Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9DIEOP)

• DOT Name: Plasma membrane calcium-transporting ATPase 3 (ATP2B3)
• Synonyms: PMCA3; EC 7.2.2.10; Plasma membrane calcium ATPase isoform 3; Plasma membrane calcium pump isoform 3
• Gene Name: ATP2B3
• Related Disease:
  Familial hypocalciuric hypercalcemia
  Adenoma
  Adrenal gland neoplasm
  Breast cancer
  Breast carcinoma
  Dementia
  Essential hypertension
  Familial hyperaldosteronism
  Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 1
  High blood pressure
  Hyperaldosteronism
  Matthew-Wood syndrome
  Neoplasm
  Pathologic nystagmus
  X-linked progressive cerebellar ataxia
  Niemann-Pick disease type A
  Primary aldosteronism
  X-linked non progressive cerebellar ataxia
  Adrenal adenoma
  Adrenocortical carcinoma
  Fetal growth restriction
  X-linked myotubular myopathy
• UniProt ID: AT2B3_HUMAN
• EC Number: 7.2.2.10
• Pfam ID: PF12424 ; PF13246 ; PF00689 ; PF00690 ; PF00122 ; PF00702
• Sequence:
  MGDMANSSIEFHPKPQQQRDVPQAGGFGCTLAELRTLMELRGAEALQKIEEAYGDVSGLC
  RRLKTSPTEGLADNTNDLEKRRQIYGQNFIPPKQPKTFLQLVWEALQDVTLIILEVAAIV
  SLGLSFYAPPGEESEACGNVSGGAEDEGEAEAGWIEGAAILLSVICVVLVTAFNDWSKEK
  QFRGLQSRIEQEQKFTVIRNGQLLQVPVAALVVGDIAQVKYGDLLPADGVLIQANDLKID
  ESSLTGESDHVRKSADKDPMLLSGTHVMEGSGRMVVTAVGVNSQTGIIFTLLGAGGEEEE
  KKDKKGKQQDGAMESSQTKAKKQDGAVAMEMQPLKSAEGGEMEEREKKKANAPKKEKSVL
  QGKLTKLAVQIGKAGLVMSAITVIILVLYFVIETFVVEGRTWLAECTPVYVQYFVKFFII
  GVTVLVVAVPEGLPLAVTISLAYSVKKMMKDNNLVRHLDACETMGNATAICSDKTGTLTT
  NRMTVVQSYLGDTHYKEIPAPSALTPKILDLLVHAISINSAYTTKILPPEKEGALPRQVG
  NKTECALLGFVLDLKRDFQPVREQIPEDKLYKVYTFNSVRKSMSTVIRMPDGGFRLFSKG
  ASEILLKKCTNILNSNGELRGFRPRDRDDMVRKIIEPMACDGLRTICIAYRDFSAGQEPD
  WDNENEVVGDLTCIAVVGIEDPVRPEVPEAIRKCQRAGITVRMVTGDNINTARAIAAKCG
  IIQPGEDFLCLEGKEFNRRIRNEKGEIEQERLDKVWPKLRVLARSSPTDKHTLVKGIIDS
  TTGEQRQVVAVTGDGTNDGPALKKADVGFAMGIAGTDVAKEASDIILTDDNFTSIVKAVM
  WGRNVYDSISKFLQFQLTVNVVAVIVAFTGACITQDSPLKAVQMLWVNLIMDTFASLALA
  TEPPTESLLLRKPYGRDKPLISRTMMKNILGHAVYQLAIIFTLLFVGELFFDIDSGRNAP
  LHSPPSEHYTIIFNTFVMMQLFNEINARKIHGERNVFDGIFSNPIFCTIVLGTFGIQIVI
  VQFGGKPFSCSPLSTEQWLWCLFVGVGELVWGQVIATIPTSQLKCLKEAGHGPGKDEMTD
  EELAEGEEEIDHAERELRRGQILWFRGLNRIQTQIRVVKAFRSSLYEGLEKPESKTSIHN
  FMATPEFLINDYTHNIPLIDDTDVDENEERLRAPPPPSPNQNNNAIDSGIYLTTHVTKSA
  TSSVFSSSPGSPLHSVETSL
• Function: ATP-driven Ca(2+) ion pump involved in the maintenance of basal intracellular Ca(2+) levels at the presynaptic terminals. Uses ATP as an energy source to transport cytosolic Ca(2+) ions across the plasma membrane to the extracellular compartment. May counter-transport protons, but the mechanism and the stoichiometry of this Ca(2+)/H(+) exchange remains to be established.
• Tissue Specificity: Highly expressed in the cerebellum . Expressed in adrenal glands .
• 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)
  Reduction of cytosolic Ca++ levels (R-HSA-418359)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial hypocalciuric hypercalcemia	DIS0K7FK	Definitive	Altered Expression	[1]
Adenoma	DIS78ZEV	Strong	Biomarker	[2]
Adrenal gland neoplasm	DISFK7RF	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Dementia	DISXL1WY	Strong	Biomarker	[5]
Essential hypertension	DIS7WI98	Strong	Genetic Variation	[6]
Familial hyperaldosteronism	DIS9R9LI	Strong	Biomarker	[7]
Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 1	DISXUJ5S	Strong	Biomarker	[8]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[9]
Hyperaldosteronism	DIS3WGAL	Strong	Genetic Variation	[3]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Pathologic nystagmus	DIS1QSPO	Strong	Genetic Variation	[12]
X-linked progressive cerebellar ataxia	DISVLG2P	Strong	X-linked	[13]
Niemann-Pick disease type A	DISRCINF	moderate	Biomarker	[14]
Primary aldosteronism	DISOEFNH	moderate	Genetic Variation	[15]
X-linked non progressive cerebellar ataxia	DISR3MGT	Supportive	X-linked	[16]
Adrenal adenoma	DISC2UN8	Limited	Genetic Variation	[17]
Adrenocortical carcinoma	DISZF4HX	Limited	Genetic Variation	[18]
Fetal growth restriction	DIS5WEJ5	Limited	Biomarker	[19]
X-linked myotubular myopathy	DISJ95GS	Limited	Biomarker	[20]

