Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT94M6A7)

• DOT Name: Ectonucleoside triphosphate diphosphohydrolase 6 (ENTPD6)
• Synonyms: NTPDase 6; EC 3.6.1.6; CD39 antigen-like 2
• Gene Name: ENTPD6
• Related Disease:
  Obesity
  Seminoma
• UniProt ID: ENTP6_HUMAN
• EC Number: 3.6.1.6
• Pfam ID: PF01150
• Sequence:
  MKKGIRYETSRKTSYIFQQPQHGPWQTRMRKISNHGSLRVAKVAYPLGLCVGVFIYVAYI
  KWHRATATQAFFSITRAAPGARWGQQAHSPLGTAADGHEVFYGIMFDAGSTGTRVHVFQF
  TRPPRETPTLTHETFKALKPGLSAYADDVEKSAQGIRELLDVAKQDIPFDFWKATPLVLK
  ATAGLRLLPGEKAQKLLQKVKKVFKASPFLVGDDCVSIMNGTDEGVSAWITINFLTGSLK
  TPGGSSVGMLDLGGGSTQIAFLPRVEGTLQASPPGYLTALRMFNRTYKLYSYSYLGLGLM
  SARLAILGGVEGQPAKDGKELVSPCLSPSFKGEWEHAEVTYRVSGQKAAASLHELCAARV
  SEVLQNRVHRTEEVKHVDFYAFSYYYDLAAGVGLIDAEKGGSLVVGDFEIAAKYVCRTLE
  TQPQSSPFSCMDLTYVSLLLQEFGFPRSKVLKLTRKIDNVETSWALGAIFHYIDSLNRQK
  SPAS
• Function: Catalyzes the hydrolysis of nucleoside triphosphates and diphosphates in a calcium- or magnesium-dependent manner. Has a strong preference for nucleoside diphosphates, preferentially hydrolyzes GDP, IDP, and UDP, with slower hydrolysis of CDP, ITP, GTP, CTP, ADP, and UTP and virtually no hydrolysis of ATP. The membrane bound form might support glycosylation reactions in the Golgi apparatus and, when released from cells, might catalyze the hydrolysis of extracellular nucleotides.
• Tissue Specificity: Expressed in most tissues, but predominantly in heart.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Pyrimidine metabolism (hsa00240)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
• Reactome Pathway: Phosphate bond hydrolysis by NTPDase proteins (R-HSA-8850843)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Obesity	DIS47Y1K	Strong	Biomarker	[1]
Seminoma	DIS3J8LJ	Strong	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ectonucleoside triphosphate diphosphohydrolase 6 (ENTPD6).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ectonucleoside triphosphate diphosphohydrolase 6 (ENTPD6).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ectonucleoside triphosphate diphosphohydrolase 6 (ENTPD6).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Ectonucleoside triphosphate diphosphohydrolase 6 (ENTPD6).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Ectonucleoside triphosphate diphosphohydrolase 6 (ENTPD6).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Ectonucleoside triphosphate diphosphohydrolase 6 (ENTPD6).	[8]

References

• [1] Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.Nat Genet. 2018 Jan;50(1):26-41. doi: 10.1038/s41588-017-0011-x. Epub 2017 Dec 22.
• [2] Ectonucleoside triphosphate diphosphohydrolase 6 expression in testis and testicular cancer and its implication in cisplatin resistance.Oncol Rep. 2011 Jul;26(1):161-7. doi: 10.3892/or.2011.1274. Epub 2011 Apr 20.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] 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.
• [5] 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.
• [6] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [7] 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.
• [8] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.