Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUOKF1A)

• DOT Name: Importin subunit alpha-6 (KPNA5)
• Synonyms: Karyopherin subunit alpha-5
• Gene Name: KPNA5
• Related Disease: Ebola virus infection
• UniProt ID: IMA6_HUMAN
• PDB ID: 4U2X
• Pfam ID: PF00514 ; PF16186 ; PF01749
• Sequence:
  MDAMASPGKDNYRMKSYKNKALNPQEMRRRREEEGIQLRKQKREEQLFKRRNVYLPRNDE
  SMLESPIQDPDISSTVPIPEEEVVTTDMVQMIFSNNADQQLTATQKFRKLLSKEPNPPID
  QVIQKPGVVQRFVKFLERNENCTLQFEAAWALTNIASGTFLHTKVVIETGAVPIFIKLLN
  SEHEDVQEQAVWALGNIAGDNAECRDFVLNCEILPPLLELLTNSNRLTTTRNAVWALSNL
  CRGKNPPPNFSKVSPCLNVLSRLLFSSDPDVLADVCWALSYLSDGPNDKIQAVIDSGVCR
  RLVELLMHNDYKVVSPALRAVGNIVTGDDIQTQVILNCSALPCLLHLLSSPKESIRKEAC
  WTVSNITAGNRAQIQAVIDANIFPVLIEILQKAEFRTRKEAAWAITNATSGGTPEQIRYL
  VALGCIKPLCDLLTVMDSKIVQVALNGLENILRLGEQESKQNGIGINPYCALIEEAYGLD
  KIEFLQSHENQEIYQKAFDLIEHYFGVEEDDPSIVPQVDENQQQFIFQQQEAPMDGFQL
• 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. Mediates nuclear import of STAT1 homodimers and STAT1/STAT2 heterodimers by recognizing non-classical NLSs of STAT1 and STAT2 through ARM repeats 8-9. Recognizes influenza A virus nucleoprotein through ARM repeat 7-9 In vitro, mediates the nuclear import of human cytomegalovirus UL84 by recognizing a non-classical NLS.
• Tissue Specificity: Testis.
• KEGG Pathway:
  Nucleocytoplasmic transport (hsa03013)
  Influenza A (hsa05164)
  Chemical carcinogenesis - receptor activation (hsa05207)
• Reactome Pathway:
  NS1 Mediated Effects on Host Pathways (R-HSA-168276)
  ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ebola virus infection	DISJAVM1	Limited	Biomarker	[1]

8 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-6 (KPNA5).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Importin subunit alpha-6 (KPNA5).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Importin subunit alpha-6 (KPNA5).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Importin subunit alpha-6 (KPNA5).	[5]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Importin subunit alpha-6 (KPNA5).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Importin subunit alpha-6 (KPNA5).	[7]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Importin subunit alpha-6 (KPNA5).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Importin subunit alpha-6 (KPNA5).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Importin subunit alpha-6 (KPNA5).	[9]

References

• [1] Investigating Ebola virus pathogenicity using molecular dynamics.BMC Genomics. 2017 Aug 11;18(Suppl 5):566. doi: 10.1186/s12864-017-3912-2.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] 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.
• [6] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [7] 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.
• [8] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [9] 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.
• [10] 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.