Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPGAU0U)

• DOT Name: Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2)
• Synonyms: SERCA2; SR Ca(2+)-ATPase 2; EC 7.2.2.10; Calcium pump 2; Calcium-transporting ATPase sarcoplasmic reticulum type, slow twitch skeletal muscle isoform; Endoplasmic reticulum class 1/2 Ca(2+) ATPase
• Gene Name: ATP2A2
• Related Disease:
  Acrokeratosis verruciformis
  Darier disease
• UniProt ID: AT2A2_HUMAN
• PDB ID: 5ZTF; 6JJU; 6LLE; 6LLY; 6LN5; 6LN6; 6LN7; 6LN8; 6LN9; 7BT2; 7E7S; 7W7T; 7W7U; 7W7V; 7W7W
• EC Number: 7.2.2.10
• Pfam ID: PF13246 ; PF00689 ; PF00690 ; PF00122 ; PF00702
• Sequence:
  MENAHTKTVEEVLGHFGVNESTGLSLEQVKKLKERWGSNELPAEEGKTLLELVIEQFEDL
  LVRILLLAACISFVLAWFEEGEETITAFVEPFVILLILVANAIVGVWQERNAENAIEALK
  EYEPEMGKVYRQDRKSVQRIKAKDIVPGDIVEIAVGDKVPADIRLTSIKSTTLRVDQSIL
  TGESVSVIKHTDPVPDPRAVNQDKKNMLFSGTNIAAGKAMGVVVATGVNTEIGKIRDEMV
  ATEQERTPLQQKLDEFGEQLSKVISLICIAVWIINIGHFNDPVHGGSWIRGAIYYFKIAV
  ALAVAAIPEGLPAVITTCLALGTRRMAKKNAIVRSLPSVETLGCTSVICSDKTGTLTTNQ
  MSVCRMFILDRVEGDTCSLNEFTITGSTYAPIGEVHKDDKPVNCHQYDGLVELATICALC
  NDSALDYNEAKGVYEKVGEATETALTCLVEKMNVFDTELKGLSKIERANACNSVIKQLMK
  KEFTLEFSRDRKSMSVYCTPNKPSRTSMSKMFVKGAPEGVIDRCTHIRVGSTKVPMTSGV
  KQKIMSVIREWGSGSDTLRCLALATHDNPLRREEMHLEDSANFIKYETNLTFVGCVGMLD
  PPRIEVASSVKLCRQAGIRVIMITGDNKGTAVAICRRIGIFGQDEDVTSKAFTGREFDEL
  NPSAQRDACLNARCFARVEPSHKSKIVEFLQSFDEITAMTGDGVNDAPALKKAEIGIAMG
  SGTAVAKTASEMVLADDNFSTIVAAVEEGRAIYNNMKQFIRYLISSNVGEVVCIFLTAAL
  GFPEALIPVQLLWVNLVTDGLPATALGFNPPDLDIMNKPPRNPKEPLISGWLFFRYLAIG
  CYVGAATVGAAAWWFIAADGGPRVSFYQLSHFLQCKEDNPDFEGVDCAIFESPYPMTMAL
  SVLVTIEMCNALNSLSENQSLLRMPPWENIWLVGSICLSMSLHFLILYVEPLPLIFQITP
  LNVTQWLMVLKISLPVILMDETLKFVARNYLEPGKECVQPATKSCSFSACTDGISWPFVL
  LIMPLVIWVYSTDTNFSDMFWS
• Function: This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. Involved in autophagy in response to starvation. Upon interaction with VMP1 and activation, controls ER-isolation membrane contacts for autophagosome formation. Also modulates ER contacts with lipid droplets, mitochondria and endosomes. In coordination with FLVCR2 mediates heme-stimulated switching from mitochondrial ATP synthesis to thermogenesis; [Isoform 2]: Involved in the regulation of the contraction/relaxation cycle. Acts as a regulator of TNFSF11-mediated Ca(2+) signaling pathways via its interaction with TMEM64 which is critical for the TNFSF11-induced CREB1 activation and mitochondrial ROS generation necessary for proper osteoclast generation. Association between TMEM64 and SERCA2 in the ER leads to cytosolic Ca(2+) spiking for activation of NFATC1 and production of mitochondrial ROS, thereby triggering Ca(2+) signaling cascades that promote osteoclast differentiation and activation.
• Tissue Specificity: Isoform 1 is widely expressed in smooth muscle and nonmuscle tissues such as in adult skin epidermis, with highest expression in liver, pancreas and lung, and intermediate expression in brain, kidney and placenta. Also expressed at lower levels in heart and skeletal muscle. Isoforms 2 and 3 are highly expressed in the heart and slow twitch skeletal muscle. Expression of isoform 3 is predominantly restricted to cardiomyocytes and in close proximity to the sarcolemma. Both isoforms are mildly expressed in lung, kidney, liver, pancreas and placenta. Expression of isoform 3 is amplified during monocytic differentiation and also observed in the fetal heart.
• 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

