Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIP2EYJ)

• DOT Name: Potassium-transporting ATPase subunit beta (ATP4B)
• Synonyms: Gastric H(+)/K(+) ATPase subunit beta; Proton pump beta chain
• Gene Name: ATP4B
• Related Disease:
  Neoplasm
  Pernicious anemia
  Coronary atherosclerosis
  Coronary heart disease
  Gastric cancer
  Gastritis
  Hepatocellular carcinoma
  Stomach cancer
  Obesity
• UniProt ID: ATP4B_HUMAN
• Pfam ID: PF00287
• Sequence:
  MAALQEKKTCGQRMEEFQRYCWNPDTGQMLGRTLSRWVWISLYYVAFYVVMTGLFALCLY
  VLMQTVDPYTPDYQDQLRSPGVTLRPDVYGEKGLEIVYNVSDNRTWADLTQTLHAFLAGY
  SPAAQEDSINCTSEQYFFQESFRAPNHTKFSCKFTADMLQNCSGLADPNFGFEEGKPCFI
  IKMNRIVKFLPSNGSAPRVDCAFLDQPRELGQPLQVKYYPPNGTFSLHYFPYYGKKAQPH
  YSNPLVAAKLLNIPRNAEVAIVCKVMAEHVTFNNPHDPYEGKVEFKLKIEK
• Function: The beta subunit of the gastric H(+)/K(+) ATPase pump which transports H(+) ions in exchange for K(+) ions across the apical membrane of parietal cells. Plays a structural and regulatory role in the assembly and membrane targeting of a functionally active pump. 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 of the alpha subunit that shifts the pump conformation from inward-facing (E1) to outward-facing state (E2). Interacts with the phosphorylation domain of the alpha subunit and functions as a ratchet, stabilizing the lumenal-open E2 conformation and preventing the reverse reaction of the transport cycle.
• 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:G66-33511-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Posttranslational Modification	[1]
Pernicious anemia	DISWV404	Strong	Biomarker	[2]
Coronary atherosclerosis	DISKNDYU	moderate	Biomarker	[3]
Coronary heart disease	DIS5OIP1	moderate	Biomarker	[3]
Gastric cancer	DISXGOUK	moderate	Biomarker	[4]
Gastritis	DIS8G07K	moderate	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[6]
Stomach cancer	DISKIJSX	moderate	Biomarker	[4]
Obesity	DIS47Y1K	Disputed	Therapeutic	[7]

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 subunit beta (ATP4B).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Potassium-transporting ATPase subunit beta (ATP4B).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Potassium-transporting ATPase subunit beta (ATP4B).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Potassium-transporting ATPase subunit beta (ATP4B).	[11]

References

• [1] Intragenic DNA methylation concomitant with repression of ATP4B and ATP4A gene expression in gastric cancer is a potential serum biomarker.Asian Pac J Cancer Prev. 2012;13(11):5563-8. doi: 10.7314/apjcp.2012.13.11.5563.
• [2] Measurement of Autoantibodies to Gastric H+,K+-ATPase (ATP4A/B) Using a Luciferase Immunoprecipitation System (LIPS).Methods Mol Biol. 2019;1901:113-131. doi: 10.1007/978-1-4939-8949-2_10.
• [3] Pharmacological effects of lipid-lowering drugs recapitulate with a larger amplitude the phenotypic effects of common variants within their target genes.Pharmacogenet Genomics. 2008 Dec;18(12):1051-7. doi: 10.1097/FPC.0b013e32831270eb.
• [4] Identification of significant biomarkers and pathways associated with gastric carcinogenesis by whole genome-wide expression profiling analysis.Int J Oncol. 2018 Mar;52(3):955-966. doi: 10.3892/ijo.2018.4243. Epub 2018 Jan 11.
• [5] Luminescent Immunoprecipitation System (LIPS) for Detection of Autoantibodies Against ATP4A and ATP4B Subunits of Gastric Proton Pump H+,K+-ATPase in Atrophic Body Gastritis Patients.Clin Transl Gastroenterol. 2017 Jan 19;8(1):e215. doi: 10.1038/ctg.2016.71.
• [6] Silencing of ATP4B of ATPase H(+)/K(+) Transporting Beta Subunit by Intragenic Epigenetic Alteration in Human Gastric Cancer Cells.Oncol Res. 2017 Mar 13;25(3):317-329. doi: 10.3727/096504016X14734735156265.
• [7] Remodeling of the residual gastric mucosa after roux-en-y gastric bypass or vertical sleeve gastrectomy in diet-induced obese rats.PLoS One. 2015 Mar 30;10(3):e0121414. doi: 10.1371/journal.pone.0121414. eCollection 2015.
• [8] 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.
• [9] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [10] 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.
• [11] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.