Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV8MNT1)

DOT Name Probable E3 ubiquitin-protein ligase IRF2BPL (IRF2BPL)
Synonyms EC 2.3.2.27; Enhanced at puberty protein 1; Interferon regulatory factor 2-binding protein-like
Gene Name IRF2BPL
Related Disease
Neurodegenerative disease ( )
Epilepsy ( )
Fragile X-associated tremor/ataxia syndrome ( )
Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures ( )
Atrial fibrillation ( )
Familial atrial fibrillation ( )
Gastric cancer ( )
Stomach cancer ( )
UniProt ID
I2BPL_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
2CS3
EC Number
2.3.2.27
Pfam ID
PF11261
Sequence
MSAAQVSSSRRQSCYLCDLPRMPWAMIWDFSEPVCRGCVNYEGADRIEFVIETARQLKRA
HGCFQDGRSPGPPPPVGVKTVALSAKEAAAAAAAAAAAAAAAQQQQQQQQQQQQQQQQQQ
QQQQQQQLNHVDGSSKPAVLAAPSGLERYGLSAAAAAAAAAAAAVEQRSRFEYPPPPVSL
GSSSHTARLPNGLGGPNGFPKPTPEEGPPELNRQSPNSSSAAASVASRRGTHGGLVTGLP
NPGGGGGPQLTVPPNLLPQTLLNGPASAAVLPPPPPHALGSRGPPTPAPPGAPGGPACLG
GTPGVSATSSSASSSTSSSVAEVGVGAGGKRPGSVSSTDQERELKEKQRNAEALAELSES
LRNRAEEWASKPKMVRDTLLTLAGCTPYEVRFKKDHSLLGRVFAFDAVSKPGMDYELKLF
IEYPTGSGNVYSSASGVAKQMYQDCMKDFGRGLSSGFKYLEYEKKHGSGDWRLLGDLLPE
AVRFFKEGVPGADMLPQPYLDASCPMLPTALVSLSRAPSAPPGTGALPPAAPSGRGAAAS
LRKRKASPEPPDSAEGALKLGEEQQRQQWMANQSEALKLTMSAGGFAAPGHAAGGPPPPP
PPLGPHSNRTTPPESAPQNGPSPMAALMSVADTLGTAHSPKDGSSVHSTTASARRNSSSP
VSPASVPGQRRLASRNGDLNLQVAPPPPSAHPGMDQVHPQNIPDSPMANSGPLCCTICHE
RLEDTHFVQCPSVPSHKFCFPCSRESIKAQGATGEVYCPSGEKCPLVGSNVPWAFMQGEI
ATILAGDVKVKKERDP
Function
Probable E3 ubiquitin protein ligase involved in the proteasome-mediated ubiquitin-dependent degradation of target proteins. Through the degradation of CTNNB1, functions downstream of FOXF2 to negatively regulate the Wnt signaling pathway. Probably plays a role in the development of the central nervous system and in neuronal maintenance (Probable). Also acts as a transcriptional regulator of genes controlling female reproductive function. May play a role in gene transcription by transactivating GNRH1 promoter and repressing PENK promoter.
Tissue Specificity Highly expressed in the heart, moderately in skeletal muscle and pancreas, and weakly in brain, kidney, liver, testis, thyroid gland and lymphocytes.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Neurodegenerative disease DISM20FF Definitive Autosomal dominant [1]
Epilepsy DISBB28L Strong Genetic Variation [2]
Fragile X-associated tremor/ataxia syndrome DISKB25R Strong Altered Expression [3]
Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures DIS82TFH Strong Autosomal dominant [4]
Atrial fibrillation DIS15W6U moderate Biomarker [5]
Familial atrial fibrillation DISL4AGF moderate Biomarker [5]
Gastric cancer DISXGOUK Limited Altered Expression [6]
Stomach cancer DISKIJSX Limited Altered Expression [6]
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⏷ Show the Full List of 8 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
This DOT Affected the Drug Response of 1 Drug(s)
Drug Name Drug ID Highest Status Interaction REF
Phenytoin DMNOKBV Approved Probable E3 ubiquitin-protein ligase IRF2BPL (IRF2BPL) increases the Hypersensitivity ADR of Phenytoin. [27]
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4 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 Probable E3 ubiquitin-protein ligase IRF2BPL (IRF2BPL). [7]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the methylation of Probable E3 ubiquitin-protein ligase IRF2BPL (IRF2BPL). [21]
TAK-243 DM4GKV2 Phase 1 TAK-243 affects the sumoylation of Probable E3 ubiquitin-protein ligase IRF2BPL (IRF2BPL). [23]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 increases the phosphorylation of Probable E3 ubiquitin-protein ligase IRF2BPL (IRF2BPL). [24]
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17 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 Probable E3 ubiquitin-protein ligase IRF2BPL (IRF2BPL). [8]
Tretinoin DM49DUI Approved Tretinoin increases the expression of Probable E3 ubiquitin-protein ligase IRF2BPL (IRF2BPL). [9]
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of Probable E3 ubiquitin-protein ligase IRF2BPL (IRF2BPL). [10]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Probable E3 ubiquitin-protein ligase IRF2BPL (IRF2BPL). [11]
Cisplatin DMRHGI9 Approved Cisplatin increases the expression of Probable E3 ubiquitin-protein ligase IRF2BPL (IRF2BPL). [12]
Estradiol DMUNTE3 Approved Estradiol decreases the expression of Probable E3 ubiquitin-protein ligase IRF2BPL (IRF2BPL). [13]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of Probable E3 ubiquitin-protein ligase IRF2BPL (IRF2BPL). [14]
Quercetin DM3NC4M Approved Quercetin decreases the expression of Probable E3 ubiquitin-protein ligase IRF2BPL (IRF2BPL). [15]
Vorinostat DMWMPD4 Approved Vorinostat decreases the expression of Probable E3 ubiquitin-protein ligase IRF2BPL (IRF2BPL). [16]
Zoledronate DMIXC7G Approved Zoledronate decreases the expression of Probable E3 ubiquitin-protein ligase IRF2BPL (IRF2BPL). [17]
Ethanol DMDRQZU Approved Ethanol increases the expression of Probable E3 ubiquitin-protein ligase IRF2BPL (IRF2BPL). [18]
Urethane DM7NSI0 Phase 4 Urethane affects the expression of Probable E3 ubiquitin-protein ligase IRF2BPL (IRF2BPL). [19]
SNDX-275 DMH7W9X Phase 3 SNDX-275 increases the expression of Probable E3 ubiquitin-protein ligase IRF2BPL (IRF2BPL). [20]
Leflunomide DMR8ONJ Phase 1 Trial Leflunomide increases the expression of Probable E3 ubiquitin-protein ligase IRF2BPL (IRF2BPL). [22]
Trichostatin A DM9C8NX Investigative Trichostatin A decreases the expression of Probable E3 ubiquitin-protein ligase IRF2BPL (IRF2BPL). [16]
Formaldehyde DM7Q6M0 Investigative Formaldehyde decreases the expression of Probable E3 ubiquitin-protein ligase IRF2BPL (IRF2BPL). [25]
AM251 DMTAWHL Investigative AM251 increases the expression of Probable E3 ubiquitin-protein ligase IRF2BPL (IRF2BPL). [26]
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⏷ Show the Full List of 17 Drug(s)

