Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJL9VYP)

• DOT Name: Protein phosphatase 1 regulatory subunit 3A (PPP1R3A)
• Synonyms: Protein phosphatase 1 glycogen-associated regulatory subunit; Protein phosphatase type-1 glycogen targeting subunit; RG1
• Gene Name: PPP1R3A
• Related Disease:
  Advanced cancer
  Atrial fibrillation
  Carcinoma
  Cardiac failure
  Congestive heart failure
  Language disorder
  Neoplasm
  Polycystic ovarian syndrome
  Prostate cancer
  Laryngeal squamous cell carcinoma
  Type-1/2 diabetes
  Adult lymphoma
  Colorectal carcinoma
  Colorectal neoplasm
  Lymphoma
  Myeloid leukaemia
  Obsolete diabetes mellitus, noninsulin-dependent
  Pediatric lymphoma
• UniProt ID: PPR3A_HUMAN
• PDB ID: 5ZQV
• Pfam ID: PF03370
• Sequence:
  MEPSEVPSQISKDNFLEVPNLSDSLCEDEEVTFQPGFSPQPSRRGSDSSEDIYLDTPSSG
  TRRVSFADSFGFNLVSVKEFDCWELPSASTTFDLGTDIFHTEEYVLAPLFDLPSSKEDLM
  QQLQIQKAILESTESLLGSTSIKGIIRVLNVSFEKLVYVRMSLDDWQTHYDILAEYVPNS
  CDGETDQFSFKIVLVPPYQKDGSKVEFCIRYETSVGTFWSNNNGTNYTFICQKKEQEPEP
  VKPWKEVPNRQIKGCLKVKSSKEESSVTSEENNFENPKNTDTYIPTIICSHEDKEDLEAS
  NRNVKDVNREHDEHNEKELELMINQHLIRTRSTASRDERNTFSTDPVNFPNKAEGLEKKQ
  IHGEICTDLFQRSLSPSSSAESSVKGDFYCNEKYSSGDDCTHQPSEETTSNMGEIKPSLG
  DTSSDELVQLHTGSKEVLDDNANPAHGNGTVQIPCPSSDQLMAGNLNKKHEGGAKNIEVK
  DLGCLRRDFHSDTSACLKESTEEGSSKEDYYGNGKDDEEQRIYLGVNEKQRKNFQTILHD
  QERKMGNPKISVAGIGASNRDLATLLSEHTAIPTRAITADVSHSPRTNLSWEEAVLTPEH
  HHLTSEGSALGGITGQVCSSRTGNVLRNDYLFQVEEKSGGINSEDQDNSPQHKQSWNVLE
  SQGKSRENKTNITEHIKGQTDCEDVWGKRDNTRSLKATTEELFTCQETVCCELSSLADHG
  ITEKAEAGTAYIIKTTSESTPESMSAREKAIIAKLPQETARSDRPIEVKETAFDPHEGRN
  DDSHYTLCQRDTVGVIYDNDFEKESRLGICNVRVDEMEKEETMSMYNPRKTHDREKCGTG
  NITSVEESSWVITEYQKATSKLDLQLGMLPTDKTVFSENRDLRQVQELSKKTDSDAIVHS
  AFNSDTNRAPQNSSPFSKHHTEISVSTNEQAIAVENAVTTMASQPISTKSENICNSTREI
  QGIEKHPYPESKPEEVSRSSGIVTSGSRKERCIGQIFQTEEYSVEKSLGPMILINKPLEN
  MEEARHENEGLVSSGQSLYTSGEKESDSSASTSLPVEESQAQGNESLFSKYTNSKIPYFL
  LFLIFLITVYHYDLMIGLTFYVLSLSWLSWEEGRQKESVKKK
• Function: Seems to act as a glycogen-targeting subunit for PP1. PP1 is essential for cell division, and participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis. Plays an important role in glycogen synthesis but is not essential for insulin activation of glycogen synthase.
• Tissue Specificity: Skeletal muscle and heart.
• KEGG Pathway:
  Insulin sig.ling pathway (hsa04910)
  Insulin resistance (hsa04931)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[2]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[3]
Cardiac failure	DISDC067	Strong	Biomarker	[4]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[4]
Language disorder	DISTLKP7	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Genetic Variation	[7]
Prostate cancer	DISF190Y	Strong	Altered Expression	[6]
Laryngeal squamous cell carcinoma	DIS9UUVF	moderate	Biomarker	[8]
Type-1/2 diabetes	DISIUHAP	moderate	Genetic Variation	[9]
Adult lymphoma	DISK8IZR	Limited	Genetic Variation	[10]
Colorectal carcinoma	DIS5PYL0	Limited	Genetic Variation	[11]
Colorectal neoplasm	DISR1UCN	Limited	Altered Expression	[11]
Lymphoma	DISN6V4S	Limited	Genetic Variation	[10]
Myeloid leukaemia	DISMN944	Limited	Biomarker	[10]
Obsolete diabetes mellitus, noninsulin-dependent	DISS46MZ	Limited	Unknown	[12]
Pediatric lymphoma	DIS51BK2	Limited	Genetic Variation	[10]

