Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRKV8WW)

• DOT Name: Inorganic pyrophosphatase 2, mitochondrial (PPA2)
• Synonyms: EC 3.6.1.1; Pyrophosphatase SID6-306; Pyrophosphate phospho-hydrolase 2; PPase 2
• Gene Name: PPA2
• Related Disease:
  Adenocarcinoma
  Breast carcinoma
  Cardiac arrest
  Cardiomyopathy
  Mitochondrial DNA depletion syndrome
  Sudden cardiac failure, infantile
  Mitochondrial disease
• UniProt ID: IPYR2_HUMAN
• EC Number: 3.6.1.1
• Pfam ID: PF00719
• Sequence:
  MSALLRLLRTGAPAAACLRLGTSAGTGSRRAMALYHTEERGQPCSQNYRLFFKNVTGHYI
  SPFHDIPLKVNSKEENGIPMKKARNDEYENLFNMIVEIPRWTNAKMEIATKEPMNPIKQY
  VKDGKLRYVANIFPYKGYIWNYGTLPQTWEDPHEKDKSTNCFGDNDPIDVCEIGSKILSC
  GEVIHVKILGILALIDEGETDWKLIAINANDPEASKFHDIDDVKKFKPGYLEATLNWFRL
  YKVPDGKPENQFAFNGEFKNKAFALEVIKSTHQCWKALLMKKCNGGAINCTNVQISDSPF
  RCTQEEARSLVESVSSSPNKESNEEEQVWHFLGK
• Function: Hydrolyzes inorganic pyrophosphate. This activity is essential for correct regulation of mitochondrial membrane potential, and mitochondrial organization and function.
• Tissue Specificity: Detected in brain, gastric carcinoma, lung, ovary, skeletal muscle, umbilical cord blood and a cell line derived from kidney proximal tubule epithelium.
• KEGG Pathway: Oxidative phosphorylation (hsa00190)
• Reactome Pathway:
  Pyrophosphate hydrolysis (R-HSA-71737)
  Mitochondrial tRNA aminoacylation (R-HSA-379726)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Cardiac arrest	DIS9DIA4	Strong	Genetic Variation	[3]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[4]
Mitochondrial DNA depletion syndrome	DISIGZSM	Strong	Genetic Variation	[5]
Sudden cardiac failure, infantile	DISET0Q7	Strong	Autosomal recessive	[6]
Mitochondrial disease	DISKAHA3	Limited	Genetic Variation	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Inorganic pyrophosphatase 2, mitochondrial (PPA2).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Inorganic pyrophosphatase 2, mitochondrial (PPA2).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Inorganic pyrophosphatase 2, mitochondrial (PPA2).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Inorganic pyrophosphatase 2, mitochondrial (PPA2).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Inorganic pyrophosphatase 2, mitochondrial (PPA2).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Inorganic pyrophosphatase 2, mitochondrial (PPA2).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Inorganic pyrophosphatase 2, mitochondrial (PPA2).	[14]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Inorganic pyrophosphatase 2, mitochondrial (PPA2).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Inorganic pyrophosphatase 2, mitochondrial (PPA2).	[16]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Inorganic pyrophosphatase 2, mitochondrial (PPA2).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Inorganic pyrophosphatase 2, mitochondrial (PPA2).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Inorganic pyrophosphatase 2, mitochondrial (PPA2).	[19]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Inorganic pyrophosphatase 2, mitochondrial (PPA2).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Inorganic pyrophosphatase 2, mitochondrial (PPA2).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Inorganic pyrophosphatase 2, mitochondrial (PPA2).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Inorganic pyrophosphatase 2, mitochondrial (PPA2).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Inorganic pyrophosphatase 2, mitochondrial (PPA2).	[24]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Inorganic pyrophosphatase 2, mitochondrial (PPA2).	[25]

References

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• [2] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [3] Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy.Am J Hum Genet. 2016 Sep 1;99(3):666-673. doi: 10.1016/j.ajhg.2016.06.021. Epub 2016 Aug 11.
• [4] 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.
• [5] Human mitochondrial pyrophosphatase: cDNA cloning and analysis of the gene in patients with mtDNA depletion syndromes.Genomics. 2006 Mar;87(3):410-6. doi: 10.1016/j.ygeno.2005.09.017. Epub 2005 Nov 21.
• [6] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [7] 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.
• [8] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [9] 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.
• [10] 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.
• [11] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [15] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [16] 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.
• [17] 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.
• [18] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [19] 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.
• [20] 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.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] Benzo[a]pyrene increases the Nrf2 content by downregulating the Keap1 message. Toxicol Sci. 2010 Aug;116(2):549-61.
• [23] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [24] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [25] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.