Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9PLMBH)

• DOT Name: Sodium/potassium-transporting ATPase subunit alpha-4 (ATP1A4)
• Synonyms: Na(+)/K(+) ATPase alpha-4 subunit; EC 7.2.2.13; Sodium pump subunit alpha-4
• Gene Name: ATP1A4
• Related Disease:
  Familial hemiplegic migraine
  Migraine, familial hemiplegic, 1
  Seminoma
  Gout
• UniProt ID: AT1A4_HUMAN
• EC Number: 7.2.2.13
• Pfam ID: PF13246 ; PF00689 ; PF00690 ; PF00122 ; PF00702
• Sequence:
  MGLWGKKGTVAPHDQSPRRRPKKGLIKKKMVKREKQKRNMEELKKEVVMDDHKLTLEELS
  TKYSVDLTKGHSHQRAKEILTRGGPNTVTPPPTTPEWVKFCKQLFGGFSLLLWTGAILCF
  VAYSIQIYFNEEPTKDNLYLSIVLSVVVIVTGCFSYYQEAKSSKIMESFKNMVPQQALVI
  RGGEKMQINVQEVVLGDLVEIKGGDRVPADLRLISAQGCKVDNSSLTGESEPQSRSPDFT
  HENPLETRNICFFSTNCVEGTARGIVIATGDSTVMGRIASLTSGLAVGQTPIAAEIEHFI
  HLITVVAVFLGVTFFALSLLLGYGWLEAIIFLIGIIVANVPEGLLATVTVCLTLTAKRMA
  RKNCLVKNLEAVETLGSTSTICSDKTGTLTQNRMTVAHMWFDMTVYEADTTEEQTGKTFT
  KSSDTWFMLARIAGLCNRADFKANQEILPIAKRATTGDASESALLKFIEQSYSSVAEMRE
  KNPKVAEIPFNSTNKYQMSIHLREDSSQTHVLMMKGAPERILEFCSTFLLNGQEYSMNDE
  MKEAFQNAYLELGGLGERVLGFCFLNLPSSFSKGFPFNTDEINFPMDNLCFVGLISMIDP
  PRAAVPDAVSKCRSAGIKVIMVTGDHPITAKAIAKGVGIISEGTETAEEVAARLKIPISK
  VDASAAKAIVVHGAELKDIQSKQLDQILQNHPEIVFARTSPQQKLIIVEGCQRLGAVVAV
  TGDGVNDSPALKKADIGIAMGISGSDVSKQAADMILLDDNFASIVTGVEEGRLIFDNLKK
  SIMYTLTSNIPEITPFLMFIILGIPLPLGTITILCIDLGTDMVPAISLAYESAESDIMKR
  LPRNPKTDNLVNHRLIGMAYGQIGMIQALAGFFTYFVILAENGFRPVDLLGIRLHWEDKY
  LNDLEDSYGQQWTYEQRKVVEFTCQTAFFVTIVVVQWADLIISKTRRNSLFQQGMRNKVL
  IFGILEETLLAAFLSYTPGMDVALRMYPLKITWWLCAIPYSILIFVYDEIRKLLIRQHPD
  GWVERETYY
• 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. Plays a role in sperm motility.
• Tissue Specificity: Specifically expressed in testis. Found in very low levels in skeletal muscle. Expressed in mature sperm (at protein level).
• 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

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial hemiplegic migraine	DISYVMKL	Strong	Genetic Variation	[1]
Migraine, familial hemiplegic, 1	DISF1GUO	Strong	Genetic Variation	[1]
Seminoma	DIS3J8LJ	Strong	Altered Expression	[2]
Gout	DISHC0U7	Limited	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Sodium/potassium-transporting ATPase subunit alpha-4 (ATP1A4).	[4]

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-4 (ATP1A4).	[5]

References

• [1] Physical mapping and characterization of the human Na,K-ATPase isoform, ATP1A4.Gene. 2002 Jun 12;292(1-2):151-66. doi: 10.1016/s0378-1119(02)00647-9.
• [2] Reduced semen quality in patients with testicular cancer seminoma is associated with alterations in the expression of sperm proteins.Asian J Androl. 2020 Jan-Feb;22(1):88-93. doi: 10.4103/aja.aja_17_19.
• [3] Gout and type 2 diabetes have a mutual inter-dependent effect on genetic risk factors and higher incidences.Rheumatology (Oxford). 2012 Apr;51(4):715-20. doi: 10.1093/rheumatology/ker373. Epub 2011 Dec 16.
• [4] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [5] 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.