Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC3HT6Y)

• DOT Name: Serine/threonine-protein phosphatase 5 (PPP5C)
• Synonyms: PP5; EC 3.1.3.16; Protein phosphatase T; PP-T; PPT
• Gene Name: PPP5C
• UniProt ID: PPP5_HUMAN
• PDB ID: 1A17; 1S95; 1WAO; 2BUG; 3H60; 3H61; 3H62; 3H63; 3H64; 3H66; 3H67; 3H68; 3H69; 4ZVZ; 4ZX2; 5HPE; 5UI1; 5WG8; 7ZR5; 7ZR6; 8GAE; 8GFT
• EC Number: 3.1.3.16
• Pfam ID: PF00149 ; PF08321 ; PF00515
• Sequence:
  MAMAEGERTECAEPPRDEPPADGALKRAEELKTQANDYFKAKDYENAIKFYSQAIELNPS
  NAIYYGNRSLAYLRTECYGYALGDATRAIELDKKYIKGYYRRAASNMALGKFRAALRDYE
  TVVKVKPHDKDAKMKYQECNKIVKQKAFERAIAGDEHKRSVVDSLDIESMTIEDEYSGPK
  LEDGKVTISFMKELMQWYKDQKKLHRKCAYQILVQVKEVLSKLSTLVETTLKETEKITVC
  GDTHGQFYDLLNIFELNGLPSETNPYIFNGDFVDRGSFSVEVILTLFGFKLLYPDHFHLL
  RGNHETDNMNQIYGFEGEVKAKYTAQMYELFSEVFEWLPLAQCINGKVLIMHGGLFSEDG
  VTLDDIRKIERNRQPPDSGPMCDLLWSDPQPQNGRSISKRGVSCQFGPDVTKAFLEENNL
  DYIIRSHEVKAEGYEVAHGGRCVTVFSAPNYCDQMGNKASYIHLQGSDLRPQFHQFTAVP
  HPNVKPMAYANTLLQLGMM
• Function: Serine/threonine-protein phosphatase that dephosphorylates a myriad of proteins involved in different signaling pathways including the kinases CSNK1E, ASK1/MAP3K5, PRKDC and RAF1, the nuclear receptors NR3C1, PPARG, ESR1 and ESR2, SMAD proteins and TAU/MAPT. Implicated in wide ranging cellular processes, including apoptosis, differentiation, DNA damage response, cell survival, regulation of ion channels or circadian rhythms, in response to steroid and thyroid hormones, calcium, fatty acids, TGF-beta as well as oxidative and genotoxic stresses. Participates in the control of DNA damage response mechanisms such as checkpoint activation and DNA damage repair through, for instance, the regulation ATM/ATR-signaling and dephosphorylation of PRKDC and TP53BP1. Inhibits ASK1/MAP3K5-mediated apoptosis induced by oxidative stress. Plays a positive role in adipogenesis, mainly through the dephosphorylation and activation of PPARG transactivation function. Also dephosphorylates and inhibits the anti-adipogenic effect of NR3C1. Regulates the circadian rhythms, through the dephosphorylation and activation of CSNK1E. May modulate TGF-beta signaling pathway by the regulation of SMAD3 phosphorylation and protein expression levels. Dephosphorylates and may play a role in the regulation of TAU/MAPT. Through their dephosphorylation, may play a role in the regulation of ions channels such as KCNH2. Dephosphorylate FNIP1, disrupting interaction with HSP90AA1/Hsp90.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: MAPK sig.ling pathway (hsa04010)
• Reactome Pathway:
  Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)
  ESR-mediated signaling (R-HSA-8939211)
  Negative regulation of MAPK pathway (R-HSA-5675221)

Molecular Interaction Atlas (MIA) of This DOT

11 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 5 (PPP5C).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Serine/threonine-protein phosphatase 5 (PPP5C).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Serine/threonine-protein phosphatase 5 (PPP5C).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine/threonine-protein phosphatase 5 (PPP5C).	[4]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Serine/threonine-protein phosphatase 5 (PPP5C).	[6]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Serine/threonine-protein phosphatase 5 (PPP5C).	[7]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Serine/threonine-protein phosphatase 5 (PPP5C).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Serine/threonine-protein phosphatase 5 (PPP5C).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Serine/threonine-protein phosphatase 5 (PPP5C).	[12]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Serine/threonine-protein phosphatase 5 (PPP5C).	[14]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Serine/threonine-protein phosphatase 5 (PPP5C).	[15]

4 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 5 (PPP5C).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Serine/threonine-protein phosphatase 5 (PPP5C).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Serine/threonine-protein phosphatase 5 (PPP5C).	[11]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Serine/threonine-protein phosphatase 5 (PPP5C).	[13]

References

• [1] 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.
• [2] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [3] Expression Profiling of Human Pluripotent Stem Cell-Derived Cardiomyocytes Exposed to Doxorubicin-Integration and Visualization of Multi-Omics Data. Toxicol Sci. 2018 May 1;163(1):182-195. doi: 10.1093/toxsci/kfy012.
• [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] 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.
• [6] Neuroprotective effects of glucomoringin-isothiocyanate against H(2)O(2)-Induced cytotoxicity in neuroblastoma (SH-SY5Y) cells. Neurotoxicology. 2019 Dec;75:89-104. doi: 10.1016/j.neuro.2019.09.008. Epub 2019 Sep 12.
• [7] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [8] 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.
• [9] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [10] 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.
• [11] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [12] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [13] 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.
• [14] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [15] 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.