Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSK5GFC)

• DOT Name: Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha (PPP2R3A)
• Synonyms: PP2A subunit B isoform PR72/PR130; PP2A subunit B isoform R3 isoform; PP2A subunit B isoforms B''-PR72/PR130; PP2A subunit B isoforms B72/B130; Serine/threonine-protein phosphatase 2A 72/130 kDa regulatory subunit B
• Gene Name: PPP2R3A
• Related Disease:
  Advanced cancer
  Atrial fibrillation
  Carcinoma of liver and intrahepatic biliary tract
  Childhood acute lymphoblastic leukemia
  Hepatocellular carcinoma
  Liver cancer
  Neoplasm
  Familial atrial fibrillation
• UniProt ID: P2R3A_HUMAN
• PDB ID: 4I5J; 4I5K
• Pfam ID: PF17958 ; PF13499 ; PF21161
• Sequence:
  MAATYRLVVSTVNHYSSVVIDRRFEQAIHYCTGTCHTFTHGIDCIVVHHSVCADLLHIPV
  SQFKDADLNSMFLPHENGLSSAEGDYPQQAFTGIPRVKRGSTFQNTYNLKDIAGEAISFA
  SGKIKEFSFEKLKNSNHAAYRKGRKVKSDSFNRRSVDLDLLCGHYNNDGNAPSFGLLRSS
  SVEEKPLSHRNSLDTNLTSMFLQNFSEEDLVTQILEKHKIDNFSSGTDIKMCLDILLKCS
  EDLKKCTDIIKQCIKKKSGSSISEGSGNDTISSSETVYMNVMTRLASYLKKLPFEFMQSG
  NNEALDLTELISNMPSLQLTPFSPVFGTEQPPKYEDVVQLSASDSGRFQTIELQNDKPNS
  RKMDTVQSIPNNSTNSLYNLEVNDPRTLKAVQVQSQSLTMNPLENVSSDDLMETLYIEEE
  SDGKKALDKGQKTENGPSHELLKVNEHRAEFPEHATHLKKCPTPMQNEIGKIFEKSFVNL
  PKEDCKSKVSKFEEGDQRDFTNSSSQEEIDKLLMDLESFSQKMETSLREPLAKGKNSNFL
  NSHSQLTGQTLVDLEPKSKVSSPIEKVSPSCLTRIIETNGHKIEEEDRALLLRILESIED
  FAQELVECKSSRGSLSQEKEMMQILQETLTTSSQANLSVCRSPVGDKAKDTTSAVLIQQT
  PEVIKIQNKPEKKPGTPLPPPATSPSSPRPLSPVPHVNNVVNAPLSINIPRFYFPEGLPD
  TCSNHEQTLSRIETAFMDIEEQKADIYEMGKIAKVCGCPLYWKAPMFRAAGGEKTGFVTA
  QSFIAMWRKLLNNHHDDASKFICLLAKPNCSSLEQEDFIPLLQDVVDTHPGLTFLKDAPE
  FHSRYITTVIQRIFYTVNRSWSGKITSTEIRKSNFLQTLALLEEEEDINQITDYFSYEHF
  YVIYCKFWELDTDHDLYISQADLSRYNDQASSSRIIERIFSGAVTRGKTIQKEGRMSYAD
  FVWFLISEEDKRNPTSIEYWFRCMDVDGDGVLSMYELEYFYEEQCERMEAMGIEPLPFHD
  LLCQMLDLVKPAVDGKITLRDLKRCRMAHIFYDTFFNLEKYLDHEQRDPFAVQKDVENDG
  PEPSDWDRFAAEEYETLVAEESAQAQFQEGFEDYETDEPASPSEFGNKSNKILSASLPEK
  CGKLQSVDEE
• Function: The B regulatory subunit might modulate substrate selectivity and catalytic activity, and also might direct the localization of the catalytic enzyme to a particular subcellular compartment.
• Tissue Specificity: Expressed in heart, brain, placenta, lung, muscle and kidney.
• KEGG Pathway:
  mR. surveillance pathway (hsa03015)
  Sphingolipid sig.ling pathway (hsa04071)
  PI3K-Akt sig.ling pathway (hsa04151)
  AMPK sig.ling pathway (hsa04152)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  T cell receptor sig.ling pathway (hsa04660)
  Dopaminergic sy.pse (hsa04728)
  Human papillomavirus infection (hsa05165)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[2]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Altered Expression	[1]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Posttranslational Modification	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[1]
Liver cancer	DISDE4BI	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha (PPP2R3A) affects the response to substance of Acetaminophen.	[16]

10 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 Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha (PPP2R3A).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha (PPP2R3A).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha (PPP2R3A).	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha (PPP2R3A).	[8]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha (PPP2R3A).	[9]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha (PPP2R3A).	[10]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha (PPP2R3A).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha (PPP2R3A).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha (PPP2R3A).	[14]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha (PPP2R3A).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha (PPP2R3A).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha (PPP2R3A).	[13]

References

• [1] Protein phosphatase 2 regulatory subunit B''Alpha silencing inhibits tumor cell proliferation in liver cancer.Cancer Med. 2019 Dec;8(18):7741-7753. doi: 10.1002/cam4.2620. Epub 2019 Oct 24.
• [2] Multi-ethnic genome-wide association study for atrial fibrillation.Nat Genet. 2018 Jun 11;50(9):1225-1233. doi: 10.1038/s41588-018-0133-9.
• [3] Epigenetic analysis of childhood acute lymphoblastic leukemia.Epigenetics. 2009 Apr 1;4(3):185-93. doi: 10.4161/epi.4.3.8752. Epub 2009 Apr 12.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [7] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [8] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [9] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [10] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [11] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [16] Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes. Arch Toxicol. 2016 May;90(5):1103-15. doi: 10.1007/s00204-015-1545-2. Epub 2015 Jun 24.