Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKMV2K5)

• DOT Name: Phospholipid-transporting ATPase IG (ATP11C)
• Synonyms: EC 7.6.2.1; ATPase IQ; ATPase class VI type 11C; P4-ATPase flippase complex alpha subunit ATP11C
• Gene Name: ATP11C
• Related Disease:
  Anemia
  Hereditary haemolytic anemia
  Intrahepatic cholestasis
  Progressive familial intrahepatic cholestasis type 1
  X-linked congenital hemolytic anemia
• UniProt ID: AT11C_HUMAN
• PDB ID: 6LKN; 7BSP; 7BSQ; 7BSS; 7BSU; 7BSV; 7BSW; 7VSG; 7VSH
• EC Number: 7.6.2.1
• Pfam ID: PF13246 ; PF00122 ; PF16212 ; PF16209
• Sequence:
  MQMVPSLPPASECAGEEKRVGTRTVFVGNHPVSETEAYIAQRFCDNRIVSSKYTLWNFLP
  KNLFEQFRRIANFYFLIIFLVQVTVDTPTSPVTSGLPLFFVITVTAIKQGYEDCLRHRAD
  NEVNKSTVYIIENAKRVRKESEKIKVGDVVEVQADETFPCDLILLSSCTTDGTCYVTTAS
  LDGESNCKTHYAVRDTIALCTAESIDTLRAAIECEQPQPDLYKFVGRINIYSNSLEAVAR
  SLGPENLLLKGATLKNTEKIYGVAVYTGMETKMALNYQGKSQKRSAVEKSINAFLIVYLF
  ILLTKAAVCTTLKYVWQSTPYNDEPWYNQKTQKERETLKVLKMFTDFLSFMVLFNFIIPV
  SMYVTVEMQKFLGSFFISWDKDFYDEEINEGALVNTSDLNEELGQVDYVFTDKTGTLTEN
  SMEFIECCIDGHKYKGVTQEVDGLSQTDGTLTYFDKVDKNREELFLRALCLCHTVEIKTN
  DAVDGATESAELTYISSSPDEIALVKGAKRYGFTFLGNRNGYMRVENQRKEIEEYELLHT
  LNFDAVRRRMSVIVKTQEGDILLFCKGADSAVFPRVQNHEIELTKVHVERNAMDGYRTLC
  VAFKEIAPDDYERINRQLIEAKMALQDREEKMEKVFDDIETNMNLIGATAVEDKLQDQAA
  ETIEALHAAGLKVWVLTGDKMETAKSTCYACRLFQTNTELLELTTKTIEESERKEDRLHE
  LLIEYRKKLLHEFPKSTRSFKKAWTEHQEYGLIIDGSTLSLILNSSQDSSSNNYKSIFLQ
  ICMKCTAVLCCRMAPLQKAQIVRMVKNLKGSPITLSIGDGANDVSMILESHVGIGIKGKE
  GRQAARNSDYSVPKFKHLKKLLLAHGHLYYVRIAHLVQYFFYKNLCFILPQFLYQFFCGF
  SQQPLYDAAYLTMYNICFTSLPILAYSLLEQHINIDTLTSDPRLYMKISGNAMLQLGPFL
  YWTFLAAFEGTVFFFGTYFLFQTASLEENGKVYGNWTFGTIVFTVLVFTVTLKLALDTRF
  WTWINHFVIWGSLAFYVFFSFFWGGIIWPFLKQQRMYFVFAQMLSSVSTWLAIILLIFIS
  LFPEILLIVLKNVRRRSARRNLSCRRASDSLSARPSVRPLLLRTFSDESNVL
• 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. Major PS-flippase in immune cell subsets. In erythrocyte plasma membrane, it is required to maintain PS in the inner leaflet preventing its exposure on the surface. This asymmetric distribution is critical for the survival of erythrocytes in circulation since externalized PS is a phagocytic signal for erythrocyte clearance by splenic macrophages. Required for B cell differentiation past the pro-B cell stage. Seems to mediate PS flipping in pro-B cells. May be involved in the transport of cholestatic bile acids.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: Efferocytosis (hsa04148)
• Reactome Pathway: Ion transport by P-type ATPases (R-HSA-936837)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anemia	DISTVL0C	Strong	Altered Expression	[1]
Hereditary haemolytic anemia	DIS487SI	Strong	Genetic Variation	[1]
Intrahepatic cholestasis	DISHITDZ	Limited	Genetic Variation	[2]
Progressive familial intrahepatic cholestasis type 1	DISU0AJE	Limited	Genetic Variation	[2]
X-linked congenital hemolytic anemia	DIS3DRZH	Limited	Unknown	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Phospholipid-transporting ATPase IG (ATP11C).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phospholipid-transporting ATPase IG (ATP11C).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phospholipid-transporting ATPase IG (ATP11C).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Phospholipid-transporting ATPase IG (ATP11C).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Phospholipid-transporting ATPase IG (ATP11C).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Phospholipid-transporting ATPase IG (ATP11C).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Phospholipid-transporting ATPase IG (ATP11C).	[7]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Phospholipid-transporting ATPase IG (ATP11C).	[10]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Phospholipid-transporting ATPase IG (ATP11C).	[12]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Phospholipid-transporting ATPase IG (ATP11C).	[14]
ORG2058	DMH1M6N	Investigative	ORG2058 decreases the expression of Phospholipid-transporting ATPase IG (ATP11C).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Phospholipid-transporting ATPase IG (ATP11C).	[11]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Phospholipid-transporting ATPase IG (ATP11C).	[13]

References

• [1] Identification and functional analyses of disease-associated P4-ATPase phospholipid flippase variants in red blood cells.J Biol Chem. 2019 Apr 26;294(17):6809-6821. doi: 10.1074/jbc.RA118.007270. Epub 2019 Mar 8.
• [2] Hepatic Tmem30a Deficiency Causes Intrahepatic Cholestasis by Impairing Expression and Localization of Bile Salt Transporters.Am J Pathol. 2017 Dec;187(12):2775-2787. doi: 10.1016/j.ajpath.2017.08.011. Epub 2017 Sep 15.
• [3] Mice deficient in the putative phospholipid flippase ATP11C exhibit altered erythrocyte shape, anemia, and reduced erythrocyte life span. J Biol Chem. 2014 Jul 11;289(28):19531-7. doi: 10.1074/jbc.C114.570267. Epub 2014 Jun 4.
• [4] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [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] 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.
• [7] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [8] 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.
• [9] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [11] 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.
• [12] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [13] 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.
• [14] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [15] The antiproliferative effects of progestins in T47D breast cancer cells are tempered by progestin induction of the ETS transcription factor Elf5. Mol Endocrinol. 2010 Jul;24(7):1380-92. doi: 10.1210/me.2009-0516. Epub 2010 Jun 2.