TLLKWLDLPKAERPRFYTMYFEEPDSSGHAGGPVSARVIKALQVVDHAFGMLMEGLKQRN
  LHNCVNIILLADHGMDQTYCNKMEYMTDYFPRINFFYMYEGPAPRIRAHNIPHDFFSFNS
  EEIVRNLSCRKPDQHFKPYLTPDLPKRLHYAKNVRIDKVHLFVDQQWLAVRSKSNTNCGG
  GNHGYNNEFRSMEAIFLAHGPSFKEKTEVEPFENIEVYNLMCDLLRIQPAPNNGTHGSLN
  HLLKVPFYEPSHAEEVSKFSVCGFANPLPTESLDCFCPHLQNSTQLEQVNQMLNLTQEEI
  TATVKVNLPFGRPRVLQKNVDHCLLYHREYVSGFGKAMRMPMWSSYTVPQLGDTSPLPPT
  VPDCLRADVRVPPSESQKCSFYLADKNITHGFLYPPASNRTSDSQYDALITSNLVPMYEE
  FRKMWDYFHSVLLIKHATERNGVNVVSGPIFDYNYDGHFDAPDEITKHLANTDVPIPTHY
  FVVLTSCKNKSHTPENCPGWLDVLPFIIPHRPTNVESCPEGKPEALWVEERFTAHIARVR
  DVELLTGLDFYQDKVQPVSEILQLKTYLPTFETTI
• Function: Hydrolase that metabolizes extracellular nucleotides, including ATP, GTP, UTP and CTP. Limits mast cell and basophil responses during inflammation and during the chronic phases of allergic responses by eliminating the extracellular ATP that functions as signaling molecule and activates basophils and mast cells and induces the release of inflammatory cytokines. Metabolizes extracellular ATP in the lumen of the small intestine, and thereby prevents ATP-induced apoptosis of intestinal plasmacytoid dendritic cells. Has also alkaline phosphodiesterase activity.
• Tissue Specificity: Detected on bile ducts in liver, and in blood serum (at protein level) . Detected in prostate and uterus . Detected on basophils, but not neutrophils .
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Pyrimidine metabolism (hsa00240)
  Starch and sucrose metabolism (hsa00500)
  Riboflavin metabolism (hsa00740)
  Nicoti.te and nicoti.mide metabolism (hsa00760)
  Pantothe.te and CoA biosynthesis (hsa00770)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
• Reactome Pathway: Vitamin B5 (pantothenate) metabolism (R-HSA-199220)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3).	[3]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3).	[4]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3).	[5]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3).	[6]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3).	[9]
Fmet-leu-phe	DMQ391A	Investigative	Fmet-leu-phe increases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3).	[10]

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 increases the methylation of Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3).	[8]

References

• [1] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [2] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [5] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [6] The effects of dasatinib on IgE receptor-dependent activation and histamine release in human basophils. Blood. 2008 Mar 15;111(6):3097-107.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [10] Stimulus-specific regulation of CD63 and CD203c membrane expression in human basophils by the flavonoid quercetin. Int Immunopharmacol. 2010 Feb;10(2):183-92. doi: 10.1016/j.intimp.2009.10.014. Epub 2009 Nov 1.