Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ1DTXU)

• DOT Name: Coatomer subunit alpha (COPA)
• Synonyms: Alpha-coat protein; Alpha-COP; HEP-COP; HEPCOP
• Gene Name: COPA
• Related Disease:
  Angiosarcoma
  Autoimmune disease
  Autoimmune interstitial lung disease-arthritis syndrome
  Gastric cancer
  Hepatocellular carcinoma
  Neoplasm
  Non-insulin dependent diabetes
  Obesity
  Pulmonary disease
  Spinal muscular atrophy
  Stomach cancer
  Gastrointestinal stromal tumour
  Polycystic ovarian syndrome
  Arthritis
  Mesothelioma
  Type-1/2 diabetes
• UniProt ID: COPA_HUMAN
• PDB ID: 6PBG; 6TZT; 6U3V
• Pfam ID: PF04053 ; PF06957 ; PF00400
• Sequence:
  MLTKFETKSARVKGLSFHPKRPWILTSLHNGVIQLWDYRMCTLIDKFDEHDGPVRGIDFH
  KQQPLFVSGGDDYKIKVWNYKLRRCLFTLLGHLDYIRTTFFHHEYPWILSASDDQTIRVW
  NWQSRTCVCVLTGHNHYVMCAQFHPTEDLVVSASLDQTVRVWDISGLRKKNLSPGAVESD
  VRGITGVDLFGTTDAVVKHVLEGHDRGVNWAAFHPTMPLIVSGADDRQVKIWRMNESKAW
  EVDTCRGHYNNVSCAVFHPRQELILSNSEDKSIRVWDMSKRTGVQTFRRDHDRFWVLAAH
  PNLNLFAAGHDGGMIVFKLERERPAYAVHGNMLHYVKDRFLRQLDFNSSKDVAVMQLRSG
  SKFPVFNMSYNPAENAVLLCTRASNLENSTYDLYTIPKDADSQNPDAPEGKRSSGLTAVW
  VARNRFAVLDRMHSLLIKNLKNEITKKVQVPNCDEIFYAGTGNLLLRDADSITLFDVQQK
  RTLASVKISKVKYVIWSADMSHVALLAKHAIVICNRKLDALCNIHENIRVKSGAWDESGV
  FIYTTSNHIKYAVTTGDHGIIRTLDLPIYVTRVKGNNVYCLDRECRPRVLTIDPTEFKFK
  LALINRKYDEVLHMVRNAKLVGQSIIAYLQKKGYPEVALHFVKDEKTRFSLALECGNIEI
  ALEAAKALDDKNCWEKLGEVALLQGNHQIVEMCYQRTKNFDKLSFLYLITGNLEKLRKMM
  KIAEIRKDMSGHYQNALYLGDVSERVRILKNCGQKSLAYLTAATHGLDEEAESLKETFDP
  EKETIPDIDPNAKLLQPPAPIMPLDTNWPLLTVSKGFFEGTIASKGKGGALAADIDIDTV
  GTEGWGEDAELQLDEDGFVEATEGLGDDALGKGQEEGGGWDVEEDLELPPELDISPGAAG
  GAEDGFFVPPTKGTSPTQIWCNNSQLPVDHILAGSFETAMRLLHDQVGVIQFGPYKQLFL
  QTYARGRTTYQALPCLPSMYGYPNRNWKDAGLKNGVPAVGLKLNDLIQRLQLCYQLTTVG
  KFEEAVEKFRSILLSVPLLVVDNKQEIAEAQQLITICREYIVGLSVETERKKLPKETLEQ
  QKRICEMAAYFTHSNLQPVHMILVLRTALNLFFKLKNFKTAATFARRLLELGPKPEVAQQ
  TRKILSACEKNPTDAYQLNYDMHNPFDICAASYRPIYRGKPVEKCPLSGACYSPEFKGQI
  CRVTTVTEIGKDVIGLRISPLQFR
• Function: The coatomer is a cytosolic protein complex that binds to dilysine motifs and reversibly associates with Golgi non-clathrin-coated vesicles, which further mediate biosynthetic protein transport from the ER, via the Golgi up to the trans Golgi network. Coatomer complex is required for budding from Golgi membranes, and is essential for the retrograde Golgi-to-ER transport of dilysine-tagged proteins. In mammals, the coatomer can only be recruited by membranes associated to ADP-ribosylation factors (ARFs), which are small GTP-binding proteins; the complex also influences the Golgi structural integrity, as well as the processing, activity, and endocytic recycling of LDL receptors; Xenin stimulates exocrine pancreatic secretion. It inhibits pentagastrin-stimulated secretion of acid, to induce exocrine pancreatic secretion and to affect small and large intestinal motility. In the gut, xenin interacts with the neurotensin receptor.
• Tissue Specificity: Uniformly expressed in a wide range of adult and fetal tissues. Xenin is found in gastric, duodenal and jejunal mucosa. Circulates in the blood. Seems to be confined to specific endocrine cells.
• Reactome Pathway:
  COPI-dependent Golgi-to-ER retrograde traffic (R-HSA-6811434)
  COPI-mediated anterograde transport (R-HSA-6807878)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Angiosarcoma	DISIYS9W	Strong	Biomarker	[1]
Autoimmune disease	DISORMTM	Strong	Biomarker	[2]
Autoimmune interstitial lung disease-arthritis syndrome	DISXH0F2	Strong	Autosomal dominant	[2]
Gastric cancer	DISXGOUK	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[6]
Obesity	DIS47Y1K	Strong	Biomarker	[7]
Pulmonary disease	DIS6060I	Strong	Genetic Variation	[2]
Spinal muscular atrophy	DISTLKOB	Strong	Biomarker	[8]
Stomach cancer	DISKIJSX	Strong	Biomarker	[3]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Altered Expression	[9]
Polycystic ovarian syndrome	DISZ2BNG	moderate	Biomarker	[10]
Arthritis	DIST1YEL	Limited	Genetic Variation	[11]
Mesothelioma	DISKWK9M	Limited	Biomarker	[5]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Coatomer subunit alpha (COPA).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Coatomer subunit alpha (COPA).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Coatomer subunit alpha (COPA).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Coatomer subunit alpha (COPA).	[22]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Coatomer subunit alpha (COPA).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Coatomer subunit alpha (COPA).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Coatomer subunit alpha (COPA).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Coatomer subunit alpha (COPA).	[16]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Coatomer subunit alpha (COPA).	[17]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Coatomer subunit alpha (COPA).	[18]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Coatomer subunit alpha (COPA).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Coatomer subunit alpha (COPA).	[23]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Coatomer subunit alpha (COPA).	[24]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Coatomer subunit alpha (COPA).	[25]

