Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3G3HTZ)

• DOT Name: MAGUK p55 subfamily member 7 (MPP7)
• Gene Name: MPP7
• Related Disease:
  Matthew-Wood syndrome
  OPTN-related open angle glaucoma
  Pancreatic ductal carcinoma
  Drug dependence
  Open-angle glaucoma
  Substance abuse
  Substance dependence
  Asthma
  Intellectual disability
• UniProt ID: MPP7_HUMAN
• PDB ID: 3LRA; 3O46
• Pfam ID: PF00625 ; PF02828 ; PF00595 ; PF00018
• Sequence:
  MPALSTGSGSDTGLYELLAALPAQLQPHVDSQEDLTFLWDMFGEKSLHSLVKIHEKLHYY
  EKQSPVPILHGAAALADDLAEELQNKPLNSEIRELLKLLSKPNVKALLSVHDTVAQKNYD
  PVLPPMPEDIDDEEDSVKIIRLVKNREPLGATIKKDEQTGAIIVARIMRGGAADRSGLIH
  VGDELREVNGIPVEDKRPEEIIQILAQSQGAITFKIIPGSKEETPSKEGKMFIKALFDYN
  PNEDKAIPCKEAGLSFKKGDILQIMSQDDATWWQAKHEADANPRAGLIPSKHFQERRLAL
  RRPEILVQPLKVSNRKSSGFRKSFRLSRKDKKTNKSMYECKKSDQYDTADVPTYEEVTPY
  RRQTNEKYRLVVLVGPVGVGLNELKRKLLISDTQHYGVTVPHTTRARRSQESDGVEYIFI
  SKHLFETDVQNNKFIEYGEYKNNYYGTSIDSVRSVLAKNKVCLLDVQPHTVKHLRTLEFK
  PYVIFIKPPSIERLRETRKNAKIISSRDDQGAAKPFTEEDFQEMIKSAQIMESQYGHLFD
  KIIINDDLTVAFNELKTTFDKLETETHWVPVSWLHS
• Function: Acts as an important adapter that promotes epithelial cell polarity and tight junction formation via its interaction with DLG1. Involved in the assembly of protein complexes at sites of cell-cell contact.
• Reactome Pathway:
  RAC2 GTPase cycle (R-HSA-9013404)
  RHOQ GTPase cycle (R-HSA-9013406)
  RHOG GTPase cycle (R-HSA-9013408)
  RHOJ GTPase cycle (R-HSA-9013409)
  RAC3 GTPase cycle (R-HSA-9013423)
  RAC1 GTPase cycle (R-HSA-9013149)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Matthew-Wood syndrome	DISA7HR7	Definitive	Biomarker	[1]
OPTN-related open angle glaucoma	DISDR98A	Definitive	Biomarker	[2]
Pancreatic ductal carcinoma	DIS26F9Q	Definitive	Biomarker	[1]
Drug dependence	DIS9IXRC	Strong	Biomarker	[3]
Open-angle glaucoma	DISSZEE8	Strong	Genetic Variation	[2]
Substance abuse	DIS327VW	Strong	Biomarker	[3]
Substance dependence	DISDRAAR	Strong	Biomarker	[3]
Asthma	DISW9QNS	moderate	Genetic Variation	[4]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of MAGUK p55 subfamily member 7 (MPP7).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of MAGUK p55 subfamily member 7 (MPP7).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of MAGUK p55 subfamily member 7 (MPP7).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of MAGUK p55 subfamily member 7 (MPP7).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of MAGUK p55 subfamily member 7 (MPP7).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of MAGUK p55 subfamily member 7 (MPP7).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of MAGUK p55 subfamily member 7 (MPP7).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of MAGUK p55 subfamily member 7 (MPP7).	[14]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of MAGUK p55 subfamily member 7 (MPP7).	[15]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of MAGUK p55 subfamily member 7 (MPP7).	[16]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of MAGUK p55 subfamily member 7 (MPP7).	[17]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of MAGUK p55 subfamily member 7 (MPP7).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of MAGUK p55 subfamily member 7 (MPP7).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of MAGUK p55 subfamily member 7 (MPP7).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of MAGUK p55 subfamily member 7 (MPP7).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of MAGUK p55 subfamily member 7 (MPP7).	[23]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of MAGUK p55 subfamily member 7 (MPP7).	[24]

2 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 MAGUK p55 subfamily member 7 (MPP7).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of MAGUK p55 subfamily member 7 (MPP7).	[20]

References

• [1] MDH1 and MPP7 Regulate Autophagy in Pancreatic Ductal Adenocarcinoma.Cancer Res. 2019 Apr 15;79(8):1884-1898. doi: 10.1158/0008-5472.CAN-18-2553. Epub 2019 Feb 14.
• [2] Genetic association and stress mediated down-regulation in trabecular meshwork implicates MPP7 as a novel candidate gene in primary open angle glaucoma.BMC Med Genomics. 2016 Mar 22;9:15. doi: 10.1186/s12920-016-0177-6.
• [3] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [4] Genome-Wide Association Study Identifies Novel Loci Associated With Diisocyanate-Induced Occupational Asthma.Toxicol Sci. 2015 Jul;146(1):192-201. doi: 10.1093/toxsci/kfv084. Epub 2015 Apr 26.
• [5] Deletion at chromosome 10p11.23-p12.1 defines characteristic phenotypes with marked midface retrusion.J Hum Genet. 2012 Mar;57(3):191-6. doi: 10.1038/jhg.2011.154. Epub 2012 Jan 19.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [14] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [15] Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res. 2006 Mar 1;66(5):2765-77.
• [16] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [17] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [18] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] 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.
• [21] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [23] 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.
• [24] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.