Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT48TSYO)

• DOT Name: Probable phospholipid-transporting ATPase IM (ATP8B4)
• Synonyms: EC 7.6.2.1; ATPase class I type 8B member 4; P4-ATPase flippase complex alpha subunit ATP8B4
• Gene Name: ATP8B4
• Related Disease:
  Helicoid peripapillary chorioretinal degeneration
  Systemic sclerosis
• UniProt ID: AT8B4_HUMAN
• EC Number: 7.6.2.1
• Pfam ID: PF13246 ; PF16212 ; PF16209
• Sequence:
  MFCSEKKLREVERIVKANDREYNEKFQYADNRIHTSKYNILTFLPINLFEQFQRVANAYF
  LCLLILQLIPEISSLTWFTTIVPLVLVITMTAVKDATDDYFRHKSDNQVNNRQSEVLINS
  KLQNEKWMNVKVGDIIKLENNQFVAADLLLLSSSEPHGLCYVETAELDGETNLKVRHALS
  VTSELGADISRLAGFDGIVVCEVPNNKLDKFMGILSWKDSKHSLNNEKIILRGCILRNTS
  WCFGMVIFAGPDTKLMQNSGKTKFKRTSIDRLMNTLVLWIFGFLICLGIILAIGNSIWES
  QTGDQFRTFLFWNEGEKSSVFSGFLTFWSYIIILNTVVPISLYVSVEVIRLGHSYFINWD
  RKMYYSRKAIPAVARTTTLNEELGQIEYIFSDKTGTLTQNIMTFKRCSINGRIYGEVHDD
  LDQKTEITQEKEPVDFSVKSQADREFQFFDHHLMESIKMGDPKVHEFLRLLALCHTVMSE
  ENSAGELIYQVQSPDEGALVTAARNFGFIFKSRTPETITIEELGTLVTYQLLAFLDFNNT
  RKRMSVIVRNPEGQIKLYSKGADTILFEKLHPSNEVLLSLTSDHLSEFAGEGLRTLAIAY
  RDLDDKYFKEWHKMLEDANAATEERDERIAGLYEEIERDLMLLGATAVEDKLQEGVIETV
  TSLSLANIKIWVLTGDKQETAINIGYACNMLTDDMNDVFVIAGNNAVEVREELRKAKQNL
  FGQNRNFSNGHVVCEKKQQLELDSIVEETITGDYALIINGHSLAHALESDVKNDLLELAC
  MCKTVICCRVTPLQKAQVVELVKKYRNAVTLAIGDGANDVSMIKSAHIGVGISGQEGLQA
  VLASDYSFAQFRYLQRLLLVHGRWSYFRMCKFLCYFFYKNFAFTLVHFWFGFFCGFSAQT
  VYDQWFITLFNIVYTSLPVLAMGIFDQDVSDQNSVDCPQLYKPGQLNLLFNKRKFFICVL
  HGIYTSLVLFFIPYGAFYNVAGEDGQHIADYQSFAVTMATSLVIVVSVQIALDTSYWTFI
  NHVFIWGSIAIYFSILFTMHSNGIFGIFPNQFPFVGNARHSLTQKCIWLVILLTTVASVM
  PVVAFRFLKVDLYPTLSDQIRRWQKAQKKARPPSSRRPRTRRSSSRRSGYAFAHQEGYGE
  LITSGKNMRAKNPPPTSGLEKTHYNSTSWIENLCKKTTDTVSSFSQDKTVKL
• Function: Component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids from the outer to the inner leaflet of various membranes and ensures the maintenance of asymmetric distribution of phospholipids. Phospholipid translocation seems also to be implicated in vesicle formation and in uptake of lipid signaling molecules (Probable).
• Tissue Specificity: Ubiquitously expressed at moderate levels.
• Reactome Pathway:
  Ion transport by P-type ATPases (R-HSA-936837)
  Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Helicoid peripapillary chorioretinal degeneration	DISFSS5N	Strong	Genetic Variation	[1]
Systemic sclerosis	DISF44L6	Limited	Genetic Variation	[1]

7 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 Probable phospholipid-transporting ATPase IM (ATP8B4).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Probable phospholipid-transporting ATPase IM (ATP8B4).	[3]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Probable phospholipid-transporting ATPase IM (ATP8B4).	[4]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Probable phospholipid-transporting ATPase IM (ATP8B4).	[5]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Probable phospholipid-transporting ATPase IM (ATP8B4).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Probable phospholipid-transporting ATPase IM (ATP8B4).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Probable phospholipid-transporting ATPase IM (ATP8B4).	[8]

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 Probable phospholipid-transporting ATPase IM (ATP8B4).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Probable phospholipid-transporting ATPase IM (ATP8B4).	[10]

References

• [1] Brief Report: Whole-Exome Sequencing to Identify Rare Variants and Gene Networks That Increase Susceptibility to Scleroderma in African Americans.Arthritis Rheumatol. 2018 Oct;70(10):1654-1660. doi: 10.1002/art.40541. Epub 2018 Aug 29.
• [2] 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.
• [3] 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.
• [4] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [5] 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.
• [6] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] 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.
• [9] 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.
• [10] 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.