Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFH05B9)

• DOT Name: Nucleoside diphosphate phosphatase ENTPD5 (ENTPD5)
• Synonyms: EC 3.6.1.6; CD39 antigen-like 4; ER-UDPase; Ectonucleoside triphosphate diphosphohydrolase 5; NTPDase 5; Guanosine-diphosphatase ENTPD5; GDPase ENTPD5; Inosine diphosphate phosphatase ENTPD5; Nucleoside diphosphatase; Uridine-diphosphatase ENTPD5; UDPase ENTPD5
• Gene Name: ENTPD5
• Related Disease:
  Breast cancer
  Breast neoplasm
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Germ cell tumor
  Glioblastoma multiforme
  Laryngeal carcinoma
  Laryngeal disorder
  Laryngeal squamous cell carcinoma
  Neoplasm
  Neoplasm of testis
  Pancreatic tumour
  Polyarteritis nodosa
  Prostate cancer
  Prostate carcinoma
  Testicular germ cell tumor
  Vasculitis due to ADA2 deficiency
  Familial steroid-resistant nephrotic syndrome with sensorineural deafness
  Lung cancer
  Lung carcinoma
  Advanced cancer
  Prostate neoplasm
• UniProt ID: ENTP5_HUMAN
• EC Number: 3.6.1.6
• Pfam ID: PF01150
• Sequence:
  MATSWGTVFFMLVVSCVCSAVSHRNQQTWFEGIFLSSMCPINVSASTLYGIMFDAGSTGT
  RIHVYTFVQKMPGQLPILEGEVFDSVKPGLSAFVDQPKQGAETVQGLLEVAKDSIPRSHW
  KKTPVVLKATAGLRLLPEHKAKALLFEVKEIFRKSPFLVPKGSVSIMDGSDEGILAWVTV
  NFLTGQLHGHRQETVGTLDLGGASTQITFLPQFEKTLEQTPRGYLTSFEMFNSTYKLYTH
  SYLGFGLKAARLATLGALETEGTDGHTFRSACLPRWLEAEWIFGGVKYQYGGNQEGEVGF
  EPCYAEVLRVVRGKLHQPEEVQRGSFYAFSYYYDRAVDTDMIDYEKGGILKVEDFERKAR
  EVCDNLENFTSGSPFLCMDLSYITALLKDGFGFADSTVLQLTKKVNNIETGWALGATFHL
  LQSLGISH
• Function: Hydrolyzes nucleoside diphosphates with a preference for GDP, IDP and UDP compared to ADP and CDP. In the lumen of the endoplasmic reticulum, hydrolyzes UDP that acts as an end-product feedback inhibitor of the UDP-Glc:glycoprotein glucosyltransferases. UMP can be transported back by an UDP-sugar antiporter to the cytosol where it is consumed to regenerate UDP-glucose. Therefore, it positively regulates protein reglucosylation by clearing UDP from the ER lumen and by promoting the regeneration of UDP-glucose. Protein reglucosylation is essential to proper glycoprotein folding and quality control in the ER.
• Tissue Specificity: Expressed in adult liver, kidney, prostate, testis and colon. Much weaker expression in other tissues.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Pyrimidine metabolism (hsa00240)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
• Reactome Pathway:
  Purinergic signaling in leishmaniasis infection (R-HSA-9660826)
  Phosphate bond hydrolysis by NTPDase proteins (R-HSA-8850843)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[4]
Germ cell tumor	DIS62070	Strong	Altered Expression	[5]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[6]
Laryngeal carcinoma	DISNHCIV	Strong	Biomarker	[7]
Laryngeal disorder	DISDKUQO	Strong	Altered Expression	[7]
Laryngeal squamous cell carcinoma	DIS9UUVF	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Neoplasm of testis	DISK4XHT	Strong	Biomarker	[5]
Pancreatic tumour	DIS3U0LK	Strong	Altered Expression	[8]
Polyarteritis nodosa	DISRQ5X8	Strong	Genetic Variation	[9]
Prostate cancer	DISF190Y	Strong	Biomarker	[10]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[10]
Testicular germ cell tumor	DIS5RN24	Strong	Altered Expression	[5]
Vasculitis due to ADA2 deficiency	DIS1UHPY	Strong	Genetic Variation	[9]
Familial steroid-resistant nephrotic syndrome with sensorineural deafness	DISIM44J	moderate	CausalMutation	[11]
Lung cancer	DISCM4YA	moderate	Biomarker	[12]
Lung carcinoma	DISTR26C	moderate	Biomarker	[12]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[6]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Nucleoside diphosphate phosphatase ENTPD5 (ENTPD5).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Nucleoside diphosphate phosphatase ENTPD5 (ENTPD5).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Nucleoside diphosphate phosphatase ENTPD5 (ENTPD5).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nucleoside diphosphate phosphatase ENTPD5 (ENTPD5).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Nucleoside diphosphate phosphatase ENTPD5 (ENTPD5).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Nucleoside diphosphate phosphatase ENTPD5 (ENTPD5).	[18]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Nucleoside diphosphate phosphatase ENTPD5 (ENTPD5).	[19]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Nucleoside diphosphate phosphatase ENTPD5 (ENTPD5).	[20]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Nucleoside diphosphate phosphatase ENTPD5 (ENTPD5).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Nucleoside diphosphate phosphatase ENTPD5 (ENTPD5).	[21]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Nucleoside diphosphate phosphatase ENTPD5 (ENTPD5).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Nucleoside diphosphate phosphatase ENTPD5 (ENTPD5).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Nucleoside diphosphate phosphatase ENTPD5 (ENTPD5).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Nucleoside diphosphate phosphatase ENTPD5 (ENTPD5).	[25]

