Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDZC2ZT)

• DOT Name: Phospholipid-transporting ATPase IB (ATP8A2)
• Synonyms: EC 7.6.2.1; ATPase class I type 8A member 2; ML-1; P4-ATPase flippase complex alpha subunit ATP8A2
• Gene Name: ATP8A2
• Related Disease:
  Nervous system disease
  Anorexia nervosa cachexia
  Bulimia nervosa
  Cerebellar ataxia
  Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1
  Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4
  Cervical cancer
  Cervical carcinoma
  Eating disorder
  Hepatitis B virus infection
  Intellectual disability
  Leukemia
  Movement disorder
  Sarcoidosis
  Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2
  Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3
  Choreatic disease
  Hearing loss, autosomal recessive
  Cerebellar ataxia, intellectual disability, and dysequilibrium
  Acute myelogenous leukaemia
• UniProt ID: AT8A2_HUMAN
• EC Number: 7.6.2.1
• Pfam ID: PF13246 ; PF00122 ; PF16212 ; PF16209
• Sequence:
  MLNGAGLDKALKMSLPRRSRIRSSVGPVRSSLGYKKAEDEMSRATSVGDQLEAPARTIYL
  NQPHLNKFRDNQISTAKYSVLTFLPRFLYEQIRRAANAFFLFIALLQQIPDVSPTGRYTT
  LVPLIIILTIAGIKEIVEDFKRHKADNAVNKKKTIVLRNGMWHTIMWKEVAVGDIVKVVN
  GQYLPADVVLLSSSEPQAMCYVETANLDGETNLKIRQGLSHTADMQTREVLMKLSGTIEC
  EGPNRHLYDFTGNLNLDGKSLVALGPDQILLRGTQLRNTQWVFGIVVYTGHDTKLMQNST
  KAPLKRSNVEKVTNVQILVLFGILLVMALVSSAGALYWNRSHGEKNWYIKKMDTTSDNFG
  YNLLTFIILYNNLIPISLLVTLEVVKYTQALFINWDTDMYYIGNDTPAMARTSNLNEELG
  QVKYLFSDKTGTLTCNIMNFKKCSIAGVTYGHFPELAREPSSDDFCRMPPPCSDSCDFDD
  PRLLKNIEDRHPTAPCIQEFLTLLAVCHTVVPEKDGDNIIYQASSPDEAALVKGAKKLGF
  VFTARTPFSVIIEAMGQEQTFGILNVLEFSSDRKRMSVIVRTPSGRLRLYCKGADNVIFE
  RLSKDSKYMEETLCHLEYFATEGLRTLCVAYADLSENEYEEWLKVYQEASTILKDRAQRL
  EECYEIIEKNLLLLGATAIEDRLQAGVPETIATLLKAEIKIWVLTGDKQETAINIGYSCR
  LVSQNMALILLKEDSLDATRAAITQHCTDLGNLLGKENDVALIIDGHTLKYALSFEVRRS
  FLDLALSCKAVICCRVSPLQKSEIVDVVKKRVKAITLAIGDGANDVGMIQTAHVGVGISG
  NEGMQATNNSDYAIAQFSYLEKLLLVHGAWSYNRVTKCILYCFYKNVVLYIIELWFAFVN
  GFSGQILFERWCIGLYNVIFTALPPFTLGIFERSCTQESMLRFPQLYKITQNGEGFNTKV
  FWGHCINALVHSLILFWFPMKALEHDTVLTSGHATDYLFVGNIVYTYVVVTVCLKAGLET
  TAWTKFSHLAVWGSMLTWLVFFGIYSTIWPTIPIAPDMRGQATMVLSSAHFWLGLFLVPT
  ACLIEDVAWRAAKHTCKKTLLEEVQELETKSRVLGKAVLRDSNGKRLNERDRLIKRLGRK
  TPPTLFRGSSLQQGVPHGYAFSQEEHGAVSQEEVIRAYDTTKKKSRKK
• Function: Catalytic 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. Able to translocate phosphatidylserine, but not phosphatidylcholine. Phospholipid translocation seems also to be implicated in vesicle formation and in uptake of lipid signaling molecules. Reconstituted to liposomes, the ATP8A2:TMEM30A flippase complex predominantly transports phosphatidylserine (PS) and to a lesser extent phosphatidylethanolamine (PE). Phospholipid translocation is not associated with a countertransport of an inorganic ion or other charged substrate from the cytoplasmic side toward the exoplasm in connection with the phosphorylation from ATP. ATP8A2:TMEM30A may be involved in regulation of neurite outgrowth. Proposed to function in the generation and maintenance of phospholipid asymmetry in photoreceptor disk membranes and neuronal axon membranes. May be involved in vesicle trafficking in neuronal cells. Required for normal visual and auditory function; involved in photoreceptor and inner ear spiral ganglion cell survival.
• Tissue Specificity: Strongly expressed in the brain, cerebellum, retina and testis.
• KEGG Pathway: Efferocytosis (hsa04148)
• Reactome Pathway: Ion transport by P-type ATPases (R-HSA-936837)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nervous system disease	DISJ7GGT	Definitive	Genetic Variation	[1]
Anorexia nervosa cachexia	DISFO5RQ	Strong	Biomarker	[2]
Bulimia nervosa	DISGQ59Y	Strong	Biomarker	[2]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[3]
Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1	DISBHBD6	Strong	Biomarker	[4]
Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4	DISF9SBX	Strong	Autosomal recessive	[5]
Cervical cancer	DISFSHPF	Strong	Biomarker	[6]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[6]
Eating disorder	DISVGXN0	Strong	Genetic Variation	[2]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[7]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[1]
Leukemia	DISNAKFL	Strong	Biomarker	[8]
Movement disorder	DISOJJ2D	Strong	Genetic Variation	[9]
Sarcoidosis	DISE5B8Z	Strong	Genetic Variation	[10]
Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2	DISUFWJU	moderate	Biomarker	[4]
Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3	DISYM1WZ	moderate	Biomarker	[4]
Choreatic disease	DISH8K3M	moderate	Genetic Variation	[9]
Hearing loss, autosomal recessive	DIS8G9R9	moderate	Biomarker	[11]
Cerebellar ataxia, intellectual disability, and dysequilibrium	DIS9923V	Supportive	Autosomal recessive	[12]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[13]

