Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJMF66Z)

• DOT Name: Cytosolic purine 5'-nucleotidase (NT5C2)
• Synonyms: EC 3.1.3.5; EC 3.1.3.99; Cytosolic 5'-nucleotidase II; cN-II; Cytosolic IMP/GMP-specific 5'-nucleotidase; Cytosolic nucleoside phosphotransferase 5'N; EC 2.7.1.77; High Km 5'-nucleotidase
• Gene Name: NT5C2
• Related Disease: Hereditary spastic paraplegia 45
• UniProt ID: 5NTC_HUMAN
• PDB ID: 2J2C ; 2JC9 ; 2JCM ; 2XCV ; 2XCW ; 2XCX ; 2XJB ; 2XJC ; 2XJD ; 2XJE ; 2XJF ; 4H4B ; 5CQZ ; 5CR7 ; 5K7Y ; 5L4Z ; 5L50 ; 5OPK ; 5OPL ; 5OPM ; 5OPN ; 5OPO ; 5OPP ; 6DD3 ; 6DDB ; 6DDC ; 6DDH ; 6DDK ; 6DDL ; 6DDO ; 6DDQ ; 6DDX ; 6DDY ; 6DDZ ; 6DE0 ; 6DE1 ; 6DE2 ; 6DE3 ; 6FIR ; 6FIS ; 6FIU ; 6FIW ; 6FXH
• EC Number: 2.7.1.77; 3.1.3.5; 3.1.3.99
• Pfam ID: PF05761
• Sequence:
  MSTSWSDRLQNAADMPANMDKHALKKYRREAYHRVFVNRSLAMEKIKCFGFDMDYTLAVY
  KSPEYESLGFELTVERLVSIGYPQELLSFAYDSTFPTRGLVFDTLYGNLLKVDAYGNLLV
  CAHGFNFIRGPETREQYPNKFIQRDDTERFYILNTLFNLPETYLLACLVDFFTNCPRYTS
  CETGFKDGDLFMSYRSMFQDVRDAVDWVHYKGSLKEKTVENLEKYVVKDGKLPLLLSRMK
  EVGKVFLATNSDYKYTDKIMTYLFDFPHGPKPGSSHRPWQSYFDLILVDARKPLFFGEGT
  VLRQVDTKTGKLKIGTYTGPLQHGIVYSGGSSDTICDLLGAKGKDILYIGDHIFGDILKS
  KKRQGWRTFLVIPELAQELHVWTDKSSLFEELQSLDIFLAELYKHLDSSSNERPDISSIQ
  RRIKKVTHDMDMCYGMMGSLFRSGSRQTLFASQVMRYADLYAASFINLLYYPFSYLFRAA
  HVLMPHESTVEHTHVDINEMESPLATRNRTSVDFKDTDYKRHQLTRSISEIKPPNLFPLA
  PQEITHCHDEDDDEEEEEEEE
• Function: Broad specificity cytosolic 5'-nucleotidase that catalyzes the dephosphorylation of 6-hydroxypurine nucleoside 5'-monophosphates. In addition, possesses a phosphotransferase activity by which it can transfer a phosphate from a donor nucleoside monophosphate to an acceptor nucleoside, preferably inosine, deoxyinosine and guanosine. Has the highest activities for IMP and GMP followed by dIMP, dGMP and XMP. Could also catalyze the transfer of phosphates from pyrimidine monophosphates but with lower efficiency. Through these activities regulates the purine nucleoside/nucleotide pools within the cell.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Pyrimidine metabolism (hsa00240)
  Nicoti.te and nicoti.mide metabolism (hsa00760)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
• Reactome Pathway:
  Purine catabolism (R-HSA-74259)
  Ribavirin ADME (R-HSA-9755088)
  Abacavir metabolism (R-HSA-2161541)
• BioCyc Pathway: MetaCyc:HS01216-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 spastic paraplegia 45	DISGQU26	Strong	Autosomal recessive	[1]

15 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 Cytosolic purine 5'-nucleotidase (NT5C2).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cytosolic purine 5'-nucleotidase (NT5C2).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cytosolic purine 5'-nucleotidase (NT5C2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cytosolic purine 5'-nucleotidase (NT5C2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cytosolic purine 5'-nucleotidase (NT5C2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cytosolic purine 5'-nucleotidase (NT5C2).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cytosolic purine 5'-nucleotidase (NT5C2).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Cytosolic purine 5'-nucleotidase (NT5C2).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cytosolic purine 5'-nucleotidase (NT5C2).	[10]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Cytosolic purine 5'-nucleotidase (NT5C2).	[12]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Cytosolic purine 5'-nucleotidase (NT5C2).	[8]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of Cytosolic purine 5'-nucleotidase (NT5C2).	[8]
Gentamicin	DMKINJO	Approved	Gentamicin increases the expression of Cytosolic purine 5'-nucleotidase (NT5C2).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cytosolic purine 5'-nucleotidase (NT5C2).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cytosolic purine 5'-nucleotidase (NT5C2).	[15]

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 Cytosolic purine 5'-nucleotidase (NT5C2).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Cytosolic purine 5'-nucleotidase (NT5C2).	[13]

References

• [1] Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science. 2014 Jan 31;343(6170):506-511. doi: 10.1126/science.1247363.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Cyclosporine A treated in vitro models induce cholestasis response through comparison of phenotype-directed gene expression analysis of in vivo Cyclosporine A-induced cholestasis. Toxicol Lett. 2013 Aug 29;221(3):225-36.
• [4] 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.
• [5] 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.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Effect of nephrotoxicants and hepatotoxicants on gene expression profile in human peripheral blood mononuclear cells. Biochem Biophys Res Commun. 2010 Oct 15;401(2):245-50. doi: 10.1016/j.bbrc.2010.09.039. Epub 2010 Sep 16.
• [9] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.