Details of Drug Off-Target (DOT)

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

• DOT Name: Polyamine-transporting ATPase 13A2 (ATP13A2)
• Synonyms: EC 7.6.2.-
• Gene Name: ATP13A2
• Related Disease:
  Kufor-Rakeb syndrome
  Adult neuronal ceroid lipofuscinosis
  Advanced cancer
  Autism spectrum disorder
  Autosomal recessive spastic paraplegia type 78
  Cerebellar ataxia
  Ceroid lipofuscinosis, neuronal, 4 (Kufs type)
  CLN2 Batten disease
  Complex hereditary spastic paraplegia
  Gaucher disease
  Hereditary spastic paraplegia 11
  Intellectual disability
  Juvenile-onset Parkinson disease
  Lafora disease
  Late infantile neuronal ceroid lipofuscinosis
  Lysosomal storage disease
  Nervous system disease
  Neurodegeneration with brain iron accumulation
  Neurodegeneration with brain iron accumulation 2A
  Neurodegeneration with brain iron accumulation 5
  Neurodegenerative disease
  Neuronal ceroid lipofuscinosis
  Parkinsonian disorder
  Polyneuropathy
  Vascular purpura
  Young-onset Parkinson disease
  Amyotrophic lateral sclerosis
  Atypical juvenile parkinsonism
  Dementia
  Hereditary spastic paraplegia
  Idiopathic parkinson disease
  Parkinsonism due to ATP13A2 deficiency
  Autosomal recessive juvenile Parkinson disease 2
  Hereditary motor and sensory neuropathy
  Melanoma
  Neuroblastoma
• UniProt ID: AT132_HUMAN
• PDB ID: 7FJM; 7FJP; 7FJQ; 7M5V; 7M5X; 7M5Y; 7N70; 7N72; 7N73; 7N74; 7N75; 7N76; 7N77; 7N78; 7VPI; 7VPJ; 7VPK; 7VPL
• EC Number: 7.6.2.-
• Pfam ID: PF00122 ; PF12409
• Sequence:
  MSADSSPLVGSTPTGYGTLTIGTSIDPLSSSVSSVRLSGYCGSPWRVIGYHVVVWMMAGI
  PLLLFRWKPLWGVRLRLRPCNLAHAETLVIEIRDKEDSSWQLFTVQVQTEAIGEGSLEPS
  PQSQAEDGRSQAAVGAVPEGAWKDTAQLHKSEEAVSVGQKRVLRYYLFQGQRYIWIETQQ
  AFYQVSLLDHGRSCDDVHRSRHGLSLQDQMVRKAIYGPNVISIPVKSYPQLLVDEALNPY
  YGFQAFSIALWLADHYYWYALCIFLISSISICLSLYKTRKQSQTLRDMVKLSMRVCVCRP
  GGEEEWVDSSELVPGDCLVLPQEGGLMPCDAALVAGECMVNESSLTGESIPVLKTALPEG
  LGPYCAETHRRHTLFCGTLILQARAYVGPHVLAVVTRTGFCTAKGGLVSSILHPRPINFK
  FYKHSMKFVAALSVLALLGTIYSIFILYRNRVPLNEIVIRALDLVTVVVPPALPAAMTVC
  TLYAQSRLRRQGIFCIHPLRINLGGKLQLVCFDKTGTLTEDGLDVMGVVPLKGQAFLPLV
  PEPRRLPVGPLLRALATCHALSRLQDTPVGDPMDLKMVESTGWVLEEEPAADSAFGTQVL
  AVMRPPLWEPQLQAMEEPPVPVSVLHRFPFSSALQRMSVVVAWPGATQPEAYVKGSPELV
  AGLCNPETVPTDFAQMLQSYTAAGYRVVALASKPLPTVPSLEAAQQLTRDTVEGDLSLLG
  LLVMRNLLKPQTTPVIQALRRTRIRAVMVTGDNLQTAVTVARGCGMVAPQEHLIIVHATH
  PERGQPASLEFLPMESPTAVNGVKDPDQAASYTVEPDPRSRHLALSGPTFGIIVKHFPKL
  LPKVLVQGTVFARMAPEQKTELVCELQKLQYCVGMCGDGANDCGALKAADVGISLSQAEA
  SVVSPFTSSMASIECVPMVIREGRCSLDTSFSVFKYMALYSLTQFISVLILYTINTNLGD
  LQFLAIDLVITTTVAVLMSRTGPALVLGRVRPPGALLSVPVLSSLLLQMVLVTGVQLGGY
  FLTLAQPWFVPLNRTVAAPDNLPNYENTVVFSLSSFQYLILAAAVSKGAPFRRPLYTNVP
  FLVALALLSSVLVGLVLVPGLLQGPLALRNITDTGFKLLLLGLVTLNFVGAFMLESVLDQ
  CLPACLRRLRPKRASKKRFKQLERELAEQPWPPLPAGPLR
• Function: ATPase which acts as a lysosomal polyamine exporter with high affinity for spermine. Also stimulates cellular uptake of polyamines and protects against polyamine toxicity. Plays a role in intracellular cation homeostasis and the maintenance of neuronal integrity. Contributes to cellular zinc homeostasis. Confers cellular protection against Mn(2+) and Zn(2+) toxicity and mitochondrial stress. Required for proper lysosomal and mitochondrial maintenance. Regulates the autophagy-lysosome pathway through the control of SYT11 expression at both transcriptional and post-translational levels. Facilitates recruitment of deacetylase HDAC6 to lysosomes to deacetylate CTTN, leading to actin polymerization, promotion of autophagosome-lysosome fusion and completion of autophagy. Promotes secretion of exosomes as well as secretion of SCNA via exosomes. Plays a role in lipid homeostasis.
• Tissue Specificity: Expressed in brain; protein levels are markedly increased in brain from subjects with Parkinson disease and subjects with dementia with Lewy bodies. Detected in pyramidal neurons located throughout the cingulate cortex (at protein level). In the substantia nigra, it is found in neuromelanin-positive dopaminergic neurons (at protein level).
• Reactome Pathway: Ion transport by P-type ATPases (R-HSA-936837)

