Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1U770U)

• DOT Name: Protein phosphatase 1A (PPM1A)
• Synonyms: EC 3.1.3.16; Protein phosphatase 2C isoform alpha; PP2C-alpha; Protein phosphatase IA
• Gene Name: PPM1A
• UniProt ID: PPM1A_HUMAN
• PDB ID: 1A6Q; 3FXJ; 3FXK; 3FXL; 3FXM; 3FXO; 4RA2; 4RAF; 4RAG; 6B67
• EC Number: 3.1.3.16
• Pfam ID: PF00481 ; PF07830
• Sequence:
  MGAFLDKPKMEKHNAQGQGNGLRYGLSSMQGWRVEMEDAHTAVIGLPSGLESWSFFAVYD
  GHAGSQVAKYCCEHLLDHITNNQDFKGSAGAPSVENVKNGIRTGFLEIDEHMRVMSEKKH
  GADRSGSTAVGVLISPQHTYFINCGDSRGLLCRNRKVHFFTQDHKPSNPLEKERIQNAGG
  SVMIQRVNGSLAVSRALGDFDYKCVHGKGPTEQLVSPEPEVHDIERSEEDDQFIILACDG
  IWDVMGNEELCDFVRSRLEVTDDLEKVCNEVVDTCLYKGSRDNMSVILICFPNAPKVSPE
  AVKKEAELDKYLECRVEEIIKKQGEGVPDLVHVMRTLASENIPSLPPGGELASKRNVIEA
  VYNRLNPYKNDDTDSTSTDDMW
• Function: Enzyme with a broad specificity. Negatively regulates TGF-beta signaling through dephosphorylating SMAD2 and SMAD3, resulting in their dissociation from SMAD4, nuclear export of the SMADs and termination of the TGF-beta-mediated signaling. Dephosphorylates PRKAA1 and PRKAA2. Plays an important role in the termination of TNF-alpha-mediated NF-kappa-B activation through dephosphorylating and inactivating IKBKB/IKKB.
• KEGG Pathway: MAPK sig.ling pathway (hsa04010)
• Reactome Pathway:
  Energy dependent regulation of mTOR by LKB1-AMPK (R-HSA-380972)
  Downregulation of SMAD2/3 (R-HSA-2173795)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Protein phosphatase 1A (PPM1A).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein phosphatase 1A (PPM1A).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein phosphatase 1A (PPM1A).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein phosphatase 1A (PPM1A).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Protein phosphatase 1A (PPM1A).	[5]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Protein phosphatase 1A (PPM1A).	[6]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Protein phosphatase 1A (PPM1A).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein phosphatase 1A (PPM1A).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Protein phosphatase 1A (PPM1A).	[9]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Protein phosphatase 1A (PPM1A).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Protein phosphatase 1A (PPM1A).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein phosphatase 1A (PPM1A).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein phosphatase 1A (PPM1A).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Protein phosphatase 1A (PPM1A).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Protein phosphatase 1A (PPM1A).	[16]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Protein phosphatase 1A (PPM1A).	[17]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Protein phosphatase 1A (PPM1A).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein phosphatase 1A (PPM1A).	[11]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [3] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [4] 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.
• [5] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [6] 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.
• [7] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] 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.
• [10] A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer. Toxicol Appl Pharmacol. 2015 Jun 1;285(2):79-88.
• [11] 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.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] 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.
• [14] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [15] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [18] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.