Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIXD60Q)

• DOT Name: Serine/threonine-protein phosphatase 6 regulatory subunit 3 (PPP6R3)
• Synonyms: SAPS domain family member 3; Sporulation-induced transcript 4-associated protein SAPL
• Gene Name: PPP6R3
• Related Disease:
  Acute myocardial infarction
  Adult respiratory distress syndrome
  Breast fibrocystic disease
  Breast neoplasm
  Chronic renal failure
  End-stage renal disease
  Kidney failure
  Myocardial infarction
  Neoplasm
  Cardiovascular disease
  Subarachnoid hemorrhage
  High blood pressure
• UniProt ID: PP6R3_HUMAN
• Pfam ID: PF04499
• Sequence:
  MFWKFDLHSSSHIDTLLEREDVTLKELMDEEDVLQECKAQNRKLIEFLLKAECLEDLVSF
  IIEEPPQDMDEKIRYKYPNISCELLTSDVSQMNDRLGEDESLLMKLYSFLLNDSPLNPLL
  ASFFSKVLSILISRKPEQIVDFLKKKHDFVDLIIKHIGTSAIMDLLLRLLTCIEPPQPRQ
  DVLNWLNEEKIIQRLVEIVHPSQEEDRHSNASQSLCEIVRLSRDQMLQIQNSTEPDPLLA
  TLEKQEIIEQLLSNIFHKEKNESAIVSAIQILLTLLETRRPTFEGHIEICPPGMSHSACS
  VNKSVLEAIRGRLGSFHELLLEPPKKSVMKTTWGVLDPPVGNTRLNVIRLISSLLQTNTS
  SINGDLMELNSIGVILNMFFKYTWNNFLHTQVEICIALILASPFENTENATITDQDSTGD
  NLLLKHLFQKCQLIERILEAWEMNEKKQAEGGRRHGYMGHLTRIANCIVHSTDKGPNSAL
  VQQLIKDLPDEVRERWETFCTSSLGETNKRNTVDLVTTCHIHSSSDDEIDFKETGFSQDS
  SLQQAFSDYQMQQMTSNFIDQFGFNDEKFADQDDIGNVSFDRVSDINFTLNTNESGNIAL
  FEACCKERIQQFDDGGSDEEDIWEEKHIAFTPESQRRSSSGSTDSEESTDSEEEDGAKQD
  LFEPSSANTEDKMEVDLSEPPNWSANFDVPMETTHGAPLDSVGSDVWSTEEPMPTKETGW
  ASFSEFTSSLSTKDSLRSNSPVEMETSTEPMDPLTPSAAALAVQPEAAGSVAMEASSDGE
  EDAESTDKVTETVMNGGMKETLSLTVDAKTETAVFKSEEGKLSTSQDAACKDAEECPETA
  EAKCAAPRPPSSSPEQRTGQPSAPGDTSVNGPV
• Function: Regulatory subunit of protein phosphatase 6 (PP6). May function as a scaffolding PP6 subunit. May have an important role in maintaining immune self-tolerance.
• Tissue Specificity: Expressed in skeletal muscle, placenta, heart, pancreas, testis, brain, lung, liver, kidney, spleen, thymus, prostate, small intestine, colon and leukocytes.
• Reactome Pathway:
  COPII-mediated vesicle transport (R-HSA-204005)
  Telomere Extension By Telomerase (R-HSA-171319)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myocardial infarction	DISE3HTG	Strong	Biomarker	[1]
Adult respiratory distress syndrome	DISIJV47	Strong	Biomarker	[2]
Breast fibrocystic disease	DISUM7ID	Strong	Altered Expression	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[3]
Chronic renal failure	DISGG7K6	Strong	Genetic Variation	[1]
End-stage renal disease	DISXA7GG	Strong	Genetic Variation	[1]
Kidney failure	DISOVQ9P	Strong	Biomarker	[1]
Myocardial infarction	DIS655KI	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Cardiovascular disease	DIS2IQDX	moderate	Biomarker	[5]
Subarachnoid hemorrhage	DISI7I8Y	Disputed	Biomarker	[6]
High blood pressure	DISY2OHH	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Serine/threonine-protein phosphatase 6 regulatory subunit 3 (PPP6R3).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Serine/threonine-protein phosphatase 6 regulatory subunit 3 (PPP6R3).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine/threonine-protein phosphatase 6 regulatory subunit 3 (PPP6R3).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine/threonine-protein phosphatase 6 regulatory subunit 3 (PPP6R3).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Serine/threonine-protein phosphatase 6 regulatory subunit 3 (PPP6R3).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Serine/threonine-protein phosphatase 6 regulatory subunit 3 (PPP6R3).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Serine/threonine-protein phosphatase 6 regulatory subunit 3 (PPP6R3).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Serine/threonine-protein phosphatase 6 regulatory subunit 3 (PPP6R3).	[16]

3 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 decreases the methylation of Serine/threonine-protein phosphatase 6 regulatory subunit 3 (PPP6R3).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Serine/threonine-protein phosphatase 6 regulatory subunit 3 (PPP6R3).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Serine/threonine-protein phosphatase 6 regulatory subunit 3 (PPP6R3).	[15]

References

• [1] Discriminatory power of scoring systems for outcome prediction in patients with extracorporeal membrane oxygenation following cardiovascular surgery?"Schrutka L. Binder C
• [2] Timing of Renal Support and Outcome of Septic Shock and Acute Respiratory Distress Syndrome. A Post Hoc Analysis of the AKIKI Randomized Clinical Trial.Am J Respir Crit Care Med. 2018 Jul 1;198(1):58-66. doi: 10.1164/rccm.201706-1255OC.
• [3] Protein phosphatase PP6 is required for homology-directed repair of DNA double-strand breaks.Cell Cycle. 2011 May 1;10(9):1411-9. doi: 10.4161/cc.10.9.15479. Epub 2011 May 1.
• [4] Involvement of DPP9 in gene fusions in serous ovarian carcinoma.BMC Cancer. 2017 Sep 11;17(1):642. doi: 10.1186/s12885-017-3625-6.
• [5] The Effectiveness of Scoring Systems in the Prediction of Diagnosis-Based Mortality.Ther Apher Dial. 2019 Oct;23(5):418-424. doi: 10.1111/1744-9987.12780. Epub 2019 Feb 10.
• [6] The use of SAPS 3, SOFA, and Glasgow Coma Scale to predict mortality in patients with subarachnoid hemorrhage: A retrospective cohort study.Medicine (Baltimore). 2018 Oct;97(41):e12769. doi: 10.1097/MD.0000000000012769.
• [7] Incidence and risk factors of acute kidney injury in critically ill patients from a single centre in Brazil: a retrospective cohort analysis.Sci Rep. 2019 Dec 2;9(1):18141. doi: 10.1038/s41598-019-54674-1.
• [8] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [9] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [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] 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.
• [12] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [14] 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.
• [15] 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.
• [16] 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.