Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCF8OWW)

• DOT Name: Sodium/potassium-transporting ATPase subunit alpha-2 (ATP1A2)
• Synonyms: Na(+)/K(+) ATPase alpha-2 subunit; EC 7.2.2.13; Sodium pump subunit alpha-2
• Gene Name: ATP1A2
• Related Disease:
  Hemiplegic migraine-developmental and epileptic encephalopathy spectrum
  Migraine, familial hemiplegic, 2
  Alternating hemiplegia of childhood 1
  Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies
  Alternating hemiplegia of childhood
  Familial or sporadic hemiplegic migraine
• UniProt ID: AT1A2_HUMAN
• EC Number: 7.2.2.13
• Pfam ID: PF13246 ; PF00689 ; PF00690 ; PF00122 ; PF00702
• Sequence:
  MGRGAGREYSPAATTAENGGGKKKQKEKELDELKKEVAMDDHKLSLDELGRKYQVDLSKG
  LTNQRAQDVLARDGPNALTPPPTTPEWVKFCRQLFGGFSILLWIGAILCFLAYGIQAAME
  DEPSNDNLYLGVVLAAVVIVTGCFSYYQEAKSSKIMDSFKNMVPQQALVIREGEKMQINA
  EEVVVGDLVEVKGGDRVPADLRIISSHGCKVDNSSLTGESEPQTRSPEFTHENPLETRNI
  CFFSTNCVEGTARGIVIATGDRTVMGRIATLASGLEVGRTPIAMEIEHFIQLITGVAVFL
  GVSFFVLSLILGYSWLEAVIFLIGIIVANVPEGLLATVTVCLTLTAKRMARKNCLVKNLE
  AVETLGSTSTICSDKTGTLTQNRMTVAHMWFDNQIHEADTTEDQSGATFDKRSPTWTALS
  RIAGLCNRAVFKAGQENISVSKRDTAGDASESALLKCIELSCGSVRKMRDRNPKVAEIPF
  NSTNKYQLSIHEREDSPQSHVLVMKGAPERILDRCSTILVQGKEIPLDKEMQDAFQNAYM
  ELGGLGERVLGFCQLNLPSGKFPRGFKFDTDELNFPTEKLCFVGLMSMIDPPRAAVPDAV
  GKCRSAGIKVIMVTGDHPITAKAIAKGVGIISEGNETVEDIAARLNIPMSQVNPREAKAC
  VVHGSDLKDMTSEQLDEILKNHTEIVFARTSPQQKLIIVEGCQRQGAIVAVTGDGVNDSP
  ALKKADIGIAMGISGSDVSKQAADMILLDDNFASIVTGVEEGRLIFDNLKKSIAYTLTSN
  IPEITPFLLFIIANIPLPLGTVTILCIDLGTDMVPAISLAYEAAESDIMKRQPRNSQTDK
  LVNERLISMAYGQIGMIQALGGFFTYFVILAENGFLPSRLLGIRLDWDDRTMNDLEDSYG
  QEWTYEQRKVVEFTCHTAFFASIVVVQWADLIICKTRRNSVFQQGMKNKILIFGLLEETA
  LAAFLSYCPGMGVALRMYPLKVTWWFCAFPYSLLIFIYDEVRKLILRRYPGGWVEKETYY
• Function: This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action creates the electrochemical gradient of sodium and potassium, providing the energy for active transport of various nutrients.
• KEGG Pathway:
  cGMP-PKG sig.ling pathway (hsa04022)
  cAMP sig.ling pathway (hsa04024)
  Cardiac muscle contraction (hsa04260)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Cytoskeleton in muscle cells (hsa04820)
  Insulin secretion (hsa04911)
  Thyroid hormone synthesis (hsa04918)
  Thyroid hormone sig.ling pathway (hsa04919)
  Aldosterone synthesis and secretion (hsa04925)
  Aldosterone-regulated sodium reabsorption (hsa04960)
  Endocrine and other factor-regulated calcium reabsorption (hsa04961)
  Proximal tubule bicarbo.te reclamation (hsa04964)
  Salivary secretion (hsa04970)
  Gastric acid secretion (hsa04971)
  Pancreatic secretion (hsa04972)
  Carbohydrate digestion and absorption (hsa04973)
  Protein digestion and absorption (hsa04974)
  Bile secretion (hsa04976)
  Mineral absorption (hsa04978)
• Reactome Pathway:
  Ion transport by P-type ATPases (R-HSA-936837)
  Potential therapeutics for SARS (R-HSA-9679191)
  Ion homeostasis (R-HSA-5578775)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hemiplegic migraine-developmental and epileptic encephalopathy spectrum	DISQN0K9	Definitive	Autosomal dominant	[1]
Migraine, familial hemiplegic, 2	DISJPXBR	Definitive	Autosomal dominant	[2]
Alternating hemiplegia of childhood 1	DISD5VAX	Strong	Autosomal dominant	[3]
Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies	DIS28C6I	Strong	Autosomal recessive	[4]
Alternating hemiplegia of childhood	DISB31JE	Supportive	Autosomal dominant	[5]
Familial or sporadic hemiplegic migraine	DISOSL2O	Supportive	Autosomal dominant	[6]

