Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7J5LT6)

• DOT Name: 5'-nucleotidase (NT5E)
• Synonyms: 5'-NT; EC 3.1.3.35; EC 3.1.3.5; EC 3.1.3.89; EC 3.1.3.91; EC 3.1.3.99; 5'-deoxynucleotidase; Ecto-5'-nucleotidase; IMP-specific 5'-nucleotidase; Thymidylate 5'-phosphatase; CD antigen CD73
• Gene Name: NT5E
• Related Disease: Hereditary arterial and articular multiple calcification syndrome
• UniProt ID: 5NTD_HUMAN
• PDB ID: 4H1S ; 4H1Y ; 4H2B ; 4H2F ; 4H2G ; 4H2I ; 6HXW ; 6S7F ; 6S7H ; 6TVE ; 6TVG ; 6TVX ; 6TW0 ; 6TWA ; 6TWF ; 6VC9 ; 6VCA ; 6XUE ; 6XUG ; 6XUQ ; 6YE1 ; 6YE2 ; 6Z9B ; 6Z9D ; 7BBJ ; 7JV8 ; 7JV9 ; 7P9N ; 7P9R ; 7P9T ; 7PA4 ; 7PB5 ; 7PBA ; 7PBB ; 7PBY ; 7PCP ; 7PD9 ; 7QGA ; 7QGL ; 7QGM ; 7QGO
• EC Number: 3.1.3.35; 3.1.3.5; 3.1.3.89; 3.1.3.91; 3.1.3.99
• Pfam ID: PF02872 ; PF00149
• Sequence:
  MCPRAARAPATLLLALGAVLWPAAGAWELTILHTNDVHSRLEQTSEDSSKCVNASRCMGG
  VARLFTKVQQIRRAEPNVLLLDAGDQYQGTIWFTVYKGAEVAHFMNALRYDAMALGNHEF
  DNGVEGLIEPLLKEAKFPILSANIKAKGPLASQISGLYLPYKVLPVGDEVVGIVGYTSKE
  TPFLSNPGTNLVFEDEITALQPEVDKLKTLNVNKIIALGHSGFEMDKLIAQKVRGVDVVV
  GGHSNTFLYTGNPPSKEVPAGKYPFIVTSDDGRKVPVVQAYAFGKYLGYLKIEFDERGNV
  ISSHGNPILLNSSIPEDPSIKADINKWRIKLDNYSTQELGKTIVYLDGSSQSCRFRECNM
  GNLICDAMINNNLRHTDEMFWNHVSMCILNGGGIRSPIDERNNGTITWENLAAVLPFGGT
  FDLVQLKGSTLKKAFEHSVHRYGQSTGEFLQVGGIHVVYDLSRKPGDRVVKLDVLCTKCR
  VPSYDPLKMDEVYKVILPNFLANGGDGFQMIKDELLRHDSGDQDINVVSTYISKMKVIYP
  AVEGRIKFSTGSHCHGSFSLIFLSLWAVIFVLYQ
• Function: Catalyzes the hydrolysis of nucleotide monophosphates, releasing inorganic phosphate and the corresponding nucleoside, with AMP being the preferred substrate. Shows a preference for ribonucleotide monophosphates over their equivalent deoxyribose forms. Other substrates include IMP, UMP, GMP, CMP, dAMP, dCMP, dTMP, NAD and NMN.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Pyrimidine metabolism (hsa00240)
  Nicoti.te and nicoti.mide metabolism (hsa00760)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
• Reactome Pathway:
  Pyrimidine catabolism (R-HSA-73621)
  Purine catabolism (R-HSA-74259)
  Purinergic signaling in leishmaniasis infection (R-HSA-9660826)
  Nicotinate metabolism (R-HSA-196807)
• BioCyc Pathway: MetaCyc:HS05981-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary arterial and articular multiple calcification syndrome	DISTD60L	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of 5'-nucleotidase (NT5E).	[2]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of 5'-nucleotidase (NT5E).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of 5'-nucleotidase (NT5E).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of 5'-nucleotidase (NT5E).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 5'-nucleotidase (NT5E).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 5'-nucleotidase (NT5E).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of 5'-nucleotidase (NT5E).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 5'-nucleotidase (NT5E).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of 5'-nucleotidase (NT5E).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of 5'-nucleotidase (NT5E).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of 5'-nucleotidase (NT5E).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of 5'-nucleotidase (NT5E).	[12]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of 5'-nucleotidase (NT5E).	[13]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of 5'-nucleotidase (NT5E).	[14]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of 5'-nucleotidase (NT5E).	[15]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of 5'-nucleotidase (NT5E).	[16]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of 5'-nucleotidase (NT5E).	[17]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of 5'-nucleotidase (NT5E).	[18]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of 5'-nucleotidase (NT5E).	[19]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of 5'-nucleotidase (NT5E).	[20]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of 5'-nucleotidase (NT5E).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 5'-nucleotidase (NT5E).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of 5'-nucleotidase (NT5E).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of 5'-nucleotidase (NT5E).	[25]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of 5'-nucleotidase (NT5E).	[26]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of 5'-nucleotidase (NT5E).	[27]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of 5'-nucleotidase (NT5E).	[28]
adenosine diphosphate	DMFUHKP	Investigative	adenosine diphosphate decreases the activity of 5'-nucleotidase (NT5E).	[29]

References

• [1] NT5E mutations and arterial calcifications. N Engl J Med. 2011 Feb 3;364(5):432-42. doi: 10.1056/NEJMoa0912923.
• [2] 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.
• [3] 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.
• [4] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] 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.
• [8] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [9] Ecto-5'-nucleotidase/CD73 inhibition by quercetin in the human U138MG glioma cell line. Biochim Biophys Acta. 2007 Sep;1770(9):1352-9.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [12] Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71.
• [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] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells. Front Physiol. 2016 Nov 24;7:559. doi: 10.3389/fphys.2016.00559. eCollection 2016.
• [17] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [18] 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.
• [19] Indomethacin stimulates activity and expression of ecto-5'-nucleotidase/CD73 in glioma cell lines. Eur J Pharmacol. 2007 Aug 13;569(1-2):8-15.
• [20] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [21] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [22] 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.
• [23] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [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] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [26] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [27] Molecular targets of chloropicrin in human airway epithelial cells. Toxicol In Vitro. 2017 Aug;42:247-254.
• [28] Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust. Clin Exp Otorhinolaryngol. 2015 Dec;8(4):345-53. doi: 10.3342/ceo.2015.8.4.345. Epub 2015 Nov 10.
• [29] Stimulation of an alpha1-adrenergic receptor downregulates ecto-5' nucleotidase activity on the apical membrane of RPE cells. Purinergic Signal. 2006 Sep;2(3):499-507.