Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7M9ZDK)

• DOT Name: Phospholipid-transporting ATPase IH (ATP11A)
• Synonyms: EC 7.6.2.1; ATPase IS; ATPase class VI type 11A; P4-ATPase flippase complex alpha subunit ATP11A
• Gene Name: ATP11A
• Related Disease:
  Auditory neuropathy, autosomal dominant 2
  Carcinoma
  Cholelithiasis
  Cytomegalovirus infection
  Leigh syndrome
  Hearing loss, autosomal dominant 84
  Acute lymphocytic leukaemia
  Basal cell carcinoma
  Basal cell neoplasm
  Colorectal carcinoma
  Leukodystrophy, hypomyelinating, 24
  Lymphoid leukemia
• UniProt ID: AT11A_HUMAN
• EC Number: 7.6.2.1
• Pfam ID: PF13246 ; PF00122 ; PF00702 ; PF16212 ; PF16209
• Sequence:
  MDCSLVRTLVHRYCAGEENWVDSRTIYVGHREPPPGAEAYIPQRYPDNRIVSSKYTFWNF
  IPKNLFEQFRRVANFYFLIIFLVQLIIDTPTSPVTSGLPLFFVITVTAIKQGYEDWLRHK
  ADNAMNQCPVHFIQHGKLVRKQSRKLRVGDIVMVKEDETFPCDLIFLSSNRGDGTCHVTT
  ASLDGESSHKTHYAVQDTKGFHTEEDIGGLHATIECEQPQPDLYKFVGRINVYSDLNDPV
  VRPLGSENLLLRGATLKNTEKIFGVAIYTGMETKMALNYQSKSQKRSAVEKSMNAFLIVY
  LCILISKALINTVLKYMWQSEPFRDEPWYNQKTESERQRNLFLKAFTDFLAFMVLFNYII
  PVSMYVTVEMQKFLGSYFITWDEDMFDEETGEGPLVNTSDLNEELGQVEYIFTDKTGTLT
  ENNMEFKECCIEGHVYVPHVICNGQVLPESSGIDMIDSSPSVNGREREELFFRALCLCHT
  VQVKDDDSVDGPRKSPDGGKSCVYISSSPDEVALVEGVQRLGFTYLRLKDNYMEILNREN
  HIERFELLEILSFDSVRRRMSVIVKSATGEIYLFCKGADSSIFPRVIEGKVDQIRARVER
  NAVEGLRTLCVAYKRLIQEEYEGICKLLQAAKVALQDREKKLAEAYEQIEKDLTLLGATA
  VEDRLQEKAADTIEALQKAGIKVWVLTGDKMETAAATCYACKLFRRNTQLLELTTKRIEE
  QSLHDVLFELSKTVLRHSGSLTRDNLSGLSADMQDYGLIIDGAALSLIMKPREDGSSGNY
  RELFLEICRSCSAVLCCRMAPLQKAQIVKLIKFSKEHPITLAIGDGANDVSMILEAHVGI
  GVIGKEGRQAARNSDYAIPKFKHLKKMLLVHGHFYYIRISELVQYFFYKNVCFIFPQFLY
  QFFCGFSQQTLYDTAYLTLYNISFTSLPILLYSLMEQHVGIDVLKRDPTLYRDVAKNALL
  RWRVFIYWTLLGLFDALVFFFGAYFVFENTTVTSNGQIFGNWTFGTLVFTVMVFTVTLKL
  ALDTHYWTWINHFVIWGSLLFYVVFSLLWGGVIWPFLNYQRMYYVFIQMLSSGPAWLAIV
  LLVTISLLPDVLKKVLCRQLWPTATERVQTKSQCLSVEQSTIFMLSQTSSSLSF
• Function: Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids, phosphatidylserines (PS) and phosphatidylethanolamines (PE), from the outer to the inner leaflet of the plasma membrane. Does not show flippase activity toward phosphatidylcholine (PC). Contributes to the maintenance of membrane lipid asymmetry with a specific role in morphogenesis of muscle cells. In myoblasts, mediates PS enrichment at the inner leaflet of plasma membrane, triggering PIEZO1-dependent Ca2+ influx and Rho GTPases signal transduction, subsequently leading to the assembly of cortical actomyosin fibers and myotube formation. May be involved in the uptake of farnesyltransferase inhibitor drugs, such as lonafarnib.
• Tissue Specificity: Widely expressed . Expressed in myoblasts .
• KEGG Pathway: Efferocytosis (hsa04148)
• Reactome Pathway:
  Ion transport by P-type ATPases (R-HSA-936837)
  Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Auditory neuropathy, autosomal dominant 2	DISEY17Q	Strong	Autosomal dominant	[1]
Carcinoma	DISH9F1N	Strong	Altered Expression	[2]
Cholelithiasis	DISERLZB	Strong	Altered Expression	[3]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[4]
Leigh syndrome	DISWQU45	Strong	Genetic Variation	[5]
Hearing loss, autosomal dominant 84	DISXVH1V	Moderate	Autosomal dominant	[6]
Acute lymphocytic leukaemia	DISPX75S	Limited	Altered Expression	[7]
Basal cell carcinoma	DIS7PYN3	Limited	Genetic Variation	[8]
Basal cell neoplasm	DIS37IXW	Limited	Genetic Variation	[8]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[9]
Leukodystrophy, hypomyelinating, 24	DISSVKRT	Limited	Autosomal dominant	[6]
Lymphoid leukemia	DIS65TYQ	Limited	Altered Expression	[7]

