Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO5NIJ2)

• DOT Name: Purine nucleoside phosphorylase (PNP)
• Synonyms: PNP; EC 2.4.2.1; Inosine phosphorylase; Inosine-guanosine phosphorylase
• Gene Name: PNP
• Related Disease: Purine nucleoside phosphorylase deficiency
• UniProt ID: PNPH_HUMAN
• PDB ID: 1M73 ; 1PF7 ; 1PWY ; 1RCT ; 1RFG ; 1RR6 ; 1RSZ ; 1RT9 ; 1ULA ; 1ULB ; 1V2H ; 1V3Q ; 1V41 ; 1V45 ; 1YRY ; 2A0W ; 2A0X ; 2A0Y ; 2OC4 ; 2OC9 ; 2ON6 ; 2Q7O ; 3BGS ; 3D1V ; 3GB9 ; 3GGS ; 3INY ; 3K8O ; 3K8Q ; 3PHB ; 4EAR ; 4EB8 ; 4ECE ; 4GKA ; 5ETJ ; 5UGF ; 7ZSL ; 7ZSM ; 7ZSN ; 7ZSO ; 7ZSP
• EC Number: 2.4.2.1
• Pfam ID: PF01048
• Sequence:
  MENGYTYEDYKNTAEWLLSHTKHRPQVAIICGSGLGGLTDKLTQAQIFDYGEIPNFPRST
  VPGHAGRLVFGFLNGRACVMMQGRFHMYEGYPLWKVTFPVRVFHLLGVDTLVVTNAAGGL
  NPKFEVGDIMLIRDHINLPGFSGQNPLRGPNDERFGDRFPAMSDAYDRTMRQRALSTWKQ
  MGEQRELQEGTYVMVAGPSFETVAECRVLQKLGADAVGMSTVPEVIVARHCGLRVFGFSL
  ITNKVIMDYESLEKANHEEVLAAGKQAAQKLEQFVSILMASIPLPDKAS
• Function: Catalyzes the phosphorolytic breakdown of the N-glycosidic bond in the beta-(deoxy)ribonucleoside molecules, with the formation of the corresponding free purine bases and pentose-1-phosphate. Preferentially acts on 6-oxopurine nucleosides including inosine and guanosine.
• Tissue Specificity: Expressed in red blood cells; overexpressed in red blood cells (cytoplasm) of patients with hereditary non-spherocytic hemolytic anemia of unknown etiology.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Nicoti.te and nicoti.mide metabolism (hsa00760)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
• Reactome Pathway:
  Purine salvage (R-HSA-74217)
  Purine catabolism (R-HSA-74259)
  Defective PNP disrupts phosphorolysis of (deoxy)guanosine and (deoxy)inosine (R-HSA-9735763)
  Ribavirin ADME (R-HSA-9755088)
  Neutrophil degranulation (R-HSA-6798695)
• BioCyc Pathway: MetaCyc:HS02151-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
Purine nucleoside phosphorylase deficiency	DIS3Z996	Strong	Autosomal recessive	[1]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Purine nucleoside phosphorylase (PNP) increases the response to substance of Arsenic.	[24]
Fluorouracil	DMUM7HZ	Approved	Purine nucleoside phosphorylase (PNP) affects the response to substance of Fluorouracil.	[25]
Azathioprine	DMMZSXQ	Approved	Purine nucleoside phosphorylase (PNP) increases the Bone marrow toxicity ADR of Azathioprine.	[26]
Adenosine	DMM2NSK	Approved	Purine nucleoside phosphorylase (PNP) increases the Disorders of purine metabolism ADR of Adenosine.	[26]

22 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 Purine nucleoside phosphorylase (PNP).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Purine nucleoside phosphorylase (PNP).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Purine nucleoside phosphorylase (PNP).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Purine nucleoside phosphorylase (PNP).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Purine nucleoside phosphorylase (PNP).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Purine nucleoside phosphorylase (PNP).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Purine nucleoside phosphorylase (PNP).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Purine nucleoside phosphorylase (PNP).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Purine nucleoside phosphorylase (PNP).	[10]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Purine nucleoside phosphorylase (PNP).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Purine nucleoside phosphorylase (PNP).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Purine nucleoside phosphorylase (PNP).	[13]
Marinol	DM70IK5	Approved	Marinol affects the expression of Purine nucleoside phosphorylase (PNP).	[14]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Purine nucleoside phosphorylase (PNP).	[15]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Purine nucleoside phosphorylase (PNP).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Purine nucleoside phosphorylase (PNP).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Purine nucleoside phosphorylase (PNP).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Purine nucleoside phosphorylase (PNP).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Purine nucleoside phosphorylase (PNP).	[20]
CI-972	DM9ZBO0	Discontinued in Phase 1	CI-972 decreases the activity of Purine nucleoside phosphorylase (PNP).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Purine nucleoside phosphorylase (PNP).	[22]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Purine nucleoside phosphorylase (PNP).	[23]

References

• [1] Purine nucleoside phosphorylase deficiency: a mutation update. Nucleosides Nucleotides Nucleic Acids. 2011 Dec;30(12):1243-7. doi: 10.1080/15257770.2011.630852.
• [2] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] 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] 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.
• [12] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [13] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [14] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [15] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [16] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] 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.
• [19] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [20] 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.
• [21] PD 141955 and CI-972: 9-deazaguanine analog purine nucleoside phosphorylase inhibitors. I. Suppression of the human mixed lymphocyte reaction (MLR). Agents Actions. 1993;39 Spec No:C96-8.
• [22] 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.
• [23] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [24] Genetic variants associated with arsenic susceptibility: study of purine nucleoside phosphorylase, arsenic (+3) methyltransferase, and glutathione S-transferase omega genes. Environ Health Perspect. 2008 Apr;116(4):501-5. doi: 10.1289/ehp.10581.
• [25] Mechanistic and predictive profiling of 5-Fluorouracil resistance in human cancer cells. Cancer Res. 2004 Nov 15;64(22):8167-76. doi: 10.1158/0008-5472.CAN-04-0970.
• [26] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.