Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO3XDR2)

• DOT Name: E3 ubiquitin-protein ligase ARIH1 (ARIH1)
• Synonyms: EC 2.3.2.31; H7-AP2; HHARI; Monocyte protein 6; MOP-6; Protein ariadne-1 homolog; ARI-1; UbcH7-binding protein; UbcM4-interacting protein; Ubiquitin-conjugating enzyme E2-binding protein 1
• Gene Name: ARIH1
• Related Disease:
  Coronary heart disease
  Prostatitis
  Type-1/2 diabetes
  Advanced cancer
  Aortic aneurysm
  Asthma
  Atrial fibrillation
  Colorectal carcinoma
  Depression
  Diabetic neuropathy
  Lung adenocarcinoma
  Neoplasm
  Non-small-cell lung cancer
  Pneumonia
  Toxic epidermal necrolysis
  Transitional cell carcinoma
  Urothelial carcinoma
  Uveitis
  Alopecia
  Non-insulin dependent diabetes
  Respiratory disease
  Benign prostatic hyperplasia
  Parkinson disease
• UniProt ID: ARI1_HUMAN
• PDB ID: 1WD2; 2M9Y; 4KBL; 4KC9; 5TTE; 5UDH; 7B5L; 7B5M; 7B5N; 7B5S
• EC Number: 2.3.2.31
• Pfam ID: PF21235 ; PF19422 ; PF01485 ; PF00097
• Sequence:
  MDSDEGYNYEFDEDEECSEEDSGAEEEEDEDDDEPDDDTLDLGEVELVEPGLGVGGERDG
  LLCGETGGGGGSALGPGGGGGGGGGGGGGGPGHEQEEDYRYEVLTAEQILQHMVECIREV
  NEVIQNPATITRILLSHFNWDKEKLMERYFDGNLEKLFAECHVINPSKKSRTRQMNTRSS
  AQDMPCQICYLNYPNSYFTGLECGHKFCMQCWSEYLTTKIMEEGMGQTISCPAHGCDILV
  DDNTVMRLITDSKVKLKYQHLITNSFVECNRLLKWCPAPDCHHVVKVQYPDAKPVRCKCG
  RQFCFNCGENWHDPVKCKWLKKWIKKCDDDSETSNWIAANTKECPKCHVTIEKDGGCNHM
  VCRNQNCKAEFCWVCLGPWEPHGSAWYNCNRYNEDDAKAARDAQERSRAALQRYLFYCNR
  YMNHMQSLRFEHKLYAQVKQKMEEMQQHNMSWIEVQFLKKAVDVLCQCRATLMYTYVFAF
  YLKKNNQSIIFENNQADLENATEVLSGYLERDISQDSLQDIKQKVQDKYRYCESRRRVLL
  QHVHEGYEKDLWEYIED
• Function: E3 ubiquitin-protein ligase, which catalyzes ubiquitination of target proteins together with ubiquitin-conjugating enzyme E2 UBE2L3. Acts as an atypical E3 ubiquitin-protein ligase by working together with cullin-RING ubiquitin ligase (CRL) complexes and initiating ubiquitination of CRL substrates: associates with CRL complexes and specifically mediates addition of the first ubiquitin on CRLs targets. The initial ubiquitin is then elongated by CDC34/UBE2R1 and UBE2R2. E3 ubiquitin-protein ligase activity is activated upon binding to neddylated cullin-RING ubiquitin ligase complexes. Plays a role in protein translation in response to DNA damage by mediating ubiquitination of EIF4E2, the consequences of EIF4E2 ubiquitination are however unclear. According to a report, EIF4E2 ubiquitination leads to promote EIF4E2 cap-binding and protein translation arrest. According to another report EIF4E2 ubiquitination leads to its subsequent degradation. Acts as the ligase involved in ISGylation of EIF4E2. In vitro, controls the degradation of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex member SUN2 and may therefore have a role in the formation and localization of the LINC complex, and as a consequence, nuclear subcellular localization and nuclear morphology.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: Mitophagy - animal (hsa04137)
• Reactome Pathway:
  PKR-mediated signaling (R-HSA-9833482)
  ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coronary heart disease	DIS5OIP1	Definitive	Biomarker	[1]
Prostatitis	DISL8OGN	Definitive	Biomarker	[2]
Type-1/2 diabetes	DISIUHAP	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Aortic aneurysm	DISQ5KRA	Strong	Biomarker	[4]
Asthma	DISW9QNS	Strong	Biomarker	[5]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[7]
Depression	DIS3XJ69	Strong	Biomarker	[8]
Diabetic neuropathy	DISX6VF8	Strong	Biomarker	[9]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[12]
Pneumonia	DIS8EF3M	Strong	Biomarker	[5]
Toxic epidermal necrolysis	DISIWPFR	Strong	Biomarker	[13]
Transitional cell carcinoma	DISWVVDR	Strong	Biomarker	[14]
Urothelial carcinoma	DISRTNTN	Strong	Biomarker	[14]
Uveitis	DISV0RYS	Strong	Biomarker	[15]
Alopecia	DIS37HU4	moderate	Biomarker	[8]
Non-insulin dependent diabetes	DISK1O5Z	Disputed	Biomarker	[16]
Respiratory disease	DISGGAGJ	Disputed	Biomarker	[5]
Benign prostatic hyperplasia	DISI3CW2	Limited	Biomarker	[17]
Parkinson disease	DISQVHKL	Limited	Biomarker	[18]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	E3 ubiquitin-protein ligase ARIH1 (ARIH1) increases the response to substance of Cisplatin.	[29]

1 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 E3 ubiquitin-protein ligase ARIH1 (ARIH1).	[19]