21 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 Sodium/potassium-transporting ATPase subunit alpha-2 (ATP1A2).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sodium/potassium-transporting ATPase subunit alpha-2 (ATP1A2).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sodium/potassium-transporting ATPase subunit alpha-2 (ATP1A2).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sodium/potassium-transporting ATPase subunit alpha-2 (ATP1A2).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sodium/potassium-transporting ATPase subunit alpha-2 (ATP1A2).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Sodium/potassium-transporting ATPase subunit alpha-2 (ATP1A2).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Sodium/potassium-transporting ATPase subunit alpha-2 (ATP1A2).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Sodium/potassium-transporting ATPase subunit alpha-2 (ATP1A2).	[14]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Sodium/potassium-transporting ATPase subunit alpha-2 (ATP1A2).	[14]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Sodium/potassium-transporting ATPase subunit alpha-2 (ATP1A2).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Sodium/potassium-transporting ATPase subunit alpha-2 (ATP1A2).	[16]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Sodium/potassium-transporting ATPase subunit alpha-2 (ATP1A2).	[12]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Sodium/potassium-transporting ATPase subunit alpha-2 (ATP1A2).	[17]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Sodium/potassium-transporting ATPase subunit alpha-2 (ATP1A2).	[18]
Mitoxantrone	DMM39BF	Approved	Mitoxantrone decreases the expression of Sodium/potassium-transporting ATPase subunit alpha-2 (ATP1A2).	[10]
Daunorubicin	DMQUSBT	Approved	Daunorubicin decreases the expression of Sodium/potassium-transporting ATPase subunit alpha-2 (ATP1A2).	[10]
Acocantherin	DM7JT24	Approved	Acocantherin increases the expression of Sodium/potassium-transporting ATPase subunit alpha-2 (ATP1A2).	[19]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Sodium/potassium-transporting ATPase subunit alpha-2 (ATP1A2).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Sodium/potassium-transporting ATPase subunit alpha-2 (ATP1A2).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Sodium/potassium-transporting ATPase subunit alpha-2 (ATP1A2).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Sodium/potassium-transporting ATPase subunit alpha-2 (ATP1A2).	[24]

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 Sodium/potassium-transporting ATPase subunit alpha-2 (ATP1A2).	[21]

References

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• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
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• [4] Degeneration of the amygdala/piriform cortex and enhanced fear/anxiety behaviors in sodium pump alpha2 subunit (Atp1a2)-deficient mice. J Neurosci. 2003 Jun 1;23(11):4667-76. doi: 10.1523/JNEUROSCI.23-11-04667.2003.
• [5] A novel mutation in the ATP1A2 gene causes alternating hemiplegia of childhood. J Med Genet. 2004 Aug;41(8):621-8. doi: 10.1136/jmg.2003.017863.
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• [10] Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment. Arch Toxicol. 2016 Nov;90(11):2763-2777.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
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• [19] Response of sodium pump to ouabain challenge in human glioblastoma cells in culture. World J Biol Psychiatry. 2009;10(4 Pt 3):884-92. doi: 10.1080/15622970902995620.
• [20] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [21] 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.
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• [24] 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.