Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF4JYGZ)

• DOT Name: Potassium voltage-gated channel subfamily E regulatory beta subunit 5 (KCNE5)
• Synonyms: AMME syndrome candidate gene 2 protein; Potassium channel subunit beta MiRP4; Potassium voltage-gated channel subfamily E member 1-like protein
• Gene Name: KCNE5
• Related Disease:
  Acute coronary syndrome
  Long QT syndrome
  Polymorphic ventricular tachycardia
  Brugada syndrome
  Atrial fibrillation
  Paroxysmal familial ventricular fibrillation
• UniProt ID: KCNE5_HUMAN
• Sequence:
  MNCSESQRLRTLLSRLLLELHHRGNASGLGAGPRPSMGMGVVPDPFVGREVTSAKGDDAY
  LYILLIMIFYACLAGGLILAYTRSRKLVEAKDEPSQACAEHEWAPGGALTADAEAAAGSQ
  AEGRRQLASEGLPALAQGAERV
• Function: Potassium channel ancillary subunit that is essential for generation of some native K(+) currents by virtue of formation of heteromeric ion channel complex with voltage-gated potassium (Kv) channel pore-forming alpha subunits. Functions as an inhibitory beta-subunit of the repolarizing cardiac potassium ion channel KCNQ1.
• Tissue Specificity: Highly expressed in heart, skeletal muscle, brain, spinal cord and placenta.
• Reactome Pathway:
  Phase 2 - plateau phase (R-HSA-5576893)
  Phase 3 - rapid repolarisation (R-HSA-5576890)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute coronary syndrome	DIS7DYEW	Strong	Genetic Variation	[1]
Long QT syndrome	DISMKWS3	Strong	Biomarker	[2]
Polymorphic ventricular tachycardia	DISCPO8T	Strong	Genetic Variation	[3]
Brugada syndrome	DISSGN0E	Disputed	Autosomal dominant	[4]
Atrial fibrillation	DIS15W6U	Limited	Genetic Variation	[3]
Paroxysmal familial ventricular fibrillation	DISRM7IX	Limited	Genetic Variation	[5]

2 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 Potassium voltage-gated channel subfamily E regulatory beta subunit 5 (KCNE5).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Potassium voltage-gated channel subfamily E regulatory beta subunit 5 (KCNE5).	[10]

3 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 Potassium voltage-gated channel subfamily E regulatory beta subunit 5 (KCNE5).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Potassium voltage-gated channel subfamily E regulatory beta subunit 5 (KCNE5).	[8]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Potassium voltage-gated channel subfamily E regulatory beta subunit 5 (KCNE5).	[9]

References

• [1] KCNE5 polymorphism rs697829 is associated with QT interval and survival in acute coronary syndromes patients.J Cardiovasc Electrophysiol. 2012 Mar;23(3):319-24. doi: 10.1111/j.1540-8167.2011.02192.x. Epub 2011 Oct 10.
• [2] Does KCNE5 play a role in long QT syndrome?.Clin Chim Acta. 2004 Jul;345(1-2):49-53. doi: 10.1016/j.cccn.2004.02.033.
• [3] Deletion in mice of X-linked, Brugada syndrome- and atrial fibrillation-associated Kcne5 augments ventricular K(V) currents and predisposes to ventricular arrhythmia.FASEB J. 2019 Feb;33(2):2537-2552. doi: 10.1096/fj.201800502R. Epub 2018 Oct 5.
• [4] 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.
• [5] KCNE5 (KCNE1L) variants are novel modulators of Brugada syndrome and idiopathic ventricular fibrillation.Circ Arrhythm Electrophysiol. 2011 Jun;4(3):352-61. doi: 10.1161/CIRCEP.110.959619. Epub 2011 Apr 14.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] 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.