Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRMZVO6)

• DOT Name: Gap junction alpha-5 protein (GJA5)
• Synonyms: Connexin-40; Cx40
• Gene Name: GJA5
• Related Disease:
  Atrial fibrillation, familial, 11
  Familial atrial fibrillation
  Heart arrhythmia
• UniProt ID: CXA5_HUMAN
• Pfam ID: PF00029 ; PF16791
• Sequence:
  MGDWSFLGNFLEEVHKHSTVVGKVWLTVLFIFRMLVLGTAAESSWGDEQADFRCDTIQPG
  CQNVCYDQAFPISHIRYWVLQIIFVSTPSLVYMGHAMHTVRMQEKRKLREAERAKEVRGS
  GSYEYPVAEKAELSCWEEGNGRIALQGTLLNTYVCSILIRTTMEVGFIVGQYFIYGIFLT
  TLHVCRRSPCPHPVNCYVSRPTEKNVFIVFMLAVAALSLLLSLAELYHLGWKKIRQRFVK
  PRQHMAKCQLSGPSVGIVQSCTPPPDFNQCLENGPGGKFFNPFSNNMASQQNTDNLVTEQ
  VRGQEQTPGEGFIQVRYGQKPEVPNGVSPGHRLPHGYHSDKRRLSKASSKARSDDLSV
• Function: One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
• Reactome Pathway: Gap junction assembly (R-HSA-190861)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atrial fibrillation, familial, 11	DIS6FI1C	Strong	Autosomal dominant	[1]
Familial atrial fibrillation	DISL4AGF	Supportive	Autosomal dominant	[2]
Heart arrhythmia	DISLKUNL	Limited	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Gap junction alpha-5 protein (GJA5).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Gap junction alpha-5 protein (GJA5).	[5]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Gap junction alpha-5 protein (GJA5).	[6]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Gap junction alpha-5 protein (GJA5).	[7]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Gap junction alpha-5 protein (GJA5).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Gap junction alpha-5 protein (GJA5).	[10]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Gap junction alpha-5 protein (GJA5).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Gap junction alpha-5 protein (GJA5).	[9]

References

• [1] Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. N Engl J Med. 2006 Jun 22;354(25):2677-88. doi: 10.1056/NEJMoa052800.
• [2] Novel connexin40 missense mutations in patients with familial atrial fibrillation. Europace. 2010 Oct;12(10):1421-7. doi: 10.1093/europace/euq274. Epub 2010 Jul 21.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] 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.
• [5] Functional cardiotoxicity assessment of cosmetic compounds using human-induced pluripotent stem cell-derived cardiomyocytes. Arch Toxicol. 2018 Jan;92(1):371-381.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [7] Cell death mechanisms of the anti-cancer drug etoposide on human cardiomyocytes isolated from pluripotent stem cells. Arch Toxicol. 2018 Apr;92(4):1507-1524.
• [8] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [9] 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.
• [10] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [11] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.