Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5MXG9W)

• DOT Name: Plasma membrane calcium-transporting ATPase 1 (ATP2B1)
• Synonyms: EC 7.2.2.10; Plasma membrane calcium ATPase isoform 1; PMCA1; Plasma membrane calcium pump isoform 1
• Gene Name: ATP2B1
• Related Disease: Intellectual developmental disorder, autosomal dominant 66
• UniProt ID: AT2B1_HUMAN
• PDB ID: 6A69
• EC Number: 7.2.2.10
• Pfam ID: PF12424 ; PF13246 ; PF00689 ; PF00690 ; PF00122 ; PF00702
• Sequence:
  MGDMANNSVAYSGVKNSLKEANHDGDFGITLAELRALMELRSTDALRKIQESYGDVYGIC
  TKLKTSPNEGLSGNPADLERREAVFGKNFIPPKKPKTFLQLVWEALQDVTLIILEIAAIV
  SLGLSFYQPPEGDNALCGEVSVGEEEGEGETGWIEGAAILLSVVCVVLVTAFNDWSKEKQ
  FRGLQSRIEQEQKFTVIRGGQVIQIPVADITVGDIAQVKYGDLLPADGILIQGNDLKIDE
  SSLTGESDHVKKSLDKDPLLLSGTHVMEGSGRMVVTAVGVNSQTGIIFTLLGAGGEEEEK
  KDEKKKEKKNKKQDGAIENRNKAKAQDGAAMEMQPLKSEEGGDGDEKDKKKANLPKKEKS
  VLQGKLTKLAVQIGKAGLLMSAITVIILVLYFVIDTFWVQKRPWLAECTPIYIQYFVKFF
  IIGVTVLVVAVPEGLPLAVTISLAYSVKKMMKDNNLVRHLDACETMGNATAICSDKTGTL
  TMNRMTVVQAYINEKHYKKVPEPEAIPPNILSYLVTGISVNCAYTSKILPPEKEGGLPRH
  VGNKTECALLGLLLDLKRDYQDVRNEIPEEALYKVYTFNSVRKSMSTVLKNSDGSYRIFS
  KGASEIILKKCFKILSANGEAKVFRPRDRDDIVKTVIEPMASEGLRTICLAFRDFPAGEP
  EPEWDNENDIVTGLTCIAVVGIEDPVRPEVPDAIKKCQRAGITVRMVTGDNINTARAIAT
  KCGILHPGEDFLCLEGKDFNRRIRNEKGEIEQERIDKIWPKLRVLARSSPTDKHTLVKGI
  IDSTVSDQRQVVAVTGDGTNDGPALKKADVGFAMGIAGTDVAKEASDIILTDDNFTSIVK
  AVMWGRNVYDSISKFLQFQLTVNVVAVIVAFTGACITQDSPLKAVQMLWVNLIMDTLASL
  ALATEPPTESLLLRKPYGRNKPLISRTMMKNILGHAFYQLVVVFTLLFAGEKFFDIDSGR
  NAPLHAPPSEHYTIVFNTFVLMQLFNEINARKIHGERNVFEGIFNNAIFCTIVLGTFVVQ
  IIIVQFGGKPFSCSELSIEQWLWSIFLGMGTLLWGQLISTIPTSRLKFLKEAGHGTQKEE
  IPEEELAEDVEEIDHAERELRRGQILWFRGLNRIQTQIRVVNAFRSSLYEGLEKPESRSS
  IHNFMTHPEFRIEDSEPHIPLIDDTDAEDDAPTKRNSSPPPSPNKNNNAVDSGIHLTIEM
  NKSATSSSPGSPLHSLETSL
• Function: Catalyzes the hydrolysis of ATP coupled with the transport of calcium from the cytoplasm to the extracellular space thereby maintaining intracellular calcium homeostasis. Plays a role in blood pressure regulation through regulation of intracellular calcium concentration and nitric oxide production leading to regulation of vascular smooth muscle cells vasoconstriction. Positively regulates bone mineralization through absorption of calcium from the intestine. Plays dual roles in osteoclast differentiation and survival by regulating RANKL-induced calcium oscillations in preosteoclasts and mediating calcium extrusion in mature osteoclasts. Regulates insulin sensitivity through calcium/calmodulin signaling pathway by regulating AKT1 activation and NOS3 activation in endothelial cells. May play a role in synaptic transmission by modulating calcium and proton dynamics at the synaptic vesicles.
• Tissue Specificity: Isoform B: Ubiquitously expressed. Isoform C: Found in brain cortex, skeletal muscle and heart muscle. Isoform D: Has only been found in fetal skeletal muscle. Isoform K: Found in small intestine and liver. Abundantly expressed in the endometrial epithelial cells and glandular epithelial cells in early-proliferative phase and early-secretory phases .
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  cAMP sig.ling pathway (hsa04024)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Aldosterone synthesis and secretion (hsa04925)
  Endocrine and other factor-regulated calcium reabsorption (hsa04961)
  Salivary secretion (hsa04970)
  Pancreatic secretion (hsa04972)
  Mineral absorption (hsa04978)
• Reactome Pathway:
  Ion homeostasis (R-HSA-5578775)
  Ion transport by P-type ATPases (R-HSA-936837)
  Sensory processing of sound by inner hair cells of the cochlea (R-HSA-9662360)
  Reduction of cytosolic Ca++ levels (R-HSA-418359)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual developmental disorder, autosomal dominant 66	DISAJ58X	Strong	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[11]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[12]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[13]
Azacitidine	DMTA5OE	Approved	Azacitidine decreases the expression of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[14]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[15]
Isoflavone	DM7U58J	Phase 4	Isoflavone increases the expression of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[16]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[18]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 decreases the expression of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[22]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[23]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Plasma membrane calcium-transporting ATPase 1 (ATP2B1).	[19]

References

• [1] Targeted ablation of plasma membrane Ca2+-ATPase (PMCA) 1 and 4 indicates a major housekeeping function for PMCA1 and a critical role in hyperactivated sperm motility and male fertility for PMCA4. J Biol Chem. 2004 Aug 6;279(32):33742-50. doi: 10.1074/jbc.M404628200. Epub 2004 Jun 3.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [8] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [9] Gene expression profile changes in NB4 cells induced by arsenic trioxide. Acta Pharmacol Sin. 2003 Jul;24(7):646-50.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [12] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [13] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [14] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [15] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [16] Soy isoflavones exert differential effects on androgen responsive genes in LNCaP human prostate cancer cells. J Nutr. 2007 Apr;137(4):964-72.
• [17] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [18] 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.
• [19] 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.
• [20] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [21] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [22] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [23] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.