Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNKT6GP)

• DOT Name: Phospholemman (FXYD1)
• Synonyms: FXYD domain-containing ion transport regulator 1; Sodium/potassium-transporting ATPase subunit FXYD1
• Gene Name: FXYD1
• Related Disease:
  Colorectal carcinoma
  Paralysis
  Adult respiratory distress syndrome
  Alzheimer disease
  Cardiac failure
  Congestive heart failure
  Hypokalemic periodic paralysis
  Hypokalemic periodic paralysis, type 1
  Myocardial ischemia
  Osteoglophonic dwarfism
  Parkinson disease
  Rett syndrome
  Schizophrenia
  Coronary atherosclerosis
  Restless legs syndrome
  Hirschsprung disease
  Osteoarthritis
  Post-traumatic stress disorder
  Stroke
• UniProt ID: PLM_HUMAN
• PDB ID: 2JO1
• Pfam ID: PF02038
• Sequence:
  MASLGHILVFCVGLLTMAKAESPKEHDPFTYDYQSLQIGGLVIAGILFILGILIVLSRRC
  RCKFNQQQRTGEPDEEEGTFRSSIRRLSTRRR
• Function: Associates with and regulates the activity of the sodium/potassium-transporting ATPase (NKA) which transports Na(+) out of the cell and K(+) into the cell. Inhibits NKA activity in its unphosphorylated state and stimulates activity when phosphorylated. Reduces glutathionylation of the NKA beta-1 subunit ATP1B1, thus reversing glutathionylation-mediated inhibition of ATP1B1. Contributes to female sexual development by maintaining the excitability of neurons which secrete gonadotropin-releasing hormone.
• Tissue Specificity: Highest expression in skeletal muscle and heart. Moderate levels in brain, placenta, lung, liver, pancreas, uterus, bladder, prostate, small intestine and colon with mucosal lining. Very low levels in kidney, colon and small intestine without mucosa, prostate without endothelial lining, spleen, and testis.
• KEGG Pathway: cAMP sig.ling pathway (hsa04024)
• 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

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Definitive	Biomarker	[1]
Paralysis	DISF9I3O	Definitive	Biomarker	[2]
Adult respiratory distress syndrome	DISIJV47	Strong	Altered Expression	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Cardiac failure	DISDC067	Strong	Biomarker	[5]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[5]
Hypokalemic periodic paralysis	DISVIXI1	Strong	Biomarker	[6]
Hypokalemic periodic paralysis, type 1	DIS5GF2M	Strong	Biomarker	[6]
Myocardial ischemia	DISFTVXF	Strong	Altered Expression	[7]
Osteoglophonic dwarfism	DISVSNPT	Strong	Altered Expression	[8]
Parkinson disease	DISQVHKL	Strong	Biomarker	[9]
Rett syndrome	DISGG5UV	Strong	Biomarker	[10]
Schizophrenia	DISSRV2N	Strong	Biomarker	[11]
Coronary atherosclerosis	DISKNDYU	moderate	Altered Expression	[7]
Restless legs syndrome	DISNWY00	moderate	Biomarker	[9]
Hirschsprung disease	DISUUSM1	Limited	Altered Expression	[12]
Osteoarthritis	DIS05URM	Limited	Biomarker	[13]
Post-traumatic stress disorder	DISHL1EY	Limited	Biomarker	[14]
Stroke	DISX6UHX	Limited	Biomarker	[15]

3 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 Phospholemman (FXYD1).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Phospholemman (FXYD1).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Phospholemman (FXYD1).	[27]

13 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 Phospholemman (FXYD1).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phospholemman (FXYD1).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Phospholemman (FXYD1).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Phospholemman (FXYD1).	[20]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Phospholemman (FXYD1).	[17]
Quercetin	DM3NC4M	Approved	Quercetin affects the expression of Phospholemman (FXYD1).	[21]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Phospholemman (FXYD1).	[22]
Ampicillin	DMHWE7P	Approved	Ampicillin increases the expression of Phospholemman (FXYD1).	[21]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Phospholemman (FXYD1).	[23]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Phospholemman (FXYD1).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Phospholemman (FXYD1).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Phospholemman (FXYD1).	[25]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE increases the expression of Phospholemman (FXYD1).	[21]

References

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• [3] FXYD1 negatively regulates Na(+)/K(+)-ATPase activity in lung alveolar epithelial cells.Respir Physiol Neurobiol. 2016 Jan;220:54-61. doi: 10.1016/j.resp.2015.09.008. Epub 2015 Sep 26.
• [4] Relevance of Follow-Up in Patients with Core Clinical Criteria for Alzheimer Disease and Normal CSF Biomarkers.Curr Alzheimer Res. 2018;15(7):691-700. doi: 10.2174/1567205015666180110113238.
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• [6] Phospholemman, a major regulator of skeletal muscle Na(+)/K(+)-ATPase, is not mutated in probands with hypokalemic periodic paralysis.Exp Ther Med. 2017 Oct;14(4):3229-3232. doi: 10.3892/etm.2017.4848. Epub 2017 Jul 28.
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• [10] Correcting deregulated Fxyd1 expression rescues deficits in neuronal arborization and potassium homeostasis in MeCP2 deficient male mice.Brain Res. 2018 Oct 15;1697:45-52. doi: 10.1016/j.brainres.2018.06.013. Epub 2018 Jun 12.
• [11] Gene expression profile for schizophrenia: discrete neuron transcription patterns in the entorhinal cortex.Arch Gen Psychiatry. 2002 Jul;59(7):631-40. doi: 10.1001/archpsyc.59.7.631.
• [12] Abnormal Scn1b and Fxyd1 gene expression in the pulled-through ganglionic colon may influence functional outcome in patients with Hirschsprung's disease.Pediatr Surg Int. 2019 Jan;35(1):9-14. doi: 10.1007/s00383-018-4370-x. Epub 2018 Nov 1.
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• [14] Different polysomnographic patterns in military veterans with obstructive sleep apnea in those with and without post-traumatic stress disorder.Sleep Breath. 2018 Mar;22(1):17-22. doi: 10.1007/s11325-017-1596-0. Epub 2018 Jan 4.
• [15] Cerebrovascular Accident Risk in a Population with Periodic Limb Movements of Sleep: A Preliminary Meta-Analysis.Cerebrovasc Dis. 2018;46(1-2):1-9. doi: 10.1159/000490065. Epub 2018 Jul 6.
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• [17] 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.
• [18] 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.
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• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] 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.
• [22] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [25] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [26] 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.
• [27] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.