Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT959A3A)

• DOT Name: Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 (ATP2A1)
• Synonyms: SERCA1; SR Ca(2+)-ATPase 1; EC 7.2.2.10; Calcium pump 1; Calcium-transporting ATPase sarcoplasmic reticulum type, fast twitch skeletal muscle isoform; Endoplasmic reticulum class 1/2 Ca(2+) ATPase
• Gene Name: ATP2A1
• Related Disease:
  B-cell neoplasm
  Brody myopathy
  Cardiac failure
  Congestive heart failure
  Dilated cardiomyopathy 1A
  Glycogen storage disease V
  Myofibrillar myopathy
  Myopathy
  Non-insulin dependent diabetes
  Skin disease
  Central core myopathy
  Cryptorchidism
  Malignant hyperthermia of anesthesia
  Myotonic dystrophy type 1
  Type-1/2 diabetes
• UniProt ID: AT2A1_HUMAN
• EC Number: 7.2.2.10
• Pfam ID: PF13246 ; PF00689 ; PF00690 ; PF00122 ; PF00702
• Sequence:
  MEAAHAKTTEECLAYFGVSETTGLTPDQVKRNLEKYGLNELPAEEGKTLWELVIEQFEDL
  LVRILLLAACISFVLAWFEEGEETITAFVEPFVILLILIANAIVGVWQERNAENAIEALK
  EYEPEMGKVYRADRKSVQRIKARDIVPGDIVEVAVGDKVPADIRILAIKSTTLRVDQSIL
  TGESVSVIKHTEPVPDPRAVNQDKKNMLFSGTNIAAGKALGIVATTGVGTEIGKIRDQMA
  ATEQDKTPLQQKLDEFGEQLSKVISLICVAVWLINIGHFNDPVHGGSWFRGAIYYFKIAV
  ALAVAAIPEGLPAVITTCLALGTRRMAKKNAIVRSLPSVETLGCTSVICSDKTGTLTTNQ
  MSVCKMFIIDKVDGDICLLNEFSITGSTYAPEGEVLKNDKPVRPGQYDGLVELATICALC
  NDSSLDFNEAKGVYEKVGEATETALTTLVEKMNVFNTDVRSLSKVERANACNSVIRQLMK
  KEFTLEFSRDRKSMSVYCSPAKSSRAAVGNKMFVKGAPEGVIDRCNYVRVGTTRVPLTGP
  VKEKIMAVIKEWGTGRDTLRCLALATRDTPPKREEMVLDDSARFLEYETDLTFVGVVGML
  DPPRKEVTGSIQLCRDAGIRVIMITGDNKGTAIAICRRIGIFGENEEVADRAYTGREFDD
  LPLAEQREACRRACCFARVEPSHKSKIVEYLQSYDEITAMTGDGVNDAPALKKAEIGIAM
  GSGTAVAKTASEMVLADDNFSTIVAAVEEGRAIYNNMKQFIRYLISSNVGEVVCIFLTAA
  LGLPEALIPVQLLWVNLVTDGLPATALGFNPPDLDIMDRPPRSPKEPLISGWLFFRYMAI
  GGYVGAATVGAAAWWFLYAEDGPHVNYSQLTHFMQCTEDNTHFEGIDCEVFEAPEPMTMA
  LSVLVTIEMCNALNSLSENQSLLRMPPWVNIWLLGSICLSMSLHFLILYVDPLPMIFKLR
  ALDLTQWLMVLKISLPVIGLDEILKFVARNYLEDPEDERRK
• Function: Key regulator of striated muscle performance by acting as the major Ca(2+) ATPase responsible for the reuptake of cytosolic Ca(2+) into the sarcoplasmic reticulum. Catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. Contributes to calcium sequestration involved in muscular excitation/contraction.
• Tissue Specificity: Skeletal muscle, fast twitch muscle (type II) fibers.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  cAMP sig.ling pathway (hsa04024)
  Efferocytosis (hsa04148)
  Cardiac muscle contraction (hsa04260)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Osteoclast differentiation (hsa04380)
  Thyroid hormone sig.ling pathway (hsa04919)
  Pancreatic secretion (hsa04972)
  Alzheimer disease (hsa05010)
  Spinocerebellar ataxia (hsa05017)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Hypertrophic cardiomyopathy (hsa05410)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
  Dilated cardiomyopathy (hsa05414)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  Reduction of cytosolic Ca++ levels (R-HSA-418359)
  Ion homeostasis (R-HSA-5578775)
  Ion transport by P-type ATPases (R-HSA-936837)
  Pre-NOTCH Processing in Golgi (R-HSA-1912420)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Strong	Biomarker	[1]
Brody myopathy	DIST9BGP	Strong	Autosomal recessive	[2]
Cardiac failure	DISDC067	Strong	Biomarker	[3]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[3]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Biomarker	[4]
Glycogen storage disease V	DISJNC0O	Strong	Biomarker	[5]
Myofibrillar myopathy	DISF24LW	Strong	Biomarker	[6]
Myopathy	DISOWG27	Strong	Genetic Variation	[7]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[8]
Skin disease	DISDW8R6	Strong	Genetic Variation	[9]
Central core myopathy	DIS18AZZ	Limited	Altered Expression	[10]
Cryptorchidism	DISYUD2P	Limited	Altered Expression	[11]
Malignant hyperthermia of anesthesia	DISYC9XI	Limited	Altered Expression	[10]
Myotonic dystrophy type 1	DISJC0OX	Limited	Altered Expression	[12]
Type-1/2 diabetes	DISIUHAP	Limited	Altered Expression	[13]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Bortezomib	DMNO38U	Approved	Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 (ATP2A1) affects the response to substance of Bortezomib.	[21]

