Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHZK1QB)

• DOT Name: Inorganic pyrophosphatase (PPA1)
• Synonyms: EC 3.6.1.1; Pyrophosphate phospho-hydrolase; PPase
• Gene Name: PPA1
• Related Disease:
  Breast carcinoma
  Lung adenocarcinoma
  Adenocarcinoma
  Atrial fibrillation
  B-cell lymphoma
  Breast cancer
  Cardiac failure
  Colon adenocarcinoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Congestive heart failure
  Epithelial ovarian cancer
  Intrahepatic cholangiocarcinoma
  Lung carcinoma
  Metastatic malignant neoplasm
  Mitochondrial disease
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Ovarian serous adenocarcinoma
  Primary progressive aphasia
  Advanced cancer
  Neoplasm
  Cardiomyopathy
  Lung cancer
  Melanoma
• UniProt ID: IPYR_HUMAN
• PDB ID: 6C45; 7BTN; 7CMO
• EC Number: 3.6.1.1
• Pfam ID: PF00719
• Sequence:
  MSGFSTEERAAPFSLEYRVFLKNEKGQYISPFHDIPIYADKDVFHMVVEVPRWSNAKMEI
  ATKDPLNPIKQDVKKGKLRYVANLFPYKGYIWNYGAIPQTWEDPGHNDKHTGCCGDNDPI
  DVCEIGSKVCARGEIIGVKVLGILAMIDEGETDWKVIAINVDDPDAANYNDINDVKRLKP
  GYLEATVDWFRRYKVPDGKPENEFAFNAEFKDKDFAIDIIKSTHDHWKALVTKKTNGKGI
  SCMNTTLSESPFKCDPDAARAIVDALPPPCESACTVPTDVDKWFHHQKN
• Tissue Specificity: Expressed ubiquitously.
• KEGG Pathway: Oxidative phosphorylation (hsa00190)
• Reactome Pathway:
  Pyrophosphate hydrolysis (R-HSA-71737)
  Cytosolic tRNA aminoacylation (R-HSA-379716)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[1]
Lung adenocarcinoma	DISD51WR	Definitive	Altered Expression	[2]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[3]
Atrial fibrillation	DIS15W6U	Strong	Posttranslational Modification	[4]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Cardiac failure	DISDC067	Strong	Altered Expression	[6]
Colon adenocarcinoma	DISDRE0J	Strong	Biomarker	[7]
Colon cancer	DISVC52G	Strong	Biomarker	[7]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[7]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[6]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[8]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Biomarker	[9]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[10]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[9]
Mitochondrial disease	DISKAHA3	Strong	Genetic Variation	[11]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[10]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[8]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[8]
Ovarian serous adenocarcinoma	DISSU72Z	Strong	Biomarker	[8]
Primary progressive aphasia	DISLRYFE	Strong	Genetic Variation	[12]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[5]
Neoplasm	DISZKGEW	moderate	Biomarker	[5]
Cardiomyopathy	DISUPZRG	Disputed	Biomarker	[13]
Lung cancer	DISCM4YA	Limited	Biomarker	[14]
Melanoma	DIS1RRCY	Limited	Biomarker	[15]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Capecitabine	DMTS85L	Approved	Inorganic pyrophosphatase (PPA1) increases the response to substance of Capecitabine.	[29]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Trisodium phosphate	DMPVI3A	Investigative	Inorganic pyrophosphatase (PPA1) increases the hydrolysis of Trisodium phosphate.	[30]

16 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 Inorganic pyrophosphatase (PPA1).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Inorganic pyrophosphatase (PPA1).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Inorganic pyrophosphatase (PPA1).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Inorganic pyrophosphatase (PPA1).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Inorganic pyrophosphatase (PPA1).	[20]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Inorganic pyrophosphatase (PPA1).	[21]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Inorganic pyrophosphatase (PPA1).	[22]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Inorganic pyrophosphatase (PPA1).	[23]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Inorganic pyrophosphatase (PPA1).	[24]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Inorganic pyrophosphatase (PPA1).	[23]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of Inorganic pyrophosphatase (PPA1).	[23]
Haloperidol	DM96SE0	Approved	Haloperidol increases the expression of Inorganic pyrophosphatase (PPA1).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Inorganic pyrophosphatase (PPA1).	[25]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Inorganic pyrophosphatase (PPA1).	[26]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Inorganic pyrophosphatase (PPA1).	[27]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Inorganic pyrophosphatase (PPA1).	[28]

