Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT25GJE9)

• DOT Name: Voltage-gated potassium channel subunit beta-1 (KCNAB1)
• Synonyms: EC 1.1.1.-; K(+) channel subunit beta-1; Kv-beta-1
• Gene Name: KCNAB1
• Related Disease:
  Early-onset non-syndromic cataract
  Epilepsy
  Focal epilepsy
  Infantile epileptic-dyskinetic encephalopathy
  Acute myelogenous leukaemia
  Coronary heart disease
  High blood pressure
• UniProt ID: KCAB1_HUMAN
• EC Number: 1.1.1.-
• Pfam ID: PF00248
• Sequence:
  MLAARTGAAGSQISEENTKLRRQSGFSVAGKDKSPKKASENAKDSSLSPSGESQLRARQL
  ALLREVEMNWYLKLCDLSSEHTTVCTTGMPHRNLGKSGLRVSCLGLGTWVTFGGQISDEV
  AERLMTIAYESGVNLFDTAEVYAAGKAEVILGSIIKKKGWRRSSLVITTKLYWGGKAETE
  RGLSRKHIIEGLKGSLQRLQLEYVDVVFANRPDSNTPMEEIVRAMTHVINQGMAMYWGTS
  RWSAMEIMEAYSVARQFNMIPPVCEQAEYHLFQREKVEVQLPELYHKIGVGAMTWSPLAC
  GIISGKYGNGVPESSRASLKCYQWLKERIVSEEGRKQQNKLKDLSPIAERLGCTLPQLAV
  AWCLRNEGVSSVLLGSSTPEQLIENLGAIQVLPKMTSHVVNEIDNILRNKPYSKKDYRS
• Function: Cytoplasmic potassium channel subunit that modulates the characteristics of the channel-forming alpha-subunits. Modulates action potentials via its effect on the pore-forming alpha subunits. Promotes expression of the pore-forming alpha subunits at the cell membrane, and thereby increases channel activity. Mediates closure of delayed rectifier potassium channels by physically obstructing the pore via its N-terminal domain and increases the speed of channel closure for other family members. Promotes the closure of KCNA1, KCNA2 and KCNA5 channels. Accelerates KCNA4 channel closure. Accelerates the closure of heteromeric channels formed by KCNA1 and KCNA4. Accelerates the closure of heteromeric channels formed by KCNA2, KCNA5 and KCNA6. Isoform KvB1.2 has no effect on KCNA1, KCNA2 or KCNB1. Enhances KCNB1 and KCNB2 channel activity. Binds NADPH; this is required for efficient down-regulation of potassium channel activity. Has NADPH-dependent aldoketoreductase activity. Oxidation of the bound NADPH strongly decreases N-type inactivation of potassium channel activity.
• Tissue Specificity: In brain, expression is most prominent in caudate nucleus, hippocampus and thalamus. Significant expression also detected in amygdala and subthalamic nucleus. Also expressed in both healthy and cardiomyopathic heart. Up to four times more abundant in left ventricle than left atrium.
• Reactome Pathway: Voltage gated Potassium channels (R-HSA-1296072)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Early-onset non-syndromic cataract	DIS4VPS0	Strong	Genetic Variation	[1]
Epilepsy	DISBB28L	Strong	Genetic Variation	[2]
Focal epilepsy	DIS4LY5L	Strong	Biomarker	[3]
Infantile epileptic-dyskinetic encephalopathy	DISD2ZNC	Strong	Genetic Variation	[2]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[4]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[5]
High blood pressure	DISY2OHH	Limited	Biomarker	[6]

5 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 Voltage-gated potassium channel subunit beta-1 (KCNAB1).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Voltage-gated potassium channel subunit beta-1 (KCNAB1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Voltage-gated potassium channel subunit beta-1 (KCNAB1).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Voltage-gated potassium channel subunit beta-1 (KCNAB1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Voltage-gated potassium channel subunit beta-1 (KCNAB1).	[11]

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 Voltage-gated potassium channel subunit beta-1 (KCNAB1).	[12]

References

• [1] Meta-analysis of genome-wide association studies in multiethnic Asians identifies two loci for age-related nuclear cataract.Hum Mol Genet. 2014 Nov 15;23(22):6119-28. doi: 10.1093/hmg/ddu315. Epub 2014 Jun 20.
• [2] Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.PLoS One. 2015 Nov 6;10(11):e0141782. doi: 10.1371/journal.pone.0141782. eCollection 2015.
• [3] Association of intronic variants of the KCNAB1 gene with lateral temporal epilepsy.Epilepsy Res. 2011 Mar;94(1-2):110-6. doi: 10.1016/j.eplepsyres.2011.01.010. Epub 2011 Feb 18.
• [4] 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.
• [5] A genome-wide association study reveals susceptibility loci for myocardial infarction/coronary artery disease in Saudi Arabs.Atherosclerosis. 2016 Feb;245:62-70. doi: 10.1016/j.atherosclerosis.2015.11.019. Epub 2015 Nov 22.
• [6] Differential expression of voltage-gated K(+) channel genes in arteries from spontaneously hypertensive and Wistar-Kyoto rats.Hypertension. 2001 May;37(5):1315-22. doi: 10.1161/01.hyp.37.5.1315.
• [7] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [8] 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.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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.
• [11] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [12] 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.