Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCJ458Q)

• DOT Name: Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1)
• Synonyms: Na(+)/K(+) ATPase alpha-1 subunit; EC 7.2.2.13; Sodium pump subunit alpha-1
• Gene Name: ATP1A1
• Related Disease:
  Charcot-marie-tooth disease, axonal, type 2DD
  Hypomagnesemia, seizures, and intellectual disability 2
• UniProt ID: AT1A1_HUMAN
• PDB ID: 7E1Z; 7E20; 7E21
• EC Number: 7.2.2.13
• Pfam ID: PF13246 ; PF00689 ; PF00690 ; PF00122
• Sequence:
  MGKGVGRDKYEPAAVSEQGDKKGKKGKKDRDMDELKKEVSMDDHKLSLDELHRKYGTDLS
  RGLTSARAAEILARDGPNALTPPPTTPEWIKFCRQLFGGFSMLLWIGAILCFLAYSIQAA
  TEEEPQNDNLYLGVVLSAVVIITGCFSYYQEAKSSKIMESFKNMVPQQALVIRNGEKMSI
  NAEEVVVGDLVEVKGGDRIPADLRIISANGCKVDNSSLTGESEPQTRSPDFTNENPLETR
  NIAFFSTNCVEGTARGIVVYTGDRTVMGRIATLASGLEGGQTPIAAEIEHFIHIITGVAV
  FLGVSFFILSLILEYTWLEAVIFLIGIIVANVPEGLLATVTVCLTLTAKRMARKNCLVKN
  LEAVETLGSTSTICSDKTGTLTQNRMTVAHMWFDNQIHEADTTENQSGVSFDKTSATWLA
  LSRIAGLCNRAVFQANQENLPILKRAVAGDASESALLKCIELCCGSVKEMRERYAKIVEI
  PFNSTNKYQLSIHKNPNTSEPQHLLVMKGAPERILDRCSSILLHGKEQPLDEELKDAFQN
  AYLELGGLGERVLGFCHLFLPDEQFPEGFQFDTDDVNFPIDNLCFVGLISMIDPPRAAVP
  DAVGKCRSAGIKVIMVTGDHPITAKAIAKGVGIISEGNETVEDIAARLNIPVSQVNPRDA
  KACVVHGSDLKDMTSEQLDDILKYHTEIVFARTSPQQKLIIVEGCQRQGAIVAVTGDGVN
  DSPALKKADIGVAMGIAGSDVSKQAADMILLDDNFASIVTGVEEGRLIFDNLKKSIAYTL
  TSNIPEITPFLIFIIANIPLPLGTVTILCIDLGTDMVPAISLAYEQAESDIMKRQPRNPK
  TDKLVNERLISMAYGQIGMIQALGGFFTYFVILAENGFLPIHLLGLRVDWDDRWINDVED
  SYGQQWTYEQRKIVEFTCHTAFFVSIVVVQWADLVICKTRRNSVFQQGMKNKILIFGLFE
  ETALAAFLSYCPGMGVALRMYPLKPTWWFCAFPYSLLIFVYDEVRKLIIRRRPGGWVEKE
  TYY
• 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 ions, providing the energy for active transport of various nutrients. Could also be part of an osmosensory signaling pathway that senses body-fluid sodium levels and controls salt intake behavior as well as voluntary water intake to regulate sodium homeostasis.
• 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

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Charcot-marie-tooth disease, axonal, type 2DD	DISA3DZK	Strong	Autosomal dominant	[1]
Hypomagnesemia, seizures, and intellectual disability 2	DISX3DXD	Strong	Autosomal dominant	[2]

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1) affects the response to substance of Etoposide.	[21]
Mitomycin	DMH0ZJE	Approved	Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1) affects the response to substance of Mitomycin.	[21]
Gentamicin	DMKINJO	Approved	Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1) increases the Necrosis ADR of Gentamicin.	[22]
Reserpine	DM6VM38	Approved	Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1) increases the Flushing ADR of Reserpine.	[22]
Digoxin	DMQCTIH	Approved	Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1) increases the Iron and trace metal metabolism disorders ADR of Digoxin.	[22]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1).	[16]

15 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 Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1).	[10]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1).	[11]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1).	[12]
Chloroquine	DMSI5CB	Phase 3 Trial	Chloroquine increases the expression of Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1).	[13]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1).	[18]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1).	[19]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1).	[20]

References

• [1] Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2. Am J Hum Genet. 2018 Mar 1;102(3):505-514. doi: 10.1016/j.ajhg.2018.01.023.
• [2] Germline De Novo Mutations in ATP1A1 Cause Renal Hypomagnesemia, Refractory Seizures, and Intellectual Disability. Am J Hum Genet. 2018 Nov 1;103(5):808-816. doi: 10.1016/j.ajhg.2018.10.004.
• [3] 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.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] 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.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [11] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [12] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [13] Downregulation of Organic Anion Transporting Polypeptide (OATP) 1B1 Transport Function by Lysosomotropic Drug Chloroquine: Implication in OATP-Mediated Drug-Drug Interactions. Mol Pharm. 2016 Mar 7;13(3):839-51. doi: 10.1021/acs.molpharmaceut.5b00763. Epub 2016 Feb 1.
• [14] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [15] 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.
• [16] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [17] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [20] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.
• [21] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [22] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.