Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEMVAJ6)

• DOT Name: Importin subunit alpha-5 (KPNA1)
• Synonyms: Karyopherin subunit alpha-1; Nucleoprotein interactor 1; NPI-1; RAG cohort protein 2; SRP1-beta
• Gene Name: KPNA1
• Related Disease:
  Crohn disease
  Hepatitis C virus infection
  Huntington disease
  Influenza
  Prostate cancer
  Prostate carcinoma
  Rheumatoid arthritis
  Schizophrenia
  Acute myelogenous leukaemia
  Non-insulin dependent diabetes
  Anxiety
  Anxiety disorder
  Ebola virus infection
  Enterovirus infection
• UniProt ID: IMA5_HUMAN
• PDB ID: 2JDQ; 3TJ3; 4B18; 6WX9
• Pfam ID: PF00514 ; PF16186 ; PF01749
• Sequence:
  MTTPGKENFRLKSYKNKSLNPDEMRRRREEEGLQLRKQKREEQLFKRRNVATAEEETEEE
  VMSDGGFHEAQISNMEMAPGGVITSDMIEMIFSKSPEQQLSATQKFRKLLSKEPNPPIDE
  VISTPGVVARFVEFLKRKENCTLQFESAWVLTNIASGNSLQTRIVIQAGAVPIFIELLSS
  EFEDVQEQAVWALGNIAGDSTMCRDYVLDCNILPPLLQLFSKQNRLTMTRNAVWALSNLC
  RGKSPPPEFAKVSPCLNVLSWLLFVSDTDVLADACWALSYLSDGPNDKIQAVIDAGVCRR
  LVELLMHNDYKVVSPALRAVGNIVTGDDIQTQVILNCSALQSLLHLLSSPKESIKKEACW
  TISNITAGNRAQIQTVIDANIFPALISILQTAEFRTRKEAAWAITNATSGGSAEQIKYLV
  ELGCIKPLCDLLTVMDSKIVQVALNGLENILRLGEQEAKRNGTGINPYCALIEEAYGLDK
  IEFLQSHENQEIYQKAFDLIEHYFGTEDEDSSIAPQVDLNQQQYIFQQCEAPMEGFQL
• Function: Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1. Binds specifically and directly to substrates containing either a simple or bipartite NLS motif. Docking of the importin/substrate complex to the nuclear pore complex (NPC) is mediated by KPNB1 through binding to nucleoporin FxFG repeats and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin-beta and the three components separate and importin-alpha and -beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus ; (Microbial infection) In vitro, mediates the nuclear import of human cytomegalovirus UL84 by recognizing a non-classical NLS.
• Tissue Specificity: Expressed ubiquitously.
• KEGG Pathway:
  Nucleocytoplasmic transport (hsa03013)
  Salmonella infection (hsa05132)
  Influenza A (hsa05164)
  Chemical carcinogenesis - receptor activation (hsa05207)
• Reactome Pathway:
  Apoptosis induced DNA fragmentation (R-HSA-140342)
  Integration of provirus (R-HSA-162592)
  Transport of Ribonucleoproteins into the Host Nucleus (R-HSA-168271)
  NS1 Mediated Effects on Host Pathways (R-HSA-168276)
  Vpr-mediated nuclear import of PICs (R-HSA-180910)
  Assembly of the ORC complex at the origin of replication (R-HSA-68616)
  Interferon alpha/beta signaling (R-HSA-909733)
  Inhibition of nitric oxide production (R-HSA-9636249)
  ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[1]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[2]
Huntington disease	DISQPLA4	Strong	Genetic Variation	[3]
Influenza	DIS3PNU3	Strong	Biomarker	[4]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[5]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[1]
Schizophrenia	DISSRV2N	Strong	Biomarker	[6]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[7]
Non-insulin dependent diabetes	DISK1O5Z	Disputed	Genetic Variation	[1]
Anxiety	DISIJDBA	Limited	Biomarker	[8]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[8]
Ebola virus infection	DISJAVM1	Limited	Biomarker	[9]
Enterovirus infection	DISH2UDP	Limited	Altered Expression	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Importin subunit alpha-5 (KPNA1).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Importin subunit alpha-5 (KPNA1).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Importin subunit alpha-5 (KPNA1).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Importin subunit alpha-5 (KPNA1).	[14]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Importin subunit alpha-5 (KPNA1).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Importin subunit alpha-5 (KPNA1).	[17]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Importin subunit alpha-5 (KPNA1).	[18]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Importin subunit alpha-5 (KPNA1).	[19]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Importin subunit alpha-5 (KPNA1).	[20]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Importin subunit alpha-5 (KPNA1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Importin subunit alpha-5 (KPNA1).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Importin subunit alpha-5 (KPNA1).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Importin subunit alpha-5 (KPNA1).	[15]