14 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 Phospholipid-transporting ATPase IH (ATP11A).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phospholipid-transporting ATPase IH (ATP11A).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Phospholipid-transporting ATPase IH (ATP11A).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phospholipid-transporting ATPase IH (ATP11A).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phospholipid-transporting ATPase IH (ATP11A).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Phospholipid-transporting ATPase IH (ATP11A).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Phospholipid-transporting ATPase IH (ATP11A).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phospholipid-transporting ATPase IH (ATP11A).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Phospholipid-transporting ATPase IH (ATP11A).	[19]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Phospholipid-transporting ATPase IH (ATP11A).	[20]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Phospholipid-transporting ATPase IH (ATP11A).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Phospholipid-transporting ATPase IH (ATP11A).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Phospholipid-transporting ATPase IH (ATP11A).	[24]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of Phospholipid-transporting ATPase IH (ATP11A).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Phospholipid-transporting ATPase IH (ATP11A).	[18]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Phospholipid-transporting ATPase IH (ATP11A).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Phospholipid-transporting ATPase IH (ATP11A).	[21]

References

• [1] Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene. Hum Genet. 2022 Apr;141(3-4):431-444. doi: 10.1007/s00439-022-02444-x. Epub 2022 Mar 12.
• [2] Post-transcriptional regulation of the mitochondrial H(+)-ATP synthase: a key regulator of the metabolic phenotype in cancer.Biochim Biophys Acta. 2011 Jun;1807(6):543-51. doi: 10.1016/j.bbabio.2010.10.016. Epub 2010 Oct 27.
• [3] An integrated analysis of differential miRNA and mRNA expressions in human gallstones.Mol Biosyst. 2015 Apr;11(4):1004-11. doi: 10.1039/c4mb00741g.
• [4] Cellular v-ATPase is required for virion assembly compartment formation in human cytomegalovirus infection.Open Biol. 2017 Nov;7(11):160298. doi: 10.1098/rsob.160298.
• [5] Inefficient coupling between proton transport and ATP synthesis may be the pathogenic mechanism for NARP and Leigh syndrome resulting from the T8993G mutation in mtDNA.Biochem J. 2006 May 1;395(3):493-500. doi: 10.1042/BJ20051748.
• [6] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [7] Resistance to farnesyltransferase inhibitors in Bcr/Abl-positive lymphoblastic leukemia by increased expression of a novel ABC transporter homolog ATP11a.Blood. 2005 Aug 15;106(4):1355-61. doi: 10.1182/blood-2004-09-3655. Epub 2005 Apr 28.
• [8] Combined analysis of keratinocyte cancers identifies novel genome-wide loci.Hum Mol Genet. 2019 Sep 15;28(18):3148-3160. doi: 10.1093/hmg/ddz121.
• [9] ATP11A is a novel predictive marker for metachronous metastasis of colorectal cancer.Oncol Rep. 2010 Feb;23(2):505-10.
• [10] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [13] 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.
• [14] 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.
• [15] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [16] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [17] 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.
• [18] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [19] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [20] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [21] 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.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [25] Comparative DNA microarray analysis of human monocyte derived dendritic cells and MUTZ-3 cells exposed to the moderate skin sensitizer cinnamaldehyde. Toxicol Appl Pharmacol. 2009 Sep 15;239(3):273-83.