2 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 Protein phosphatase 1 regulatory subunit 3A (PPP1R3A).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein phosphatase 1 regulatory subunit 3A (PPP1R3A).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein phosphatase 1 regulatory subunit 3A (PPP1R3A).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein phosphatase 1 regulatory subunit 3A (PPP1R3A).	[15]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Protein phosphatase 1 regulatory subunit 3A (PPP1R3A).	[16]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Protein phosphatase 1 regulatory subunit 3A (PPP1R3A).	[17]
Mitoxantrone	DMM39BF	Approved	Mitoxantrone decreases the expression of Protein phosphatase 1 regulatory subunit 3A (PPP1R3A).	[15]
Daunorubicin	DMQUSBT	Approved	Daunorubicin decreases the expression of Protein phosphatase 1 regulatory subunit 3A (PPP1R3A).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein phosphatase 1 regulatory subunit 3A (PPP1R3A).	[19]

References

• [1] PPP2R1B gene alterations inhibit interaction of PP2A-Abeta and PP2A-C proteins in colorectal cancers.Oncol Rep. 2004 Mar;11(3):655-9.
• [2] 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.
• [3] Somatic mutations and genetic polymorphisms of the PPP1R3 gene in patients with several types of cancers.Oncogene. 2000 Feb 10;19(6):836-40. doi: 10.1038/sj.onc.1203388.
• [4] Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure.Nat Commun. 2019 Jun 24;10(1):2760. doi: 10.1038/s41467-019-10591-5.
• [5] Phenotype of FOXP2 haploinsufficiency in a mother and son.Am J Med Genet A. 2012 Jan;158A(1):174-81. doi: 10.1002/ajmg.a.34354. Epub 2011 Nov 21.
• [6] Identification of a novel prostate tumor target, mindin/RG-1, for antibody-based radiotherapy of prostate cancer.Cancer Res. 2005 Sep 15;65(18):8397-405. doi: 10.1158/0008-5472.CAN-05-1203.
• [7] Association of the (AU)AT-rich element polymorphism in PPP1R3 with hormonal and metabolic features of polycystic ovary syndrome.J Clin Endocrinol Metab. 2004 Jun;89(6):2973-6. doi: 10.1210/jc.2003-031189.
• [8] Integrated miRNA and mRNA expression analysis uncovers drug targets in laryngeal squamous cell carcinoma patients.Oral Oncol. 2019 Jun;93:76-84. doi: 10.1016/j.oraloncology.2019.04.018. Epub 2019 Apr 29.
• [9] Male preponderance in early diagnosed type 2 diabetes is associated with the ARE insertion/deletion polymorphism in the PPP1R3A locus.BMC Genet. 2003 Jun 28;4:11. doi: 10.1186/1471-2156-4-11.
• [10] Alterations of the PPP1R3 gene in hematological malignancies.Int J Oncol. 2000 Oct;17(4):717-21. doi: 10.3892/ijo.17.4.717.
• [11] PPP1R3 gene (protein phosphatase 1) alterations in colorectal cancer and its relationship to metastasis.Oncol Rep. 2005 Jun;13(6):1223-7.
• [12] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [13] 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.
• [14] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [15] Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment. Arch Toxicol. 2016 Nov;90(11):2763-2777.
• [16] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [17] 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.
• [18] 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.
• [19] 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.