Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT97BX21)

• DOT Name: Sodium/potassium-transporting ATPase subunit gamma (FXYD2)
• Synonyms: Na(+)/K(+) ATPase subunit gamma; FXYD domain-containing ion transport regulator 2; Sodium pump gamma chain
• Gene Name: FXYD2
• Related Disease: Renal hypomagnesemia 2
• UniProt ID: ATNG_HUMAN
• PDB ID: 2MKV; 7E1Z; 7E20; 7E21
• Pfam ID: PF02038
• Sequence:
  MTGLSMDGGGSPKGDVDPFYYDYETVRNGGLIFAGLAFIVGLLILLSRRFRCGGNKKRRQ
  INEDEP
• Function: May be involved in forming the receptor site for cardiac glycoside binding or may modulate the transport function of the sodium ATPase.
• Tissue Specificity: Expressed in the distal convoluted tubule in the kidney. Found on basolateral membranes of nephron epithelial cells.
• KEGG Pathway:
  cGMP-PKG sig.ling pathway (hsa04022)
  cAMP sig.ling pathway (hsa04024)
  Cardiac muscle contraction (hsa04260)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Insulin secretion (hsa04911)
  Thyroid hormone synthesis (hsa04918)
  Thyroid hormone sig.ling pathway (hsa04919)
  Aldosterone-regulated sodium reabsorption (hsa04960)
  Endocrine and other factor-regulated calcium reabsorption (hsa04961)
  Proximal tubule bicarbo.te reclamation (hsa04964)
  Salivary secretion (hsa04970)
  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

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Renal hypomagnesemia 2	DISAK1QC	Strong	Autosomal dominant	[1]

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
2-deoxyglucose	DMIAHVU	Approved	Sodium/potassium-transporting ATPase subunit gamma (FXYD2) increases the transport of 2-deoxyglucose.	[13]
Spermidine	DMVJNFI	Phase 3	Sodium/potassium-transporting ATPase subunit gamma (FXYD2) increases the transport of Spermidine.	[13]

1 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 Sodium/potassium-transporting ATPase subunit gamma (FXYD2).	[2]

10 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 gamma (FXYD2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Sodium/potassium-transporting ATPase subunit gamma (FXYD2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Sodium/potassium-transporting ATPase subunit gamma (FXYD2).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Sodium/potassium-transporting ATPase subunit gamma (FXYD2).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Sodium/potassium-transporting ATPase subunit gamma (FXYD2).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Sodium/potassium-transporting ATPase subunit gamma (FXYD2).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Sodium/potassium-transporting ATPase subunit gamma (FXYD2).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Sodium/potassium-transporting ATPase subunit gamma (FXYD2).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Sodium/potassium-transporting ATPase subunit gamma (FXYD2).	[11]
Manganese	DMKT129	Investigative	Manganese increases the expression of Sodium/potassium-transporting ATPase subunit gamma (FXYD2).	[12]

References

• [1] Dominant isolated renal magnesium loss is caused by misrouting of the Na(+),K(+)-ATPase gamma-subunit. Nat Genet. 2000 Nov;26(3):265-6. doi: 10.1038/81543.
• [2] 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.
• [3] Evidence for a role of claudin 2 as a proximal tubular stress responsive paracellular water channel. Toxicol Appl Pharmacol. 2014 Sep 1;279(2):163-72.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [7] 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.
• [8] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [9] 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.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [12] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.
• [13] Heterologous expression of the Na(+),K(+)-ATPase gamma subunit in Xenopus oocytes induces an endogenous, voltage-gated large diameter pore. J Physiol. 2001 Sep 1;535(Pt 2):407-17.