References

• [1] Identification of potential target genes associated with the effect of propranolol on angiosarcoma via microarray analysis.Oncol Lett. 2017 Jun;13(6):4267-4275. doi: 10.3892/ol.2017.5968. Epub 2017 Mar 31.
• [2] COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis. Nat Genet. 2015 Jun;47(6):654-60. doi: 10.1038/ng.3279. Epub 2015 Apr 20.
• [3] M-COPA, a Golgi Disruptor, Inhibits Cell Surface Expression of MET Protein and Exhibits Antitumor Activity against MET-Addicted Gastric Cancers.Cancer Res. 2016 Jul 1;76(13):3895-903. doi: 10.1158/0008-5472.CAN-15-2220. Epub 2016 Apr 12.
• [4] A disrupted RNA editing balance mediated by ADARs (Adenosine DeAminases that act on RNA) in human hepatocellular carcinoma.Gut. 2014 May;63(5):832-43. doi: 10.1136/gutjnl-2012-304037. Epub 2013 Jun 13.
• [5] Knockdown of COPA, identified by loss-of-function screen, induces apoptosis and suppresses tumor growth in mesothelioma mouse model.Genomics. 2010 Apr;95(4):210-6. doi: 10.1016/j.ygeno.2010.02.002. Epub 2010 Feb 11.
• [6] A novel GLP-1/xenin hybrid peptide improves glucose homeostasis, circulating lipids and restores GIP sensitivity in high fat fed mice.Peptides. 2018 Feb;100:202-211. doi: 10.1016/j.peptides.2017.10.015.
• [7] Emerging therapeutic potential for xenin and related peptides in obesity and diabetes.Diabetes Metab Res Rev. 2018 Sep;34(6):e3006. doi: 10.1002/dmrr.3006. Epub 2018 Apr 26.
• [8] Interaction between alpha-COP and SMN ameliorates disease phenotype in a mouse model of spinal muscular atrophy.Biochem Biophys Res Commun. 2019 Jun 25;514(2):530-537. doi: 10.1016/j.bbrc.2019.04.176. Epub 2019 May 3.
• [9] Oncogenic Kit signalling on the Golgi is suppressed by blocking secretory trafficking with M-COPA in gastrointestinal stromal tumours.Cancer Lett. 2018 Feb 28;415:1-10. doi: 10.1016/j.canlet.2017.11.032. Epub 2017 Nov 28.
• [10] The relationship between elevated serum xenin and insulin resistance in women with polycystic ovary syndrome: a case-control study.Gynecol Endocrinol. 2019 Nov;35(11):960-964. doi: 10.1080/09513590.2019.1604663. Epub 2019 Apr 23.
• [11] Use of ruxolitinib in COPA syndrome manifesting as life-threatening alveolar haemorrhage.Thorax. 2020 Jan;75(1):92-95. doi: 10.1136/thoraxjnl-2019-213892. Epub 2019 Oct 30.
• [12] Effects of long-acting GIP, xenin and oxyntomodulin peptide analogues on alpha-cell transdifferentiation in insulin-deficient diabetic Glu(CreERT2);ROSA26-eYFP mice.Peptides. 2020 Mar;125:170205. doi: 10.1016/j.peptides.2019.170205. Epub 2019 Nov 16.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [18] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [19] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [20] 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.
• [21] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [22] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [23] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [24] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [25] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.