12 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 E3 ubiquitin-protein ligase ARIH1 (ARIH1).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of E3 ubiquitin-protein ligase ARIH1 (ARIH1).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase ARIH1 (ARIH1).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of E3 ubiquitin-protein ligase ARIH1 (ARIH1).	[23]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of E3 ubiquitin-protein ligase ARIH1 (ARIH1).	[24]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of E3 ubiquitin-protein ligase ARIH1 (ARIH1).	[25]
Selenium	DM25CGV	Approved	Selenium decreases the expression of E3 ubiquitin-protein ligase ARIH1 (ARIH1).	[26]
Acocantherin	DM7JT24	Approved	Acocantherin decreases the expression of E3 ubiquitin-protein ligase ARIH1 (ARIH1).	[27]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of E3 ubiquitin-protein ligase ARIH1 (ARIH1).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of E3 ubiquitin-protein ligase ARIH1 (ARIH1).	[28]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of E3 ubiquitin-protein ligase ARIH1 (ARIH1).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of E3 ubiquitin-protein ligase ARIH1 (ARIH1).	[30]

References

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• [3] Use of 5-reductase inhibitors for benign prostate hypertrophy and risk of high grade prostate cancer: a French population-based study.BJU Int. 2019 Feb;123(2):293-299. doi: 10.1111/bju.14495. Epub 2018 Sep 11.
• [4] Ari-1 Regulates Myonuclear Organization Together with Parkin and Is Associated with Aortic Aneurysms.Dev Cell. 2018 Apr 23;45(2):226-244.e8. doi: 10.1016/j.devcel.2018.03.020.
• [5] Virome and bacteriome characterization of children with pneumonia and asthma in Mexico City during winter seasons 2014 and 2015.PLoS One. 2018 Feb 15;13(2):e0192878. doi: 10.1371/journal.pone.0192878. eCollection 2018.
• [6] Indexes of cerebral autoregulation do not reflect impairment in syncope: insights from head-up tilt test of vasovagal and autonomic failure subjects.Eur J Appl Physiol. 2017 Sep;117(9):1817-1831. doi: 10.1007/s00421-017-3674-1. Epub 2017 Jul 5.
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• [9] Aldose reductase structures: implications for mechanism and inhibition.Cell Mol Life Sci. 2004 Apr;61(7-8):750-62. doi: 10.1007/s00018-003-3403-2.
• [10] Parkin-Independent Mitophagy Controls Chemotherapeutic Response in Cancer Cells.Cell Rep. 2017 Sep 19;20(12):2846-2859. doi: 10.1016/j.celrep.2017.08.087.
• [11] Association between 5-reductase inhibitors therapy and incidence, cancer-specific mortality, and progression of prostate cancer: evidence from a meta-analysis.Asian J Androl. 2020 Sep-Oct;22(5):532-538. doi: 10.4103/aja.aja_112_19.
• [12] Novel ROR1 inhibitor ARI-1 suppresses the development of non-small cell lung cancer.Cancer Lett. 2019 Aug 28;458:76-85. doi: 10.1016/j.canlet.2019.05.016. Epub 2019 May 21.
• [13] Improved multiparametric MRI discrimination between low-risk prostate cancer and benign tissues in a small cohort of 5-reductase inhibitor treated individuals as compared with an untreated cohort.NMR Biomed. 2017 May;30(5):10.1002/nbm.3696. doi: 10.1002/nbm.3696. Epub 2017 Feb 6.
• [14] Receipt of 5-Alpha Reductase Inhibitors Before Radical Cystectomy: Do They Render High-Grade Bladder Tumors Less Aggressive?.Clin Genitourin Cancer. 2019 Dec;17(6):e1122-e1128. doi: 10.1016/j.clgc.2019.07.016. Epub 2019 Aug 5.
• [15] Objective Quantification of Anterior Chamber Inflammation: Measuring Cells and Flare by Anterior Segment Optical Coherence Tomography.Ophthalmology. 2017 Nov;124(11):1670-1677. doi: 10.1016/j.ophtha.2017.05.013. Epub 2017 Jun 16.
• [16] Benefit and harm of intensive blood pressure treatment: Derivation and validation of risk models using data from the SPRINT and ACCORD trials.PLoS Med. 2017 Oct 17;14(10):e1002410. doi: 10.1371/journal.pmed.1002410. eCollection 2017 Oct.
• [17] 5-ARI induces autophagy of prostate epithelial cells through suppressing IGF-1 expression in prostate fibroblasts.Cell Prolif. 2019 May;52(3):e12590. doi: 10.1111/cpr.12590. Epub 2019 Mar 18.
• [18] Ariadne-1: a vital Drosophila gene is required in development and defines a new conserved family of ring-finger proteins.Genetics. 2000 Jul;155(3):1231-44. doi: 10.1093/genetics/155.3.1231.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] Ouabain at pathological concentrations might induce damage in human vascular endothelial cells. Acta Pharmacol Sin. 2006 Feb;27(2):165-72. doi: 10.1111/j.1745-7254.2006.00244.x.
• [28] 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.
• [29] The E3 ubiquitin ligase ARIH1 protects against genotoxic stress by initiating a 4EHP-mediated mRNA translation arrest. Mol Cell Biol. 2015 Apr;35(7):1254-68. doi: 10.1128/MCB.01152-14. Epub 2015 Jan 26.
• [30] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [31] The E3 ubiquitin ligase ARIH1 protects against genotoxic stress by initiating a 4EHP-mediated mRNA translation arrest. Mol Cell Biol. 2015 Apr;35(7):1254-68. doi: 10.1128/MCB.01152-14. Epub 2015 Jan 26.