Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTUU92F)

• DOT Name: Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2)
• Synonyms: E-NPP 2; EC 3.1.4.39; Autotaxin; Extracellular lysophospholipase D; LysoPLD
• Gene Name: ENPP2
• UniProt ID: ENPP2_HUMAN
• PDB ID: 4ZG6; 4ZG7; 4ZG9; 4ZGA; 5KXA; 5M7M; 5MHP; 8C3O; 8C3P
• EC Number: 3.1.4.39
• Pfam ID: PF01223 ; PF01663 ; PF01033
• Sequence:
  MARRSSFQSCQIISLFTFAVGVNICLGFTAHRIKRAEGWEEGPPTVLSDSPWTNISGSCK
  GRCFELQEAGPPDCRCDNLCKSYTSCCHDFDELCLKTARGWECTKDRCGEVRNEENACHC
  SEDCLARGDCCTNYQVVCKGESHWVDDDCEEIKAAECPAGFVRPPLIIFSVDGFRASYMK
  KGSKVMPNIEKLRSCGTHSPYMRPVYPTKTFPNLYTLATGLYPESHGIVGNSMYDPVFDA
  TFHLRGREKFNHRWWGGQPLWITATKQGVKAGTFFWSVVIPHERRILTILQWLTLPDHER
  PSVYAFYSEQPDFSGHKYGPFGPEMTNPLREIDKIVGQLMDGLKQLKLHRCVNVIFVGDH
  GMEDVTCDRTEFLSNYLTNVDDITLVPGTLGRIRSKFSNNAKYDPKAIIANLTCKKPDQH
  FKPYLKQHLPKRLHYANNRRIEDIHLLVERRWHVARKPLDVYKKPSGKCFFQGDHGFDNK
  VNSMQTVFVGYGSTFKYKTKVPPFENIELYNVMCDLLGLKPAPNNGTHGSLNHLLRTNTF
  RPTMPEEVTRPNYPGIMYLQSDFDLGCTCDDKVEPKNKLDELNKRLHTKGSTEERHLLYG
  RPAVLYRTRYDILYHTDFESGYSEIFLMPLWTSYTVSKQAEVSSVPDHLTSCVRPDVRVS
  PSFSQNCLAYKNDKQMSYGFLFPPYLSSSPEAKYDAFLVTNMVPMYPAFKRVWNYFQRVL
  VKKYASERNGVNVISGPIFDYDYDGLHDTEDKIKQYVEGSSIPVPTHYYSIITSCLDFTQ
  PADKCDGPLSVSSFILPHRPDNEESCNSSEDESKWVEELMKMHTARVRDIEHLTSLDFFR
  KTSRSYPEILTLKTYLHTYESEI
• Function: Hydrolyzes lysophospholipids to produce the signaling molecule lysophosphatidic acid (LPA) in extracellular fluids. Major substrate is lysophosphatidylcholine. Can also act on sphingosylphosphorylcholine producing sphingosine-1-phosphate, a modulator of cell motility. Can hydrolyze, in vitro, bis-pNPP, to some extent pNP-TMP, and barely ATP. Involved in several motility-related processes such as angiogenesis and neurite outgrowth. Acts as an angiogenic factor by stimulating migration of smooth muscle cells and microtubule formation. Stimulates migration of melanoma cells, probably via a pertussis toxin-sensitive G protein. May have a role in induction of parturition. Possible involvement in cell proliferation and adipose tissue development (Probable). Tumor cell motility-stimulating factor. Required for LPA production in activated platelets, cleaves the sn-1 lysophospholipids to generate sn-1 lysophosphatidic acids containing predominantly 18:2 and 20:4 fatty acids. Shows a preference for the sn-1 to the sn-2 isomer of 1-O-alkyl-sn-glycero-3-phosphocholine (lyso-PAF).
• Tissue Specificity: Detected in blood plasma (at protein level) . Predominantly expressed in brain, placenta, ovary, and small intestine. Expressed in a number of carcinomas such as hepatocellular and prostate carcinoma, neuroblastoma and non-small-cell lung cancer. Expressed in body fluids such as plasma, cerebral spinal fluid (CSF), saliva, follicular and amniotic fluids. Not detected in leukocytes. Isoform 1 is more highly expressed in peripheral tissues than in the central nervous system (CNS). Adipocytes only express isoform 1. Isoform 3 is more highly expressed in the brain than in peripheral tissues.
• KEGG Pathway:
  Ether lipid metabolism (hsa00565)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Vitamin B5 (pantothenate) metabolism (R-HSA-199220)
• BioCyc Pathway: MetaCyc:HS06258-MONOMER

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
Cisplatin	DMRHGI9	Approved	Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2) affects the response to substance of Cisplatin.	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2).	[2]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2).	[6]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2).	[8]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2).	[9]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2).	[10]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2).	[8]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2).	[11]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2).	[12]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2).	[13]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2).	[14]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2).	[10]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2).	[19]

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 decreases the methylation of Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (ENPP2).	[15]

References

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• [2] 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.
• [3] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [4] Association between In Utero arsenic exposure, placental gene expression, and infant birth weight: a US birth cohort study. Environ Health. 2013 Jul 16;12:58. doi: 10.1186/1476-069X-12-58.
• [5] 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.
• [6] 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.
• [7] Exocrine pancreatic carcinogenesis and autotaxin expression. PLoS One. 2012;7(8):e43209. doi: 10.1371/journal.pone.0043209. Epub 2012 Aug 29.
• [8] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [9] 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.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [11] Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009 Aug 21;138(4):645-659. doi: 10.1016/j.cell.2009.06.034. Epub 2009 Aug 13.
• [12] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [13] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [14] Regulation of gene expression and inhibition of experimental prostate cancer bone metastasis by dietary genistein. Neoplasia. 2004 Jul-Aug;6(4):354-63. doi: 10.1593/neo.03478.
• [15] 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.
• [16] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [17] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [18] 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.
• [19] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [20] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.