Details of Drug Off-Target (DOT)

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

• DOT Name: Serine/threonine-protein phosphatase 6 regulatory subunit 2 (PPP6R2)
• Synonyms: SAPS domain family member 2
• Gene Name: PPP6R2
• Related Disease:
  Advanced cancer
  Cardiovascular disease
  High blood pressure
  Leukopenia
  Myocardial infarction
  Respiratory failure
  Status epilepticus seizure
  Acute respiratory failure
  Myasthenia gravis
  Pneumonia
• UniProt ID: PP6R2_HUMAN
• Pfam ID: PF04499
• Sequence:
  MFWKFDLNTTSHVDKLLDKEHVTLQELMDEDDILQECKAQNQKLLDFLCRQQCMEELVSL
  ITQDPPLDMEEKVRFKYPNTACELLTCDVPQISDRLGGDESLLSLLYDFLDHEPPLNPLL
  ASFFSKTIGNLIARKTEQVITFLKKKDKFISLVLKHIGTSALMDLLLRLVSCVEPAGLRQ
  DVLHWLNEEKVIQRLVELIHPSQDEDRQSNASQTLCDIVRLGRDQGSQLQEALEPDPLLT
  ALESQDCVEQLLKNMFDGDRTESCLVSGTQVLLTLLETRRVGTEGLVDSFSQGLERSYAV
  SSSVLHGIEPRLKDFHQLLLNPPKKKAILTTIGVLEEPLGNARLHGARLMAALLHTNTPS
  INQELCRLNTMDLLLDLFFKYTWNNFLHFQVELCIAAILSHAAREERTEASGSESRVEPP
  HENGNRSLETPQPAASLPDNTMVTHLFQKCCLVQRILEAWEANDHTQAAGGMRRGNMGHL
  TRIANAVVQNLERGPVQTHISEVIRGLPADCRGRWESFVEETLTETNRRNTVDLVSTHHL
  HSSSEDEDIEGAFPNELSLQQAFSDYQIQQMTANFVDQFGFNDEEFADQDDNINAPFDRI
  AEINFNIDADEDSPSAALFEACCSDRIQPFDDDEDEDIWEDSDTRCAARVMARPRFGAPH
  ASESCSKNGPERGGQDGKASLEAHRDAPGAGAPPAPGKKEAPPVEGDSEGAMWTAVFDEP
  ANSTPTAPGVVRDVGSSVWAAGTSAPEEKGWAKFTDFQPFCCSESGPRCSSPVDTECSHA
  EGSRSQGPEKASQASYFAVSPASPCAWNVCVTRKAPLLASDSSSSGGSHSEDGDQKAASA
  MDAVSRGPGREAPPLPTVARTEEAVGRVGCADSRLLSPACPAPKEVTAAPAVAVPPEATV
  AITTALSKAGPAIPTPAVSSALAVAVPLGPIMAVTAAPAMVATLGTVTKDGKTDAPPEGA
  ALNGPV
• Function: Regulatory subunit of protein phosphatase 6 (PP6). May function as a scaffolding PP6 subunit. Involved in the PP6-mediated dephosphorylation of NFKBIE opposing its degradation in response to TNF-alpha.
• Tissue Specificity: Ubiquitously expressed with strongest expression in the testis followed by liver, heart, kidney, brain and placenta.

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[2]
High blood pressure	DISY2OHH	Strong	Biomarker	[3]
Leukopenia	DISJMBMM	Strong	Biomarker	[1]
Myocardial infarction	DIS655KI	Strong	Biomarker	[4]
Respiratory failure	DISVMYJO	Strong	Genetic Variation	[5]
Status epilepticus seizure	DISY3BIC	Strong	Genetic Variation	[6]
Acute respiratory failure	DIS5KQ5Y	Limited	Genetic Variation	[7]
Myasthenia gravis	DISELRCI	Limited	Altered Expression	[8]
Pneumonia	DIS8EF3M	Limited	Biomarker	[9]

5 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 6 regulatory subunit 2 (PPP6R2).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Serine/threonine-protein phosphatase 6 regulatory subunit 2 (PPP6R2).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Serine/threonine-protein phosphatase 6 regulatory subunit 2 (PPP6R2).	[12]
Selenium	DM25CGV	Approved	Selenium increases the expression of Serine/threonine-protein phosphatase 6 regulatory subunit 2 (PPP6R2).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Serine/threonine-protein phosphatase 6 regulatory subunit 2 (PPP6R2).	[14]

1 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 6 regulatory subunit 2 (PPP6R2).	[15]

References

• [1] Candidemia in a major regional tertiary referral hospital - epidemiology, practice patterns and outcomes.Antimicrob Resist Infect Control. 2017 Mar 11;6:27. doi: 10.1186/s13756-017-0184-1. eCollection 2017.
• [2] ICU-treated influenza A(H1N1) pdm09 infections more severe post pandemic than during 2009 pandemic: a retrospective analysis.BMC Infect Dis. 2017 Nov 21;17(1):728. doi: 10.1186/s12879-017-2829-3.
• [3] Extracorporeal Membrane Oxygenation Support in Trauma Versus Nontrauma Patients with Noninfectious Acute Respiratory Failure.Artif Organs. 2017 May;41(5):431-439. doi: 10.1111/aor.12794. Epub 2016 Nov 28.
• [4] Are we ever too old?: Characteristics and outcome of octogenarians admitted to a medical intensive care unit.Medicine (Baltimore). 2017 Sep;96(37):e7776. doi: 10.1097/MD.0000000000007776.
• [5] Photoplethysmographic determination of the respiratory rate in acutely ill patients: validation of a new algorithm and implementation into a biomedical device.Ann Intensive Care. 2019 Jan 21;9(1):11. doi: 10.1186/s13613-019-0485-z.
• [6] Illness severity scoring in status epilepticus-When STESS meets APACHE II, SAPS II, and SOFA.Epilepsia. 2019 Feb;60(2):189-200. doi: 10.1111/epi.14623. Epub 2018 Dec 25.
• [7] COPD is independently associated with 6-month survival in patients who have life support withheld in intensive care.Clin Respir J. 2018 Jul;12(7):2249-2256. doi: 10.1111/crj.12899. Epub 2018 May 11.
• [8] Profiling of patient-specific myocytes identifies altered gene expression in the ophthalmoplegic subphenotype of myasthenia gravis.Orphanet J Rare Dis. 2019 Jan 29;14(1):24. doi: 10.1186/s13023-019-1003-y.
• [9] Frequency, associated factors and outcome of multi-drug-resistant intensive care unit-acquired pneumonia among patients colonized with extended-spectrum -lactamase-producing Enterobacteriaceae.Ann Intensive Care. 2017 Dec;7(1):61. doi: 10.1186/s13613-017-0283-4. Epub 2017 Jun 12.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [13] 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.
• [14] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [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.