Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ3OX6P)

• DOT Name: Importin subunit alpha-7 (KPNA6)
• Synonyms: Karyopherin subunit alpha-6
• Gene Name: KPNA6
• Related Disease:
  Adult respiratory distress syndrome
  Prostate cancer
  Prostate carcinoma
  Zika virus infection
• UniProt ID: IMA7_HUMAN
• PDB ID: 4UAD; 7RHT
• Pfam ID: PF00514 ; PF16186 ; PF01749
• Sequence:
  METMASPGKDNYRMKSYKNNALNPEEMRRRREEEGIQLRKQKREQQLFKRRNVELINEEA
  AMFDSLLMDSYVSSTTGESVITREMVEMLFSDDSDLQLATTQKFRKLLSKEPSPPIDEVI
  NTPRVVDRFVEFLKRNENCTLQFEAAWALTNIASGTSQQTKIVIEAGAVPIFIELLNSDF
  EDVQEQAVWALGNIAGDSSVCRDYVLNCSILNPLLTLLTKSTRLTMTRNAVWALSNLCRG
  KNPPPEFAKVSPCLPVLSRLLFSSDSDLLADACWALSYLSDGPNEKIQAVIDSGVCRRLV
  ELLMHNDYKVASPALRAVGNIVTGDDIQTQVILNCSALPCLLHLLSSPKESIRKEACWTI
  SNITAGNRAQIQAVIDANIFPVLIEILQKAEFRTRKEAAWAITNATSGGTPEQIRYLVSL
  GCIKPLCDLLTVMDSKIVQVALNGLENILRLGEQEGKRSGSGVNPYCGLIEEAYGLDKIE
  FLQSHENQEIYQKAFDLIEHYFGVEDDDSSLAPQVDETQQQFIFQQPEAPMEGFQL
• 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.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Nucleocytoplasmic transport (hsa03013)
  Influenza A (hsa05164)
  Chemical carcinogenesis - receptor activation (hsa05207)
• Reactome Pathway: Assembly of the ORC complex at the origin of replication (R-HSA-68616)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult respiratory distress syndrome	DISIJV47	Strong	Biomarker	[1]
Prostate cancer	DISF190Y	Strong	Biomarker	[2]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[2]
Zika virus infection	DISQUCTY	Strong	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Importin subunit alpha-7 (KPNA6).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Importin subunit alpha-7 (KPNA6).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Importin subunit alpha-7 (KPNA6).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Importin subunit alpha-7 (KPNA6).	[8]
Selenium	DM25CGV	Approved	Selenium increases the expression of Importin subunit alpha-7 (KPNA6).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Importin subunit alpha-7 (KPNA6).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Importin subunit alpha-7 (KPNA6).	[12]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Importin subunit alpha-7 (KPNA6).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Importin subunit alpha-7 (KPNA6).	[5]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Importin subunit alpha-7 (KPNA6).	[11]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Importin subunit alpha-7 (KPNA6).	[11]

References

• [1] H7N9 Influenza A Virus Exhibits Importin-7-Mediated Replication in the Mammalian Respiratory Tract.Am J Pathol. 2017 Apr;187(4):831-840. doi: 10.1016/j.ajpath.2016.12.017. Epub 2017 Feb 9.
• [2] 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.
• [3] Karyopherin Alpha 6 Is Required for Replication of Porcine Reproductive and Respiratory Syndrome Virus and Zika Virus.J Virol. 2018 Apr 13;92(9):e00072-18. doi: 10.1128/JVI.00072-18. Print 2018 May 1.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] 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.
• [10] Comparison of quantitation methods in proteomics to define relevant toxicological information on AhR activation of HepG2 cells by BaP. Toxicology. 2021 Jan 30;448:152652. doi: 10.1016/j.tox.2020.152652. Epub 2020 Dec 2.
• [11] 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.
• [12] 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.
• [13] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.