Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7Y43A1)

• DOT Name: Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA)
• Synonyms: PP-1A; EC 3.1.3.16
• Gene Name: PPP1CA
• UniProt ID: PP1A_HUMAN
• PDB ID: 3E7A ; 3E7B ; 3EGG ; 3EGH ; 3HVQ ; 3N5U ; 3V4Y ; 4G9J ; 4MOV ; 4MOY ; 4MP0 ; 4XPN ; 5IOH ; 6ALZ ; 6CZO ; 6DCX ; 6DNO ; 6G0I ; 6G0J ; 6GHM ; 6OBN ; 6OBP ; 6OBQ ; 6OBR ; 6OBS ; 6OBU ; 6ZEE ; 6ZEF ; 6ZEG ; 6ZEH ; 6ZEI ; 6ZEJ ; 6ZK6 ; 7QFB ; 7QM2 ; 7T0Y ; 7TVF ; 7TXH ; 7UPI ; 8DWK ; 8DWL ; 8U5G
• EC Number: 3.1.3.16
• Pfam ID: PF00149 ; PF16891
• Sequence:
  MSDSEKLNLDSIIGRLLEVQGSRPGKNVQLTENEIRGLCLKSREIFLSQPILLELEAPLK
  ICGDIHGQYYDLLRLFEYGGFPPESNYLFLGDYVDRGKQSLETICLLLAYKIKYPENFFL
  LRGNHECASINRIYGFYDECKRRYNIKLWKTFTDCFNCLPIAAIVDEKIFCCHGGLSPDL
  QSMEQIRRIMRPTDVPDQGLLCDLLWSDPDKDVQGWGENDRGVSFTFGAEVVAKFLHKHD
  LDLICRAHQVVEDGYEFFAKRQLVTLFSAPNYCGEFDNAGAMMSVDETLMCSFQILKPAD
  KNKGKYGQFSGLNPGGRPITPPRNSAKAKK
• Function: Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets. Protein phosphatase 1 (PP1) is essential for cell division, and participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis. Involved in regulation of ionic conductances and long-term synaptic plasticity. May play an important role in dephosphorylating substrates such as the postsynaptic density-associated Ca(2+)/calmodulin dependent protein kinase II. Component of the PTW/PP1 phosphatase complex, which plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase. Regulates NEK2 function in terms of kinase activity and centrosome number and splitting, both in the presence and absence of radiation-induced DNA damage. Regulator of neural tube and optic fissure closure, and enteric neural crest cell (ENCCs) migration during development. In balance with CSNK1D and CSNK1E, determines the circadian period length, through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation. May dephosphorylate CSNK1D and CSNK1E. Dephosphorylates the 'Ser-418' residue of FOXP3 in regulatory T-cells (Treg) from patients with rheumatoid arthritis, thereby inactivating FOXP3 and rendering Treg cells functionally defective. Dephosphorylates CENPA. Dephosphorylates the 'Ser-139' residue of ATG16L1 causing dissociation of ATG12-ATG5-ATG16L1 complex, thereby inhibiting autophagy ; (Microbial infection) Necessary for alphaviruses replication.
• KEGG Pathway:
  mR. surveillance pathway (hsa03015)
  cGMP-PKG sig.ling pathway (hsa04022)
  cAMP sig.ling pathway (hsa04024)
  Oocyte meiosis (hsa04114)
  Cellular senescence (hsa04218)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Vascular smooth muscle contraction (hsa04270)
  Hippo sig.ling pathway (hsa04390)
  Focal adhesion (hsa04510)
  Platelet activation (hsa04611)
  Long-term potentiation (hsa04720)
  Dopaminergic sy.pse (hsa04728)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Regulation of actin cytoskeleton (hsa04810)
  Insulin sig.ling pathway (hsa04910)
  Oxytocin sig.ling pathway (hsa04921)
  Insulin resistance (hsa04931)
  Amphetamine addiction (hsa05031)
  Alcoholism (hsa05034)
  Herpes simplex virus 1 infection (hsa05168)
  Proteoglycans in cancer (hsa05205)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  DARPP-32 events (R-HSA-180024)
  Downregulation of TGF-beta receptor signaling (R-HSA-2173788)
  Circadian Clock (R-HSA-400253)
  Triglyceride catabolism (R-HSA-163560)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA) affects the response to substance of Fluorouracil.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA).	[1]
Amiloride	DMRTSGP	Approved	Amiloride decreases the phosphorylation of Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA).	[10]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA).	[2]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA).	[3]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA).	[6]
Selenium	DM25CGV	Approved	Selenium increases the expression of Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA).	[7]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA).	[8]
Aminoglutethimide	DMWFHMZ	Approved	Aminoglutethimide decreases the expression of Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA).	[9]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA).	[15]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA).	[16]
Pyrrolidine dithiocarbamate	DM5ZAS6	Investigative	Pyrrolidine dithiocarbamate decreases the expression of Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA).	[17]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA).	[11]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [6] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [7] 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.
• [8] Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
• [9] Proteomic profile of aminoglutethimide-induced apoptosis in HL-60 cells: role of myeloperoxidase and arylamine free radicals. Chem Biol Interact. 2015 Sep 5;239:129-38.
• [10] Role of HER-2/neu signaling in sensitivity to tumor necrosis factor-related apoptosis-inducing ligand: enhancement of TRAIL-mediated apoptosis by amiloride. J Cell Biochem. 2005 Oct 1;96(2):376-89. doi: 10.1002/jcb.20512.
• [11] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [12] 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.
• [13] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [14] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [15] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [16] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [17] Effects of a redox-active agent on lymphocyte activation and early gene expression patterns. Free Radic Biol Med. 2004 Nov 15;37(10):1550-63.
• [18] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.