Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJQP0IZ)

• DOT Name: Translocon-associated protein subunit gamma (SSR3)
• Synonyms: TRAP-gamma; Signal sequence receptor subunit gamma; SSR-gamma
• Gene Name: SSR3
• Related Disease:
  Congenital disorder of glycosylation
  Advanced cancer
  Hepatocellular carcinoma
  Neoplasm
• UniProt ID: SSRG_HUMAN
• PDB ID: 8B6L
• Pfam ID: PF07074
• Sequence:
  MAPKGSSKQQSEEDLLLQDFSRNLSAKSSALFFGNAFIVSAIPIWLYWRIWHMDLIQSAV
  LYSVMTLVSTYLVAFAYKNVKFVLKHKVAQKREDAVSKEVTRKLSEADNRKMSRKEKDER
  ILWKKNEVADYEATTFSIFYNNTLFLVVVIVASFFILKNFNPTVNYILSISASSGLIALL
  STGSK
• Function: TRAP proteins are part of a complex whose function is to bind calcium to the ER membrane and thereby regulate the retention of ER resident proteins.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway: SRP-dependent cotranslational protein targeting to membrane (R-HSA-1799339)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital disorder of glycosylation	DIS400QP	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[2]
Neoplasm	DISZKGEW	Limited	Altered Expression	[2]

20 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 Translocon-associated protein subunit gamma (SSR3).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Translocon-associated protein subunit gamma (SSR3).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Translocon-associated protein subunit gamma (SSR3).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Translocon-associated protein subunit gamma (SSR3).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Translocon-associated protein subunit gamma (SSR3).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Translocon-associated protein subunit gamma (SSR3).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Translocon-associated protein subunit gamma (SSR3).	[9]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Translocon-associated protein subunit gamma (SSR3).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Translocon-associated protein subunit gamma (SSR3).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Translocon-associated protein subunit gamma (SSR3).	[12]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Translocon-associated protein subunit gamma (SSR3).	[13]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Translocon-associated protein subunit gamma (SSR3).	[14]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Translocon-associated protein subunit gamma (SSR3).	[15]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Translocon-associated protein subunit gamma (SSR3).	[16]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Translocon-associated protein subunit gamma (SSR3).	[17]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Translocon-associated protein subunit gamma (SSR3).	[12]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Translocon-associated protein subunit gamma (SSR3).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Translocon-associated protein subunit gamma (SSR3).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Translocon-associated protein subunit gamma (SSR3).	[22]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Translocon-associated protein subunit gamma (SSR3).	[23]

2 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 Translocon-associated protein subunit gamma (SSR3).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Translocon-associated protein subunit gamma (SSR3).	[19]

References

• [1] Mutations in the translocon-associated protein complex subunit SSR3 cause a novel congenital disorder of glycosylation.J Inherit Metab Dis. 2019 Sep;42(5):993-997. doi: 10.1002/jimd.12091. Epub 2019 Apr 16.
• [2] Overexpression of signal sequence receptor predicts poor survival in patients with hepatocellular carcinoma.Hum Pathol. 2018 Nov;81:47-54. doi: 10.1016/j.humpath.2018.06.014. Epub 2018 Jun 23.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [13] 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.
• [14] Effects of aspirin on metastasis-associated gene expression detected by cDNA microarray. Acta Pharmacol Sin. 2004 Oct;25(10):1327-33.
• [15] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [16] 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.
• [17] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [18] 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.
• [19] 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.
• [20] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [21] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.