Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3MPPYX)

• DOT Name: Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1)
• Synonyms: E-NPP 1; Membrane component chromosome 6 surface marker 1; Phosphodiesterase I/nucleotide pyrophosphatase 1; Plasma-cell membrane glycoprotein PC-1
• Gene Name: ENPP1
• Related Disease:
  Arterial calcification, generalized, of infancy, 1
  Hypophosphatemic rickets, autosomal recessive, 2
  Hypopigmentation-punctate palmoplantar keratoderma syndrome
  Arterial calcification
  Autosomal recessive hypophosphatemic rickets
  Autosomal recessive inherited pseudoxanthoma elasticum
• UniProt ID: ENPP1_HUMAN
• PDB ID: 2YS0; 6WET; 6WEU; 6WEV; 6WEW; 6WFJ; 8GHR
• EC Number: 3.1.4.1; 3.6.1.9
• Pfam ID: PF01223 ; PF01663 ; PF01033
• Sequence:
  MERDGCAGGGSRGGEGGRAPREGPAGNGRDRGRSHAAEAPGDPQAAASLLAPMDVGEEPL
  EKAARARTAKDPNTYKVLSLVLSVCVLTTILGCIFGLKPSCAKEVKSCKGRCFERTFGNC
  RCDAACVELGNCCLDYQETCIEPEHIWTCNKFRCGEKRLTRSLCACSDDCKDKGDCCINY
  SSVCQGEKSWVEEPCESINEPQCPAGFETPPTLLFSLDGFRAEYLHTWGGLLPVISKLKK
  CGTYTKNMRPVYPTKTFPNHYSIVTGLYPESHGIIDNKMYDPKMNASFSLKSKEKFNPEW
  YKGEPIWVTAKYQGLKSGTFFWPGSDVEINGIFPDIYKMYNGSVPFEERILAVLQWLQLP
  KDERPHFYTLYLEEPDSSGHSYGPVSSEVIKALQRVDGMVGMLMDGLKELNLHRCLNLIL
  ISDHGMEQGSCKKYIYLNKYLGDVKNIKVIYGPAARLRPSDVPDKYYSFNYEGIARNLSC
  REPNQHFKPYLKHFLPKRLHFAKSDRIEPLTFYLDPQWQLALNPSERKYCGSGFHGSDNV
  FSNMQALFVGYGPGFKHGIEADTFENIEVYNLMCDLLNLTPAPNNGTHGSLNHLLKNPVY
  TPKHPKEVHPLVQCPFTRNPRDNLGCSCNPSILPIEDFQTQFNLTVAEEKIIKHETLPYG
  RPRVLQKENTICLLSQHQFMSGYSQDILMPLWTSYTVDRNDSFSTEDFSNCLYQDFRIPL
  SPVHKCSFYKNNTKVSYGFLSPPQLNKNSSGIYSEALLTTNIVPMYQSFQVIWRYFHDTL
  LRKYAEERNGVNVVSGPVFDFDYDGRCDSLENLRQKRRVIRNQEILIPTHFFIVLTSCKD
  TSQTPLHCENLDTLAFILPHRTDNSESCVHGKHDSSWVEELLMLHRARITDVEHITGLSF
  YQQRKEPVSDILKLKTHLPTFSQED
• Function: Nucleotide pyrophosphatase that generates diphosphate (PPi) and functions in bone mineralization and soft tissue calcification by regulating pyrophosphate levels. PPi inhibits bone mineralization and soft tissue calcification by binding to nascent hydroxyapatite crystals, thereby preventing further growth of these crystals. Preferentially hydrolyzes ATP, but can also hydrolyze other nucleoside 5' triphosphates such as GTP, CTP and UTP to their corresponding monophosphates with release of pyrophosphate, as well as diadenosine polyphosphates, and also 3',5'-cAMP to AMP. May also be involved in the regulation of the availability of nucleotide sugars in the endoplasmic reticulum and Golgi, and the regulation of purinergic signaling. Inhibits ectopic joint calcification and maintains articular chondrocytes by repressing hedgehog signaling; it is however unclear whether hedgehog inhibition is direct or indirect. Appears to modulate insulin sensitivity and function. Also involved in melanogenesis. Also able to hydrolyze 2',3'-cGAMP (cyclic GMP-AMP), a second messenger that activates TMEM173/STING and triggers type-I interferon production. 2',3'-cGAMP degradation takes place in the lumen or extracellular space, and not in the cytosol where it is produced; the role of 2',3'-cGAMP hydrolysis is therefore unclear. Not able to hydrolyze the 2',3'-cGAMP linkage isomer 3'-3'-cGAMP.
• Tissue Specificity: Expressed in plasma cells and also in a number of non-lymphoid tissues, including the distal convoluted tubule of the kidney, chondrocytes and epididymis . Expressed in melanocytes but not in keratinocytes .
• 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)
  Vitamin B2 (riboflavin) metabolism (R-HSA-196843)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arterial calcification, generalized, of infancy, 1	DISGZ0TD	Definitive	Autosomal recessive	[1]
Hypophosphatemic rickets, autosomal recessive, 2	DISG98UR	Strong	Autosomal recessive	[1]
Hypopigmentation-punctate palmoplantar keratoderma syndrome	DISB3HOZ	Strong	Autosomal dominant	[2]
Arterial calcification	DIS9BJ1Y	Supportive	Autosomal dominant	[3]
Autosomal recessive hypophosphatemic rickets	DIS8E3KA	Supportive	Autosomal recessive	[4]
Autosomal recessive inherited pseudoxanthoma elasticum	DISV7IU5	Supportive	Autosomal recessive	[5]

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 1 (ENPP1).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1).	[12]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1).	[13]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1).	[14]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1).	[15]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1).	[12]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1).	[16]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1).	[24]
Glycerol-2-Phosphate	DM0J5KF	Investigative	Glycerol-2-Phosphate increases the expression of Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1).	[22]

References

• [1] Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am J Hum Genet. 2010 Feb 12;86(2):273-8. doi: 10.1016/j.ajhg.2010.01.010. Epub 2010 Feb 4.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] Generalized Arterial Calcification of Infancy. 2014 Nov 13 [updated 2020 Dec 30]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [4] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [5] Genetic heterogeneity of pseudoxanthoma elasticum: the Chinese signature profile of ABCC6 and ENPP1 mutations. J Invest Dermatol. 2015 May;135(5):1294-1302. doi: 10.1038/jid.2015.10. Epub 2015 Jan 23.
• [6] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [7] 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.
• [8] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [9] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [10] 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.
• [11] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [12] 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.
• [13] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [14] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [15] 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.
• [16] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [17] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [18] Genome-wide transcriptional and functional analysis of human T lymphocytes treated with benzo[alpha]pyrene. Int J Mol Sci. 2018 Nov 17;19(11).
• [19] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] 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.
• [22] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [23] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [24] 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.
• [25] The role of tissue-nonspecific alkaline phosphatase in the phosphate-induced activation of alkaline phosphatase and mineralization in SaOS-2 human osteoblast-like cells. Mol Cell Biochem. 2008 Aug;315(1-2):51-60.