Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQJU3OJ)

• DOT Name: Guided entry of tail-anchored proteins factor 1 (GET1)
• Synonyms: Congenital heart disease 5 protein; Tail-anchored protein insertion receptor WRB; Tryptophan-rich basic protein
• Gene Name: GET1
• Related Disease:
  Congenital heart disease
  Stroke
• UniProt ID: GET1_HUMAN
• PDB ID: 6SO5; 8CQZ; 8CR1; 8CR2
• Pfam ID: PF04420
• Sequence:
  MSSAAADHWAWLLVLSFVFGCNVLRILLPSFSSFMSRVLQKDAEQESQMRAEIQDMKQEL
  STVNMMDEFARYARLERKINKMTDKLKTHVKARTAQLAKIKWVISVAFYVLQAALMISLI
  WKYYSVPVAVVPSKWITPLDRLVAFPTRVAGGVGITCWILVCNKVVAIVLHPFS
• Function: Required for the post-translational delivery of tail-anchored (TA) proteins to the endoplasmic reticulum (ER). Together with CAMLG/GET2, acts as a membrane receptor for soluble GET3/TRC40, which recognizes and selectively binds the transmembrane domain of TA proteins in the cytosol. Required to ensure correct topology and ER insertion of CAMLG.
• KEGG Pathway: Protein export (hsa03060)
• Reactome Pathway: Insertion of tail-anchored proteins into the endoplasmic reticulum membrane (R-HSA-9609523)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital heart disease	DISQBA23	Limited	Genetic Variation	[1]
Stroke	DISX6UHX	Limited	Biomarker	[2]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Guided entry of tail-anchored proteins factor 1 (GET1).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Guided entry of tail-anchored proteins factor 1 (GET1).	[9]

12 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 Guided entry of tail-anchored proteins factor 1 (GET1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Guided entry of tail-anchored proteins factor 1 (GET1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Guided entry of tail-anchored proteins factor 1 (GET1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Guided entry of tail-anchored proteins factor 1 (GET1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Guided entry of tail-anchored proteins factor 1 (GET1).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Guided entry of tail-anchored proteins factor 1 (GET1).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Guided entry of tail-anchored proteins factor 1 (GET1).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Guided entry of tail-anchored proteins factor 1 (GET1).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Guided entry of tail-anchored proteins factor 1 (GET1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Guided entry of tail-anchored proteins factor 1 (GET1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Guided entry of tail-anchored proteins factor 1 (GET1).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Guided entry of tail-anchored proteins factor 1 (GET1).	[15]

References

• [1] Expression of the congenital heart disease 5/tryptophan rich basic protein homologue gene during heart development in medaka fish, Oryzias latipes.Dev Growth Differ. 2009 Feb;51(2):95-107. doi: 10.1111/j.1440-169X.2008.01084.x.
• [2] Astrocytic endothelin-1 overexpression promotes neural progenitor cells proliferation and differentiation into astrocytes via the Jak2/Stat3 pathway after stroke.J Neuroinflammation. 2019 Nov 16;16(1):227. doi: 10.1186/s12974-019-1597-y.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [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] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [8] 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.
• [9] 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.
• [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] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [13] The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet. 2009 Feb;41(2):178-186.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.