Details of Drug Off-Target (DOT)

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

• DOT Name: ATP-sensitive inward rectifier potassium channel 11 (KCNJ11)
• Synonyms: IKATP; Inward rectifier K(+) channel Kir6.2; Potassium channel, inwardly rectifying subfamily J member 11
• Gene Name: KCNJ11
• Related Disease:
  Diabetes mellitus, transient neonatal, 3
  Hyperinsulinemic hypoglycemia, familial, 2
  Monogenic diabetes
  Diabetes mellitus, permanent neonatal 2
  Maturity-onset diabetes of the young type 13
  Obsolete diabetes mellitus, noninsulin-dependent
  Autosomal dominant hyperinsulinism due to Kir6.2 deficiency
  Autosomal recessive hyperinsulinism due to Kir6.2 deficiency
  DEND syndrome
  Diazoxide-resistant focal hyperinsulinism due to Kir6.2 deficiency
  Intermediate DEND syndrome
  Maturity-onset diabetes of the young
  Permanent neonatal diabetes mellitus
  Transient neonatal diabetes mellitus
• UniProt ID: KCJ11_HUMAN
• PDB ID: 6C3O; 6C3P; 7S5T; 7S5X; 7S5Y; 7S5Z; 7S60; 7S61
• Pfam ID: PF01007 ; PF17655
• Sequence:
  MLSRKGIIPEEYVLTRLAEDPAKPRYRARQRRARFVSKKGNCNVAHKNIREQGRFLQDVF
  TTLVDLKWPHTLLIFTMSFLCSWLLFAMAWWLIAFAHGDLAPSEGTAEPCVTSIHSFSSA
  FLFSIEVQVTIGFGGRMVTEECPLAILILIVQNIVGLMINAIMLGCIFMKTAQAHRRAET
  LIFSKHAVIALRHGRLCFMLRVGDLRKSMIISATIHMQVVRKTTSPEGEVVPLHQVDIPM
  ENGVGGNSIFLVAPLIIYHVIDANSPLYDLAPSDLHHHQDLEIIVILEGVVETTGITTQA
  RTSYLADEILWGQRFVPIVAEEDGRYSVDYSKFGNTVKVPTPLCTARQLDEDHSLLEALT
  LASARGPLRKRSVPMAKAKPKFSISPDSLS
• Function: This receptor is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by extracellular barium. Subunit of ATP-sensitive potassium channels (KATP). Can form cardiac and smooth muscle-type KATP channels with ABCC9. KCNJ11 forms the channel pore while ABCC9 is required for activation and regulation.
• KEGG Pathway:
  Insulin secretion (hsa04911)
  GnRH secretion (hsa04929)
  Type II diabetes mellitus (hsa04930)
• Reactome Pathway:
  ABC-family proteins mediated transport (R-HSA-382556)
  Regulation of insulin secretion (R-HSA-422356)
  Ion homeostasis (R-HSA-5578775)
  Defective ABCC9 causes CMD10, ATFB12 and Cantu syndrome (R-HSA-5678420)
  Defective ABCC8 can cause hypo- and hyper-glycemias (R-HSA-5683177)
  ATP sensitive Potassium channels (R-HSA-1296025)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Diabetes mellitus, transient neonatal, 3	DIS291OS	Definitive	Autosomal dominant	[1]
Hyperinsulinemic hypoglycemia, familial, 2	DIS5DEVG	Definitive	Autosomal recessive	[2]
Monogenic diabetes	DISEB8Q0	Definitive	Autosomal dominant	[2]
Diabetes mellitus, permanent neonatal 2	DISTGFQ7	Strong	Autosomal dominant	[3]
Maturity-onset diabetes of the young type 13	DISN6PZR	Strong	Autosomal dominant	[3]
Obsolete diabetes mellitus, noninsulin-dependent	DISS46MZ	Strong	Autosomal dominant	[3]
Autosomal dominant hyperinsulinism due to Kir6.2 deficiency	DISLXSXT	Supportive	Autosomal dominant	[4]
Autosomal recessive hyperinsulinism due to Kir6.2 deficiency	DIS4XHXN	Supportive	Autosomal recessive	[1]
DEND syndrome	DISRNWGB	Supportive	Autosomal dominant	[5]
Diazoxide-resistant focal hyperinsulinism due to Kir6.2 deficiency	DISM0NJG	Supportive	Autosomal recessive	[6]
Intermediate DEND syndrome	DISCHN6V	Supportive	Autosomal dominant	[7]
Maturity-onset diabetes of the young	DISG75M5	Supportive	Autosomal dominant	[8]
Permanent neonatal diabetes mellitus	DIS5AEXS	Supportive	Autosomal dominant	[9]
Transient neonatal diabetes mellitus	DIST826V	Supportive	Autosomal dominant	[9]

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 ATP-sensitive inward rectifier potassium channel 11 (KCNJ11).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of ATP-sensitive inward rectifier potassium channel 11 (KCNJ11).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ATP-sensitive inward rectifier potassium channel 11 (KCNJ11).	[11]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of ATP-sensitive inward rectifier potassium channel 11 (KCNJ11).	[12]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of ATP-sensitive inward rectifier potassium channel 11 (KCNJ11).	[13]
Tolbutamide	DM02AWV	Approved	Tolbutamide decreases the activity of ATP-sensitive inward rectifier potassium channel 11 (KCNJ11).	[14]
Diazoxide	DML1538	Approved	Diazoxide decreases the expression of ATP-sensitive inward rectifier potassium channel 11 (KCNJ11).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of ATP-sensitive inward rectifier potassium channel 11 (KCNJ11).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of ATP-sensitive inward rectifier potassium channel 11 (KCNJ11).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of ATP-sensitive inward rectifier potassium channel 11 (KCNJ11).	[19]

References

• [1] Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Hum Mol Genet. 1996 Nov;5(11):1809-12. doi: 10.1093/hmg/5.11.1809.
• [2] 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.
• [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] Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations. J Clin Invest. 2008 Aug;118(8):2877-86. doi: 10.1172/JCI35414.
• [5] The lessons of early-onset monogenic diabetes for the understanding of diabetes pathogenesis. Best Pract Res Clin Endocrinol Metab. 2012 Apr;26(2):171-87. doi: 10.1016/j.beem.2011.12.001.
• [6] Congenital hyperinsulinism: current trends in diagnosis and therapy. Orphanet J Rare Dis. 2011 Oct 3;6:63. doi: 10.1186/1750-1172-6-63.
• [7] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [8] Whole-exome sequencing and high throughput genotyping identified KCNJ11 as the thirteenth MODY gene. PLoS One. 2012;7(6):e37423. doi: 10.1371/journal.pone.0037423. Epub 2012 Jun 11.
• [9] Review on monogenic diabetes. Curr Opin Endocrinol Diabetes Obes. 2011 Aug;18(4):252-8. doi: 10.1097/MED.0b013e3283488275.
• [10] 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.
• [11] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] 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.
• [14] Increased ATPase activity produced by mutations at arginine-1380 in nucleotide-binding domain 2 of ABCC8 causes neonatal diabetes. Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):18988-92. doi: 10.1073/pnas.0707428104. Epub 2007 Nov 19.
• [15] Combined contributions of over-secreted glucagon-like peptide 1 and suppressed insulin secretion to hyperglycemia induced by gatifloxacin in rats. Toxicol Appl Pharmacol. 2013 Feb 1;266(3):375-84. doi: 10.1016/j.taap.2012.11.015. Epub 2012 Nov 28.
• [16] 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.
• [17] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [18] 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.
• [19] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.