References

• [1] An SNP-guided microRNA map of fifteen common human disorders identifies a consensus disease phenocode aiming at principal components of the nuclear import pathway.Cell Cycle. 2008 Aug 15;7(16):2570-83. doi: 10.4161/cc.7.16.6524. Epub 2008 Aug 30.
• [2] Functional characterization of nuclear localization and export signals in hepatitis C virus proteins and their role in the membranous web.PLoS One. 2014 Dec 8;9(12):e114629. doi: 10.1371/journal.pone.0114629. eCollection 2014.
• [3] SNP-guided microRNA maps (MirMaps) of 16 common human disorders identify a clinically accessible therapy reversing transcriptional aberrations of nuclear import and inflammasome pathways.Cell Cycle. 2008 Nov 15;7(22):3564-76. doi: 10.4161/cc.7.22.7073. Epub 2008 Nov 26.
• [4] Importin 3/Qip1 is involved in multiplication of mutant influenza virus with alanine mutation at amino acid 9 independently of nuclear transport function.PLoS One. 2013;8(1):e55765. doi: 10.1371/journal.pone.0055765. Epub 2013 Jan 30.
• [5] Septin 9 isoform 1 (SEPT9_i1) specifically interacts with importin-7 to drive hypoxia-inducible factor (HIF)-1 nuclear translocation.Cytoskeleton (Hoboken). 2019 Jan;76(1):123-130. doi: 10.1002/cm.21450. Epub 2018 Aug 24.
• [6] Increased exonic de novo mutation rate in individuals with schizophrenia. Nat Genet. 2011 Jul 10;43(9):860-3. doi: 10.1038/ng.886.
• [7] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [8] Importin 5 Regulates Anxiety through MeCP2 and Sphingosine Kinase 1.Cell Rep. 2018 Dec 11;25(11):3169-3179.e7. doi: 10.1016/j.celrep.2018.11.066.
• [9] Ebola virus encodes a miR-155 analog to regulate importin-5 expression.Cell Mol Life Sci. 2016 Oct;73(19):3733-44. doi: 10.1007/s00018-016-2215-0. Epub 2016 Apr 19.
• [10] Enterovirus 71 suppresses interferon responses by blocking Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling through inducing karyopherin-1 degradation.J Biol Chem. 2017 Jun 16;292(24):10262-10274. doi: 10.1074/jbc.M116.745729. Epub 2017 Apr 28.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] Differentiation-associated alteration in gene expression of importins and exportins in human leukemia HL-60 cells. Biomed Res. 2008 Jun;29(3):141-5. doi: 10.2220/biomedres.29.141.
• [13] 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.
• [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] 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.
• [16] 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.
• [17] DNA microarray analysis of changes in gene expression induced by 1,25-dihydroxyvitamin D3 in human promyelocytic leukemia HL-60 cells. Biomed Res. 2006 Jun;27(3):99-109. doi: 10.2220/biomedres.27.99.
• [18] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [19] 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.
• [20] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [21] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.