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acrokeratosis verruciformis	DIS45JEK	Definitive	Autosomal dominant	[1]
Darier disease	DIS4WI7S	Definitive	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2) affects the response to substance of Hydrogen peroxide.	[28]

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 Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[3]

24 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 Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[12]
Marinol	DM70IK5	Approved	Marinol increases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[13]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[14]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[15]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[18]
Clioquinol	DM746BZ	Withdrawn from market	Clioquinol decreases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[19]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[20]
Tetramethylpyrazine	DMC0WNB	Discontinued in Phase 2	Tetramethylpyrazine increases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[21]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[23]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[24]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[25]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[26]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl decreases the expression of Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (ATP2A2).	[27]

References

• [1] Acrokeratosis verruciformis of Hopf is caused by mutation in ATP2A2: evidence that it is allelic to Darier's disease. J Invest Dermatol. 2003 Feb;120(2):229-32. doi: 10.1046/j.1523-1747.2003.t01-1-12045.x.
• [2] Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease. Nat Genet. 1999 Mar;21(3):271-7. doi: 10.1038/6784.
• [3] 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.
• [4] 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.
• [5] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [6] 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.
• [7] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [8] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [9] 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.
• [10] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [13] Inhibiting Heat Shock Proteins Can Potentiate the Cytotoxic Effect of Cannabidiol in Human Glioma Cells. Anticancer Res. 2015 Nov;35(11):5827-37.
• [14] Rosiglitazone transiently disturbs calcium homeostasis in monocytic cells. Biochem Biophys Res Commun. 2008 Feb 1;366(1):149-55. doi: 10.1016/j.bbrc.2007.11.095. Epub 2007 Nov 29.
• [15] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [16] Molecular mechanisms of action of angiopreventive anti-oxidants on endothelial cells: microarray gene expression analyses. Mutat Res. 2005 Dec 11;591(1-2):198-211.
• [17] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] Clioquinol inhibits cell growth?in a SERCA2-dependent manner. J Biochem Mol Toxicol. 2021 May;35(5):e22727. doi: 10.1002/jbt.22727. Epub 2021 Jan 28.
• [20] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [21] Preparation of cardiovascular disease-related genes microarray and its application in exploring ligustrazine-induced changes in endothelial gene expression. Pol J Pharmacol. 2004 Jul-Aug;56(4):427-33.
• [22] Rosiglitazone induces the unfolded protein response, but has no significant effect on cell viability, in monocytic and vascular smooth muscle cells. Biochem Biophys Res Commun. 2010 Oct 1;400(4):689-95. doi: 10.1016/j.bbrc.2010.08.129. Epub 2010 Sep 9.
• [23] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [24] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [25] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.
• [26] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [27] Tributyltin-induced endoplasmic reticulum stress and its Ca(2+)-mediated mechanism. Toxicol Appl Pharmacol. 2013 Oct 1;272(1):137-46. doi: 10.1016/j.taap.2013.05.026. Epub 2013 Jun 3.
• [28] Bcl-2 suppresses sarcoplasmic/endoplasmic reticulum Ca2+-ATPase expression in cystic fibrosis airways: role in oxidant-mediated cell death. Am J Respir Crit Care Med. 2009 May 1;179(9):816-26. doi: 10.1164/rccm.200807-1104OC. Epub 2009 Feb 6.