Details of Drug Off-Target (DOT)

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

• DOT Name: Potassium-transporting ATPase alpha chain 1 (ATP4A)
• Synonyms: EC 7.2.2.19; Gastric H(+)/K(+) ATPase subunit alpha; Proton pump
• Gene Name: ATP4A
• Related Disease:
  Familial gastric type 1 neuroendocrine tumor
  Gastric neuroendocrine neoplasm
• UniProt ID: ATP4A_HUMAN
• EC Number: 7.2.2.19
• Pfam ID: PF13246 ; PF00689 ; PF00690 ; PF00122 ; PF09040 ; PF00702
• Sequence:
  MGKAENYELYSVELGPGPGGDMAAKMSKKKKAGGGGGKRKEKLENMKKEMEINDHQLSVA
  ELEQKYQTSATKGLSASLAAELLLRDGPNALRPPRGTPEYVKFARQLAGGLQCLMWVAAA
  ICLIAFAIQASEGDLTTDDNLYLAIALIAVVVVTGCFGYYQEFKSTNIIASFKNLVPQQA
  TVIRDGDKFQINADQLVVGDLVEMKGGDRVPADIRILAAQGCKVDNSSLTGESEPQTRSP
  ECTHESPLETRNIAFFSTMCLEGTVQGLVVNTGDRTIIGRIASLASGVENEKTPIAIEIE
  HFVDIIAGLAILFGATFFIVAMCIGYTFLRAMVFFMAIVVAYVPEGLLATVTVCLSLTAK
  RLASKNCVVKNLEAVETLGSTSVICSDKTGTLTQNRMTVSHLWFDNHIHTADTTEDQSGQ
  TFDQSSETWRALCRVLTLCNRAAFKSGQDAVPVPKRIVIGDASETALLKFSELTLGNAMG
  YRDRFPKVCEIPFNSTNKFQLSIHTLEDPRDPRHLLVMKGAPERVLERCSSILIKGQELP
  LDEQWREAFQTAYLSLGGLGERVLGFCQLYLNEKDYPPGYAFDVEAMNFPSSGLCFAGLV
  SMIDPPRATVPDAVLKCRTAGIRVIMVTGDHPITAKAIAASVGIISEGSETVEDIAARLR
  VPVDQVNRKDARACVINGMQLKDMDPSELVEALRTHPEMVFARTSPQQKLVIVESCQRLG
  AIVAVTGDGVNDSPALKKADIGVAMGIAGSDAAKNAADMILLDDNFASIVTGVEQGRLIF
  DNLKKSIAYTLTKNIPELTPYLIYITVSVPLPLGCITILFIELCTDIFPSVSLAYEKAES
  DIMHLRPRNPKRDRLVNEPLAAYSYFQIGAIQSFAGFTDYFTAMAQEGWFPLLCVGLRAQ
  WEDHHLQDLQDSYGQEWTFGQRLYQQYTCYTVFFISIEVCQIADVLIRKTRRLSAFQQGF
  FRNKILVIAIVFQVCIGCFLCYCPGMPNIFNFMPIRFQWWLVPLPYGILIFVYDEIRKLG
  VRCCPGSWWDQELYY
• Function: The catalytic subunit of the gastric H(+)/K(+) ATPase pump which transports H(+) ions in exchange for K(+) ions across the apical membrane of parietal cells. Uses ATP as an energy source to pump H(+) ions to the gastric lumen while transporting K(+) ion from the lumen into the cell. Remarkably generates a million-fold proton gradient across the gastric parietal cell membrane, acidifying the gastric juice down to pH 1. Within a transport cycle, the transfer of a H(+) ion across the membrane is coupled to ATP hydrolysis and is associated with a transient phosphorylation that shifts the pump conformation from inward-facing (E1) to outward-facing state (E2). The release of the H(+) ion in the stomach lumen is followed by binding of K(+) ion converting the pump conformation back to the E1 state.
• Tissue Specificity: Expressed in gastric parietal cells (at protein level).
• KEGG Pathway:
  Oxidative phosphorylation (hsa00190)
  Metabolic pathways (hsa01100)
  Collecting duct acid secretion (hsa04966)
  Gastric acid secretion (hsa04971)
• Reactome Pathway: Ion transport by P-type ATPases (R-HSA-936837)
• BioCyc Pathway: MetaCyc:HS02790-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial gastric type 1 neuroendocrine tumor	DIS38WS1	Supportive	Autosomal recessive	[1]
Gastric neuroendocrine neoplasm	DISQBSKS	Limited	Autosomal recessive	[2]

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 Potassium-transporting ATPase alpha chain 1 (ATP4A).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Potassium-transporting ATPase alpha chain 1 (ATP4A).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of Potassium-transporting ATPase alpha chain 1 (ATP4A).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Potassium-transporting ATPase alpha chain 1 (ATP4A).	[5]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Potassium-transporting ATPase alpha chain 1 (ATP4A).	[7]

References

• [1] Exome sequencing identifies ATP4A gene as responsible of an atypical familial type I gastric neuroendocrine tumour. Hum Mol Genet. 2015 May 15;24(10):2914-22. doi: 10.1093/hmg/ddv054. Epub 2015 Feb 11.
• [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.
• [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] Molecular characterization of a toxicological tipping point during human stem cell differentiation. Reprod Toxicol. 2020 Jan;91:1-13. doi: 10.1016/j.reprotox.2019.10.001. Epub 2019 Oct 7.
• [5] 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.
• [6] 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.
• [7] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.