References

• [1] Identification of Critical Elements for Regulation of Inorganic Pyrophosphatase (PPA1) in MCF7 Breast Cancer Cells.PLoS One. 2015 Apr 29;10(4):e0124864. doi: 10.1371/journal.pone.0124864. eCollection 2015.
• [2] Proteomic analysis of lung adenocarcinoma: identification of a highly expressed set of proteins in tumors.Clin Cancer Res. 2002 Jul;8(7):2298-305.
• [3] Targeted Proteomics for Multiplexed Verification of Markers of Colorectal Tumorigenesis.Mol Cell Proteomics. 2017 Mar;16(3):407-427. doi: 10.1074/mcp.M116.062273. Epub 2017 Jan 4.
• [4] Loss of Protein Phosphatase 1 Regulatory Subunit PPP1R3A Promotes Atrial Fibrillation.Circulation. 2019 Aug 20;140(8):681-693. doi: 10.1161/CIRCULATIONAHA.119.039642. Epub 2019 Jun 12.
• [5] Clinical significance and functional validation of inorganic pyrophosphatase in diffuse large B cell lymphoma in humans.Cytotechnology. 2018 Apr;70(2):641-649. doi: 10.1007/s10616-017-0165-5. Epub 2017 Dec 12.
• [6] Decreased protein and phosphorylation level of the protein phosphatase inhibitor-1 in failing human hearts.Cardiovasc Res. 2004 Jan 1;61(1):87-93. doi: 10.1016/j.cardiores.2003.11.005.
• [7] PPA1 regulates tumor malignant potential and clinical outcome of colon adenocarcinoma through JNK pathways.Oncotarget. 2017 Apr 24;8(35):58611-58624. doi: 10.18632/oncotarget.17381. eCollection 2017 Aug 29.
• [8] Expression of Inorganic Pyrophosphatase (PPA1) Correlates with Poor Prognosis of Epithelial Ovarian Cancer.Tohoku J Exp Med. 2017 Feb;241(2):165-173. doi: 10.1620/tjem.241.165.
• [9] Pyrophosphatase 1 expression is associated with future recurrence and overall survival in Chinese patients with intrahepatic cholangiocarcinoma.Oncol Lett. 2018 May;15(5):8095-8101. doi: 10.3892/ol.2018.8278. Epub 2018 Mar 15.
• [10] PPA1 promotes NSCLC progression via a JNK- and TP53-dependent manner.Oncogenesis. 2019 Sep 24;8(10):53. doi: 10.1038/s41389-019-0162-y.
• [11] Sudden Cardiac Death Due to Deficiency of the Mitochondrial Inorganic Pyrophosphatase PPA2.Am J Hum Genet. 2016 Sep 1;99(3):674-682. doi: 10.1016/j.ajhg.2016.06.027. Epub 2016 Aug 11.
• [12] Progranulin mutations in primary progressive aphasia: the PPA1 and PPA3 families.Arch Neurol. 2007 Jan;64(1):43-7. doi: 10.1001/archneur.64.1.43.
• [13] Sudden unexpected death in asymptomatic infants due to PPA2 variants.Mol Genet Genomic Med. 2020 Jan;8(1):e1008. doi: 10.1002/mgg3.1008. Epub 2019 Nov 9.
• [14] Genetic alterations and expression of the protein phosphatase 1 genes in human cancers.Int J Oncol. 2001 Apr;18(4):817-24. doi: 10.3892/ijo.18.4.817.
• [15] Tumor Lysate-Loaded Lipid Hybrid Nanovaccine Collaborated with an Immune Checkpoint Antagonist for Combination Immunotherapy.Adv Healthc Mater. 2019 Jan;8(1):e1800837. doi: 10.1002/adhm.201800837. Epub 2018 Dec 3.
• [16] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [17] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [18] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] 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.
• [21] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [22] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [23] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [24] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [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.
• [26] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [27] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [28] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.
• [29] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.
• [30] High-throughput assay for inorganic pyrophosphatases using the cytosolic enzymes of Saccharomyces cerevisiae and human as an example. Protein Expr Purif. 2000 Apr;18(3):303-9. doi: 10.1006/prep.1999.1189.