Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT43TTX0)

• DOT Name: Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform (PPP2R5D)
• Synonyms: PP2A B subunit isoform B'-delta; PP2A B subunit isoform B56-delta; PP2A B subunit isoform PR61-delta; PP2A B subunit isoform R5-delta
• Gene Name: PPP2R5D
• Related Disease:
  Autism
  Intellectual disability, autosomal dominant 40
  Neurodevelopmental disorder
  Ovarian neoplasm
  Pervasive developmental disorder
  Syndromic intellectual disability
  Hogue-Janssens syndrome 1
  Intellectual disability
  Autism spectrum disorder
  Megalencephaly
• UniProt ID: 2A5D_HUMAN
• Pfam ID: PF01603
• Sequence:
  MPYKLKKEKEPPKVAKCTAKPSSSGKDGGGENTEEAQPQPQPQPQPQAQSQPPSSNKRPS
  NSTPPPTQLSKIKYSGGPQIVKKERRQSSSRFNLSKNRELQKLPALKDSPTQEREELFIQ
  KLRQCCVLFDFVSDPLSDLKFKEVKRAGLNEMVEYITHSRDVVTEAIYPEAVTMFSVNLF
  RTLPPSSNPTGAEFDPEEDEPTLEAAWPHLQLVYEFFLRFLESPDFQPNIAKKYIDQKFV
  LALLDLFDSEDPRERDFLKTILHRIYGKFLGLRAYIRRQINHIFYRFIYETEHHNGIAEL
  LEILGSIINGFALPLKEEHKMFLIRVLLPLHKVKSLSVYHPQLAYCVVQFLEKESSLTEP
  VIVGLLKFWPKTHSPKEVMFLNELEEILDVIEPSEFSKVMEPLFRQLAKCVSSPHFQVAE
  RALYYWNNEYIMSLISDNAARVLPIMFPALYRNSKSHWNKTIHGLIYNALKLFMEMNQKL
  FDDCTQQYKAEKQKGRFRMKEREEMWQKIEELARLNPQYPMFRAPPPLPPVYSMETETPT
  AEDIQLLKRTVETEAVQMLKDIKKEKVLLRRKSELPQDVYTIKALEAHKRAEEFLTASQE
  AL
• 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: Isoform Delta-2 is widely expressed. Isoform Delta-1 is highly expressed in brain.
• KEGG Pathway:
  mR. surveillance pathway (hsa03015)
  Sphingolipid sig.ling pathway (hsa04071)
  Cell cycle (hsa04110)
  Oocyte meiosis (hsa04114)
  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)
• Reactome Pathway:
  Integration of energy metabolism (R-HSA-163685)
  PP2A-mediated dephosphorylation of key metabolic factors (R-HSA-163767)
  DARPP-32 events (R-HSA-180024)
  Degradation of beta-catenin by the destruction complex (R-HSA-195253)
  Beta-catenin phosphorylation cascade (R-HSA-196299)
  ERK/MAPK targets (R-HSA-198753)
  ERKs are inactivated (R-HSA-202670)
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  CTLA4 inhibitory signaling (R-HSA-389513)
  Platelet sensitization by LDL (R-HSA-432142)
  Disassembly of the destruction complex and recruitment of AXIN to the membrane (R-HSA-4641262)
  Signaling by GSK3beta mutants (R-HSA-5339716)
  CTNNB1 S33 mutants aren't phosphorylated (R-HSA-5358747)
  CTNNB1 S37 mutants aren't phosphorylated (R-HSA-5358749)
  CTNNB1 S45 mutants aren't phosphorylated (R-HSA-5358751)
  CTNNB1 T41 mutants aren't phosphorylated (R-HSA-5358752)
  APC truncation mutants have impaired AXIN binding (R-HSA-5467337)
  AXIN missense mutants destabilize the destruction complex (R-HSA-5467340)
  Truncations of AMER1 destabilize the destruction complex (R-HSA-5467348)
  RHO GTPases Activate Formins (R-HSA-5663220)
  RAF activation (R-HSA-5673000)
  Negative regulation of MAPK pathway (R-HSA-5675221)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  Mitotic Prometaphase (R-HSA-68877)
  Regulation of glycolysis by fructose 2,6-bisphosphate metabolism (R-HSA-9634600)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Definitive	Genetic Variation	[1]
Intellectual disability, autosomal dominant 40	DISAI0IH	Definitive	Autosomal dominant	[2]
Neurodevelopmental disorder	DIS372XH	Definitive	Biomarker	[3]
Ovarian neoplasm	DISEAFTY	Definitive	Altered Expression	[4]
Pervasive developmental disorder	DIS51975	Definitive	Genetic Variation	[1]
Syndromic intellectual disability	DISH7SDF	Definitive	Autosomal dominant	[5]
Hogue-Janssens syndrome 1	DISI5QUE	Strong	Autosomal dominant	[6]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[1]
Autism spectrum disorder	DISXK8NV	moderate	Genetic Variation	[1]
Megalencephaly	DISYW5SV	moderate	Genetic Variation	[1]

12 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 Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform (PPP2R5D).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform (PPP2R5D).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform (PPP2R5D).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform (PPP2R5D).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform (PPP2R5D).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform (PPP2R5D).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform (PPP2R5D).	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform (PPP2R5D).	[14]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform (PPP2R5D).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform (PPP2R5D).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform (PPP2R5D).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform (PPP2R5D).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform (PPP2R5D).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform (PPP2R5D).	[18]

References

• [1] De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism. Neurogenetics. 2016 Jan;17(1):43-9. doi: 10.1007/s10048-015-0466-9. Epub 2015 Nov 17.
• [2] Clinical, neuroimaging and molecular characteristics of PPP2R5D-related neurodevelopmental disorders: an expanded series with functional characterisation and genotype-phenotype analysis. J Med Genet. 2023 May;60(5):511-522. doi: 10.1136/jmg-2022-108713. Epub 2022 Oct 10.
• [3] Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet. 2017 Apr;49(4):515-526. doi: 10.1038/ng.3792. Epub 2017 Feb 13.
• [4] Gonadotropin-releasing hormone retards doxorubicin-induced apoptosis and serine/threonine phosphatase inhibition in ovarian cancer cells.Oncol Rep. 2005 May;13(5):813-7.
• [5] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [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] 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.
• [8] 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.
• [9] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [14] 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.
• [15] 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.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] 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.
• [19] 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.