Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH5WJ09)

• DOT Name: Phospholipid-transporting ATPase ID (ATP8B2)
• Synonyms: EC 7.6.2.1; ATPase class I type 8B member 2; P4-ATPase flippase complex alpha subunit ATP8B2
• Gene Name: ATP8B2
• Related Disease: Non-insulin dependent diabetes
• UniProt ID: AT8B2_HUMAN
• EC Number: 7.6.2.1
• Pfam ID: PF13246 ; PF16212 ; PF16209
• Sequence:
  MTVPKEMPEKWARAQAPPSWSRKKPSWGTEEERRARANDREYNEKFQYASNCIKTSKYNI
  LTFLPVNLFEQFQEVANTYFLFLLILQLIPQISSLSWFTTIVPLVLVLTITAVKDATDDY
  FRHKSDNQVNNRQSQVLINGILQQEQWMNVCVGDIIKLENNQFVAADLLLLSSSEPHGLC
  YIETAELDGETNMKVRQAIPVTSELGDISKLAKFDGEVICEPPNNKLDKFSGTLYWKENK
  FPLSNQNMLLRGCVLRNTEWCFGLVIFAGPDTKLMQNSGRTKFKRTSIDRLMNTLVLWIF
  GFLVCMGVILAIGNAIWEHEVGMRFQVYLPWDEAVDSAFFSGFLSFWSYIIILNTVVPIS
  LYVSVEVIRLGHSYFINWDKKMFCMKKRTPAEARTTTLNEELGQVEYIFSDKTGTLTQNI
  MVFNKCSINGHSYGDVFDVLGHKAELGERPEPVDFSFNPLADKKFLFWDPSLLEAVKIGD
  PHTHEFFRLLSLCHTVMSEEKNEGELYYKAQSPDEGALVTAARNFGFVFRSRTPKTITVH
  EMGTAITYQLLAILDFNNIRKRMSVIVRNPEGKIRLYCKGADTILLDRLHHSTQELLNTT
  MDHLNEYAGEGLRTLVLAYKDLDEEYYEEWAERRLQASLAQDSREDRLASIYEEVENNMM
  LLGATAIEDKLQQGVPETIALLTLANIKIWVLTGDKQETAVNIGYSCKMLTDDMTEVFIV
  TGHTVLEVREELRKAREKMMDSSRSVGNGFTYQDKLSSSKLTSVLEAVAGEYALVINGHS
  LAHALEADMELEFLETACACKAVICCRVTPLQKAQVVELVKKYKKAVTLAIGDGANDVSM
  IKTAHIGVGISGQEGIQAVLASDYSFSQFKFLQRLLLVHGRWSYLRMCKFLCYFFYKNFA
  FTMVHFWFGFFCGFSAQTVYDQYFITLYNIVYTSLPVLAMGVFDQDVPEQRSMEYPKLYE
  PGQLNLLFNKREFFICIAQGIYTSVLMFFIPYGVFADATRDDGTQLADYQSFAVTVATSL
  VIVVSVQIGLDTGYWTAINHFFIWGSLAVYFAILFAMHSNGLFDMFPNQFRFVGNAQNTL
  AQPTVWLTIVLTTVVCIMPVVAFRFLRLNLKPDLSDTVRYTQLVRKKQKAQHRCMRRVGR
  TGSRRSGYAFSHQEGFGELIMSGKNMRLSSLALSSFTTRSSSSWIESLRRKKSDSASSPS
  GGADKPLKG
• Function: Catalytic component of P4-ATPase flippase complex, which catalyzes the hydrolysis of ATP coupled to the transport of phosphatidylcholine (PC) from the outer to the inner leaflet of the plasma membrane. May contribute to the maintenance of membrane lipid asymmetry.
• Tissue Specificity: Isoform 3 is ubiquitous, with highest expression in aorta, cerebellum and uterus.
• Reactome Pathway: Ion transport by P-type ATPases (R-HSA-936837)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorpyrifos	DMKPUI6	Investigative	Phospholipid-transporting ATPase ID (ATP8B2) decreases the response to substance of Chlorpyrifos.	[13]

11 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 ID (ATP8B2).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phospholipid-transporting ATPase ID (ATP8B2).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Phospholipid-transporting ATPase ID (ATP8B2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Phospholipid-transporting ATPase ID (ATP8B2).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Phospholipid-transporting ATPase ID (ATP8B2).	[6]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Phospholipid-transporting ATPase ID (ATP8B2).	[7]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of Phospholipid-transporting ATPase ID (ATP8B2).	[8]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Phospholipid-transporting ATPase ID (ATP8B2).	[9]
Genistein	DM0JETC	Phase 2/3	Genistein affects the expression of Phospholipid-transporting ATPase ID (ATP8B2).	[8]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Phospholipid-transporting ATPase ID (ATP8B2).	[11]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Phospholipid-transporting ATPase ID (ATP8B2).	[12]

1 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 affects the methylation of Phospholipid-transporting ATPase ID (ATP8B2).	[10]

References

• [1] Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population.Nat Genet. 2019 Mar;51(3):379-386. doi: 10.1038/s41588-018-0332-4. Epub 2019 Feb 4.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [7] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [8] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [9] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [10] 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.
• [11] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [12] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [13] Application of human haploid cell genetic screening model in identifying the genes required for resistance to environmental toxicants: Chlorpyrifos as a case study. J Pharmacol Toxicol Methods. 2015 Nov-Dec;76:76-82. doi: 10.1016/j.vascn.2015.08.154. Epub 2015 Aug 20.