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 Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 (ATP2A1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 (ATP2A1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 (ATP2A1).	[15]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 (ATP2A1).	[16]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 (ATP2A1).	[17]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 (ATP2A1).	[18]
Sulindac	DM2QHZU	Approved	Sulindac decreases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 (ATP2A1).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 (ATP2A1).	[19]

References

• [1] Comparative analysis of testis transcriptomes associated with male infertility in triploid cyprinid fish.Reprod Fertil Dev. 2019 Jan;31(2):248-260. doi: 10.1071/RD18034.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] Differential contractile impairment of fast- and slow-twitch skeletal muscles in a rat model of doxorubicin-induced congestive heart failure.Pharmacology. 2009;84(4):240-8. doi: 10.1159/000241723. Epub 2009 Sep 24.
• [4] Cardiomyocyte marker expression in dogs with left atrial enlargement due to dilated cardiomyopathy or myxomatous mitral valve disease.Folia Histochem Cytobiol. 2017;55(2):52-61. doi: 10.5603/FHC.a2017.0009. Epub 2017 Jun 14.
• [5] A transcriptomic approach to search for novel phenotypic regulators in McArdle disease.PLoS One. 2012;7(2):e31718. doi: 10.1371/journal.pone.0031718. Epub 2012 Feb 9.
• [6] Skeletal muscle sarcoplasmic reticulum phenotype in myotonic dystrophy.Neuromuscul Disord. 1996 Jan;6(1):33-47. doi: 10.1016/0960-8966(95)00016-x.
• [7] SERCA1 protein expression in muscle of patients with Brody disease and Brody syndrome and in cultured human muscle fibers.Mol Genet Metab. 2013 Sep-Oct;110(1-2):162-9. doi: 10.1016/j.ymgme.2013.07.015. Epub 2013 Jul 20.
• [8] Contractility of ventricular myocytes is well preserved despite altered mechanisms of Ca2+ transport and a changing pattern of mRNA in aged type 2 Zucker diabetic fatty rat heart.Mol Cell Biochem. 2012 Feb;361(1-2):267-80. doi: 10.1007/s11010-011-1112-y. Epub 2011 Oct 19.
• [9] Physiological functions of plasma membrane and intracellular Ca2+ pumps revealed by analysis of null mutants.Ann N Y Acad Sci. 2003 Apr;986:453-60. doi: 10.1111/j.1749-6632.2003.tb07229.x.
• [10] Measurement of resting cytosolic Ca2+ concentrations and Ca2+ store size in HEK-293 cells transfected with malignant hyperthermia or central core disease mutant Ca2+ release channels.J Biol Chem. 1999 Jan 8;274(2):693-702. doi: 10.1074/jbc.274.2.693.
• [11] Sarco(endo)plasmic reticulum and plasmalemmal Ca(2+)-ATPase activities in cremaster muscles and sacs differ according to the associated inguinal pathology.Cell Biochem Funct. 2007 Sep-Oct;25(5):515-9. doi: 10.1002/cbf.1341.
• [12] Altered mRNA splicing of the skeletal muscle ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase in myotonic dystrophy type 1.Hum Mol Genet. 2005 Aug 1;14(15):2189-200. doi: 10.1093/hmg/ddi223. Epub 2005 Jun 22.
• [13] Early energy metabolism-related molecular events in skeletal muscle of diabetic rats: The effects of l-arginine and SOD mimic.Chem Biol Interact. 2017 Jun 25;272:188-196. doi: 10.1016/j.cbi.2017.05.003. Epub 2017 May 5.
• [14] 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.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [16] 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.
• [17] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [18] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Genome-wide alteration in DNA hydroxymethylation in the sperm from bisphenol A-exposed men. PLoS One. 2017 Jun 5;12(6):e0178535. doi: 10.1371/journal.pone.0178535. eCollection 2017.
• [21] Preferential cytotoxicity of bortezomib toward highly malignant human liposarcoma cells via suppression of MDR1 expression and function. Toxicol Appl Pharmacol. 2015 Feb 15;283(1):1-8. doi: 10.1016/j.taap.2014.12.015. Epub 2015 Jan 6.