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 Plasma membrane calcium-transporting ATPase 3 (ATP2B3).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Plasma membrane calcium-transporting ATPase 3 (ATP2B3).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Plasma membrane calcium-transporting ATPase 3 (ATP2B3).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Plasma membrane calcium-transporting ATPase 3 (ATP2B3).	[22]

References

• [1] Calcium-ATPase activity in erythrocyte ghosts from patients with familial benign hypercalcaemia.Scand J Clin Lab Invest. 1985 Jun;45(4):349-53. doi: 10.3109/00365518509161018.
• [2] Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension.Nat Genet. 2013 Apr;45(4):440-4, 444e1-2. doi: 10.1038/ng.2550. Epub 2013 Feb 17.
• [3] A Novel Somatic Deletion Mutation of ATP2B3 in Aldosterone-Producing Adenoma.Endocr Pathol. 2015 Dec;26(4):328-33. doi: 10.1007/s12022-015-9400-9.
• [4] Plasma membrane Ca2+-ATPase expression during colon cancer cell line differentiation.Biochem Biophys Res Commun. 2007 Apr 20;355(4):932-6. doi: 10.1016/j.bbrc.2007.02.050. Epub 2007 Feb 20.
• [5] Cerebellar ataxia, dementia, pyramidal signs, cortical cataract of the posterior pole and a raised IgG index in a patient with a sporadic form of olivopontocerebellar atrophy.Clin Neurol Neurosurg. 1997 May;99(2):99-101. doi: 10.1016/s0303-8467(97)00604-5.
• [6] Investigation of the Met-267 Arg exchange in isoform 1 of the human plasma membrane calcium pump in patients with essential hypertension by the amplification-created restriction site technique.J Mol Med (Berl). 1997 Jan;75(1):62-6. doi: 10.1007/s001090050088.
• [7] CACNA1H Mutations Are Associated With Different Forms of Primary Aldosteronism.EBioMedicine. 2016 Nov;13:225-236. doi: 10.1016/j.ebiom.2016.10.002. Epub 2016 Oct 4.
• [8] Missense mutations in the phosphomannomutase 2 gene of two Japanese siblings with carbohydrate-deficient glycoprotein syndrome type I.Brain Dev. 1999 Jun;21(4):223-8. doi: 10.1016/s0387-7604(99)00004-2.
• [9] Reduced expression of PMCA1 is associated with increased blood pressure with age which is preceded by remodelling of resistance arteries.Aging Cell. 2017 Oct;16(5):1104-1113. doi: 10.1111/acel.12637. Epub 2017 Aug 9.
• [10] Cutting off the fuel supply to calcium pumps in pancreatic cancer cells: role of pyruvate kinase-M2 (PKM2).Br J Cancer. 2020 Jan;122(2):266-278. doi: 10.1038/s41416-019-0675-3. Epub 2019 Dec 10.
• [11] Novel somatic mutations and distinct molecular signature in aldosterone-producing adenomas.Endocr Relat Cancer. 2015 Oct;22(5):735-44. doi: 10.1530/ERC-15-0321.
• [12] A novel PMCA3 mutation in an ataxic patient with hypomorphic phosphomannomutase 2 (PMM2) heterozygote mutations: Biochemical characterization of the pump defect.Biochim Biophys Acta Mol Basis Dis. 2017 Dec;1863(12):3303-3312. doi: 10.1016/j.bbadis.2017.08.006. Epub 2017 Aug 12.
• [13] Mutation of plasma membrane Ca2+ ATPase isoform 3 in a family with X-linked congenital cerebellar ataxia impairs Ca2+ homeostasis. Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14514-9. doi: 10.1073/pnas.1207488109. Epub 2012 Aug 21.
• [14] Sphingomyelin-induced inhibition of the plasma membrane calcium ATPase causes neurodegeneration in type A Niemann-Pick disease.Mol Psychiatry. 2017 May;22(5):711-723. doi: 10.1038/mp.2016.148. Epub 2016 Sep 13.
• [15] Clinicopathologic Correlates of Primary Aldosteronism.Arch Pathol Lab Med. 2015 Jul;139(7):948-54. doi: 10.5858/arpa.2014-0156-RS.
• [16] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [17] Molecular Heterogeneity in Aldosterone-Producing Adenomas.J Clin Endocrinol Metab. 2016 Mar;101(3):999-1007. doi: 10.1210/jc.2015-3239. Epub 2016 Jan 14.
• [18] ENDOCRINE TUMOURS: The genomics of adrenocortical tumors.Eur J Endocrinol. 2016 Jun;174(6):R249-65. doi: 10.1530/EJE-15-1118. Epub 2016 Jan 6.
• [19] Mechanisms Underpinning Adaptations in Placental Calcium Transport in Normal Mice and Those With Fetal Growth Restriction.Front Endocrinol (Lausanne). 2018 Nov 20;9:671. doi: 10.3389/fendo.2018.00671. eCollection 2018.
• [20] Detection of a new polymorphism in the plasma-membrane Ca2+ ATPase isoform-3 gene and its exclusion as a candidate for X-linked myotubular myopathy (MTM1).Hum Genet. 1996 Dec;98(6):681-4. doi: 10.1007/s004390050284.
• [21] 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.
• [22] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [23] 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.
• [24] 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.