References

• [1] Deregulated expression of the PCPH proto-oncogene in human breast cancers.Int J Oncol. 2004 Oct;25(4):821-30.
• [2] Deregulated expression of the PCPH proto-oncogene in rat mammary tumors induced with 7,12-dimethylbenz[a]anthracene.Mol Carcinog. 2002 Apr;33(4):219-27. doi: 10.1002/mc.10039.
• [3] Integrating proteomic and transcriptomic high-throughput surveys for search of new biomarkers of colon tumors.Funct Integr Genomics. 2011 Jun;11(2):215-24. doi: 10.1007/s10142-010-0200-5. Epub 2010 Nov 9.
• [4] The ENTPD5/mt-PCPH oncoprotein is a catalytically inactive member of the ectonucleoside triphosphate diphosphohydrolase family.Int J Oncol. 2013 Oct;43(4):1244-52. doi: 10.3892/ijo.2013.2052. Epub 2013 Aug 6.
• [5] PCPH expression is an early event in the development of testicular germ cell tumors.Int J Oncol. 2006 Mar;28(3):595-604.
• [6] Identifying small molecule probes of ENTPD5 through high throughput screening.PLoS One. 2019 Jun 26;14(6):e0210305. doi: 10.1371/journal.pone.0210305. eCollection 2019.
• [7] Gradual deregulation and loss of PCPH expression in the progression of human laryngeal neoplasia.Mol Carcinog. 2002 Dec;35(4):186-95. doi: 10.1002/mc.10091.
• [8] Expression of the protein product of the PCPH proto-oncogene in human tumor cell lines.Radiat Res. 2001 Jan;155(1 Pt 2):181-187. doi: 10.1667/0033-7587(2001)155[0181:eotppo]2.0.co;2.
• [9] Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5.Proc Natl Acad Sci U S A. 2016 Dec 27;113(52):E8433-E8442. doi: 10.1073/pnas.1612711114. Epub 2016 Dec 12.
• [10] PCPH/ENTPD5 expression confers to prostate cancer cells resistance against cisplatin-induced apoptosis through protein kinase Calpha-mediated Bcl-2 stabilization.Cancer Res. 2009 Jan 1;69(1):102-10. doi: 10.1158/0008-5472.CAN-08-2922.
• [11] Effect of vanillic acid on COQ6 mutants identified in patients with coenzyme Q10 deficiency.Biochim Biophys Acta. 2014 Jan;1842(1):1-6. doi: 10.1016/j.bbadis.2013.10.007. Epub 2013 Oct 18.
• [12] ENTPD5 induces apoptosis in lung cancer cells via regulating caspase 3 expression.PLoS One. 2015 Mar 20;10(3):e0120046. doi: 10.1371/journal.pone.0120046. eCollection 2015.
• [13] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [19] 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.
• [20] 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.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [23] 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.
• [24] 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.
• [25] 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.