5 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 IB (ATP8A2).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phospholipid-transporting ATPase IB (ATP8A2).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Phospholipid-transporting ATPase IB (ATP8A2).	[17]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Phospholipid-transporting ATPase IB (ATP8A2).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Phospholipid-transporting ATPase IB (ATP8A2).	[21]

4 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 IB (ATP8A2).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Phospholipid-transporting ATPase IB (ATP8A2).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Phospholipid-transporting ATPase IB (ATP8A2).	[20]
1,6-hexamethylene diisocyanate	DMLB3RT	Investigative	1,6-hexamethylene diisocyanate increases the methylation of Phospholipid-transporting ATPase IB (ATP8A2).	[22]

References

• [1] Expression and functional characterization of missense mutations in ATP8A2 linked to severe neurological disorders.Hum Mutat. 2019 Dec;40(12):2353-2364. doi: 10.1002/humu.23889. Epub 2019 Aug 23.
• [2] Genetic variants associated with disordered eating.Int J Eat Disord. 2013 Sep;46(6):594-608. doi: 10.1002/eat.22133. Epub 2013 Apr 9.
• [3] ATP8A2-related disorders as recessive cerebellar ataxia.J Neurol. 2020 Jan;267(1):203-213. doi: 10.1007/s00415-019-09579-4. Epub 2019 Oct 14.
• [4] Loss of Tmem30a leads to photoreceptor degeneration.Sci Rep. 2017 Aug 24;7(1):9296. doi: 10.1038/s41598-017-09506-5.
• [5] Disruption of the ATP8A2 gene in a patient with a t(10;13) de novo balanced translocation and a severe neurological phenotype. Eur J Hum Genet. 2010 Dec;18(12):1360-3. doi: 10.1038/ejhg.2010.126. Epub 2010 Aug 4.
• [6] Circ-ATP8A2 promotes cell proliferation and invasion as a ceRNA to target EGFR by sponging miR-433 in cervical cancer.Gene. 2019 Jul 15;705:103-108. doi: 10.1016/j.gene.2019.04.068. Epub 2019 Apr 25.
• [7] A novel HBV genotypes detecting system combined with microfluidic chip, loop-mediated isothermal amplification and GMR sensors.Biosens Bioelectron. 2014 Apr 15;54:372-7. doi: 10.1016/j.bios.2013.11.025. Epub 2013 Nov 15.
• [8] Induction of Fas ligand (CD95L) by the toxic mistletoe lectins in human lymphocytes.Anticancer Res. 1999 May-Jun;19(3A):1785-90.
• [9] Recessive mutations in ATP8A2 cause severe hypotonia, cognitive impairment, hyperkinetic movement disorders and progressive optic atrophy.Orphanet J Rare Dis. 2018 May 31;13(1):86. doi: 10.1186/s13023-018-0825-3.
• [10] Genome-wide association study of African and European Americans implicates multiple shared and ethnic specific loci in sarcoidosis susceptibility.PLoS One. 2012;7(8):e43907. doi: 10.1371/journal.pone.0043907. Epub 2012 Aug 27.
• [11] Wide spectrum of congenital anomalies including choanal atresia, malformed extremities, and brain and spinal malformations in a girl with a de novo 5.6-Mb deletion of 13q12.11-13q12.13.Am J Med Genet A. 2014 Jul;164A(7):1734-43. doi: 10.1002/ajmg.a.36391. Epub 2014 May 7.
• [12] Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion. Eur J Hum Genet. 2013 Mar;21(3):281-5. doi: 10.1038/ejhg.2012.170. Epub 2012 Aug 15.
• [13] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [14] 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.
• [15] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [16] 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.
• [17] 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.
• [18] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [19] 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.
• [20] 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.
• [21] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [22] DNA methylation modifies urine biomarker levels in 1,6-hexamethylene diisocyanate exposed workers: a pilot study. Toxicol Lett. 2014 Dec 1;231(2):217-26. doi: 10.1016/j.toxlet.2014.10.024. Epub 2014 Oct 22.