Details of Drug Off-Target (DOT)

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

• DOT Name: Potassium voltage-gated channel subfamily H member 5 (KCNH5)
• Synonyms: Ether-a-go-go potassium channel 2; hEAG2; Voltage-gated potassium channel subunit Kv10.2
• Gene Name: KCNH5
• Related Disease: Infantile-onset epilepsy
• UniProt ID: KCNH5_HUMAN
• PDB ID: 7YID; 7YIE; 7YIF; 7YIG; 7YIH; 7YIJ
• Pfam ID: PF00027 ; PF00520 ; PF13426
• Sequence:
  MPGGKRGLVAPQNTFLENIVRRSSESSFLLGNAQIVDWPVVYSNDGFCKLSGYHRADVMQ
  KSSTCSFMYGELTDKKTIEKVRQTFDNYESNCFEVLLYKKNRTPVWFYMQIAPIRNEHEK
  VVLFLCTFKDITLFKQPIEDDSTKGWTKFARLTRALTNSRSVLQQLTPMNKTEVVHKHSR
  LAEVLQLGSDILPQYKQEAPKTPPHIILHYCAFKTTWDWVILILTFYTAIMVPYNVSFKT
  KQNNIAWLVLDSVVDVIFLVDIVLNFHTTFVGPGGEVISDPKLIRMNYLKTWFVIDLLSC
  LPYDIINAFENVDEGISSLFSSLKVVRLLRLGRVARKLDHYLEYGAAVLVLLVCVFGLVA
  HWLACIWYSIGDYEVIDEVTNTIQIDSWLYQLALSIGTPYRYNTSAGIWEGGPSKDSLYV
  SSLYFTMTSLTTIGFGNIAPTTDVEKMFSVAMMMVGSLLYATIFGNVTTIFQQMYANTNR
  YHEMLNNVRDFLKLYQVPKGLSERVMDYIVSTWSMSKGIDTEKVLSICPKDMRADICVHL
  NRKVFNEHPAFRLASDGCLRALAVEFQTIHCAPGDLIYHAGESVDALCFVVSGSLEVIQD
  DEVVAILGKGDVFGDIFWKETTLAHACANVRALTYCDLHIIKREALLKVLDFYTAFANSF
  SRNLTLTCNLRKRIIFRKISDVKKEEEERLRQKNEVTLSIPVDHPVRKLFQKFKQQKELR
  NQGSTQGDPERNQLQVESRSLQNGASITGTSVVTVSQITPIQTSLAYVKTSESLKQNNRD
  AMELKPNGGADQKCLKVNSPIRMKNGNGKGWLRLKNNMGAHEEKKEDWNNVTKAESMGLL
  SEDPKSSDSENSVTKNPLRKTDSCDSGITKSDLRLDKAGEARSPLEHSPIQADAKHPFYP
  IPEQALQTTLQEVKHELKEDIQLLSCRMTALEKQVAEILKILSEKSVPQASSPKSQMPLQ
  VPPQIPCQDIFSVSRPESPESDKDEIHF
• Function: Pore-forming (alpha) subunit of voltage-gated potassium channel. Elicits a non-inactivating outward rectifying current. Channel properties may be modulated by cAMP and subunit assembly.
• Tissue Specificity: Detected in brain, skeletal muscle, heart, placenta, lung and liver, and at low levels in kidney.
• Reactome Pathway: Voltage gated Potassium channels (R-HSA-1296072)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Infantile-onset epilepsy	DISPMANQ	Definitive	Autosomal dominant	[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 Potassium voltage-gated channel subfamily H member 5 (KCNH5).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Potassium voltage-gated channel subfamily H member 5 (KCNH5).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Potassium voltage-gated channel subfamily H member 5 (KCNH5).	[4]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Potassium voltage-gated channel subfamily H member 5 (KCNH5).	[5]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Potassium voltage-gated channel subfamily H member 5 (KCNH5).	[6]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Potassium voltage-gated channel subfamily H member 5 (KCNH5).	[7]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Potassium voltage-gated channel subfamily H member 5 (KCNH5).	[9]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Potassium voltage-gated channel subfamily H member 5 (KCNH5).	[10]

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 increases the methylation of Potassium voltage-gated channel subfamily H member 5 (KCNH5).	[8]

References

• [1] 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.
• [2] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [3] 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.
• [4] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [5] 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.
• [6] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [7] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [8] 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.
• [9] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [10] 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.