References

1 Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
2 IRF2BPL gene mutation: Expanding on neurologic phenotypes.Am J Med Genet A. 2019 Nov;179(11):2263-2271. doi: 10.1002/ajmg.a.61328. Epub 2019 Aug 20.
3 Blood expression profiles of fragile X premutation carriers identify candidate genes involved in neurodegenerative and infertility phenotypes.Neurobiol Dis. 2014 May;65:43-54. doi: 10.1016/j.nbd.2013.12.020. Epub 2014 Jan 10.
4 IRF2BPL Is Associated with Neurological Phenotypes. Am J Hum Genet. 2018 Aug 2;103(2):245-260. doi: 10.1016/j.ajhg.2018.07.006. Epub 2018 Jul 26.
5 Biobank-driven genomic discovery yields new insight into atrial fibrillation biology.Nat Genet. 2018 Sep;50(9):1234-1239. doi: 10.1038/s41588-018-0171-3. Epub 2018 Jul 30.
6 Forkhead Box F2 Suppresses Gastric Cancer through a Novel FOXF2-IRF2BPL--Catenin Signaling Axis.Cancer Res. 2018 Apr 1;78(7):1643-1656. doi: 10.1158/0008-5472.CAN-17-2403. Epub 2018 Jan 26.
7 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.
8 Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
9 Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
10 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.
11 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.
12 Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
13 High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.
14 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.
15 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.
16 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.
17 Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
18 Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
19 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
20 A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
21 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.
22 Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
23 Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
24 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.
25 Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
26 Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 2006 Mar 20;580(7):1733-9.
27 Genome-wide mapping for clinically relevant predictors of lamotrigine- and phenytoin-induced hypersensitivity reactions. Pharmacogenomics. 2012 Mar;13(4):399-405. doi: 10.2217/pgs.11.165.