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Kufor-Rakeb syndrome	DIS09C7Z	Definitive	Autosomal recessive	[1]
Adult neuronal ceroid lipofuscinosis	DIS5UHAA	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[4]
Autosomal recessive spastic paraplegia type 78	DIS8MMBW	Strong	Autosomal recessive	[5]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[6]
Ceroid lipofuscinosis, neuronal, 4 (Kufs type)	DISC5V9S	Strong	Biomarker	[2]
CLN2 Batten disease	DISZC5YB	Strong	Biomarker	[2]
Complex hereditary spastic paraplegia	DIS9KXQY	Strong	Biomarker	[7]
Gaucher disease	DISTW5JG	Strong	Genetic Variation	[8]
Hereditary spastic paraplegia 11	DIS8K8V4	Strong	Genetic Variation	[9]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[10]
Juvenile-onset Parkinson disease	DISNT5BI	Strong	Genetic Variation	[11]
Lafora disease	DIS83JHH	Strong	Altered Expression	[12]
Late infantile neuronal ceroid lipofuscinosis	DISI3RIL	Strong	Biomarker	[2]
Lysosomal storage disease	DIS6QM6U	Strong	Altered Expression	[13]
Nervous system disease	DISJ7GGT	Strong	Biomarker	[7]
Neurodegeneration with brain iron accumulation	DISRK4DZ	Strong	Genetic Variation	[14]
Neurodegeneration with brain iron accumulation 2A	DIS9XEBF	Strong	Genetic Variation	[15]
Neurodegeneration with brain iron accumulation 5	DISW9SFJ	Strong	Genetic Variation	[9]
Neurodegenerative disease	DISM20FF	Strong	Biomarker	[2]
Neuronal ceroid lipofuscinosis	DIS9A4K4	Strong	Genetic Variation	[16]
Parkinsonian disorder	DISHGY45	Strong	Genetic Variation	[6]
Polyneuropathy	DISB9G3W	Strong	Genetic Variation	[6]
Vascular purpura	DIS6ZZMF	Strong	Genetic Variation	[8]
Young-onset Parkinson disease	DIS05LFS	Strong	Altered Expression	[17]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Genetic Variation	[18]
Atypical juvenile parkinsonism	DISYXFE3	moderate	Genetic Variation	[19]
Dementia	DISXL1WY	moderate	Genetic Variation	[20]
Hereditary spastic paraplegia	DISGZQV1	moderate	Genetic Variation	[13]
Idiopathic parkinson disease	DIS18PD0	moderate	Biomarker	[21]
Parkinsonism due to ATP13A2 deficiency	DISOMWF3	Supportive	Autosomal recessive	[22]
Autosomal recessive juvenile Parkinson disease 2	DISNSTD1	Limited	Biomarker	[23]
Hereditary motor and sensory neuropathy	DISR0X2K	Limited	Genetic Variation	[24]
Melanoma	DIS1RRCY	Limited	Genetic Variation	[25]
Neuroblastoma	DISVZBI4	Limited	Genetic Variation	[25]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Polyamine-transporting ATPase 13A2 (ATP13A2) decreases the response to substance of Hydrogen peroxide.	[2]
MG-132	DMKA2YS	Preclinical	Polyamine-transporting ATPase 13A2 (ATP13A2) decreases the response to substance of MG-132.	[2]
Paraquat	DMR8O3X	Investigative	Polyamine-transporting ATPase 13A2 (ATP13A2) increases the response to substance of Paraquat.	[35]
Manganese	DMKT129	Investigative	Polyamine-transporting ATPase 13A2 (ATP13A2) decreases the response to substance of Manganese.	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Polyamine-transporting ATPase 13A2 (ATP13A2).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Polyamine-transporting ATPase 13A2 (ATP13A2).	[27]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Polyamine-transporting ATPase 13A2 (ATP13A2).	[28]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Polyamine-transporting ATPase 13A2 (ATP13A2).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Polyamine-transporting ATPase 13A2 (ATP13A2).	[30]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Polyamine-transporting ATPase 13A2 (ATP13A2).	[31]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Polyamine-transporting ATPase 13A2 (ATP13A2).	[32]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Polyamine-transporting ATPase 13A2 (ATP13A2).	[33]

References

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• [2] Characterization of cellular protective effects of ATP13A2/PARK9 expression and alterations resulting from pathogenic mutants. J Neurosci Res. 2012 Dec;90(12):2306-16. doi: 10.1002/jnr.23112. Epub 2012 Jul 30.
• [3] The strategic function of the P5-ATPase ATP13A2 in toxic waste disposal.Neurochem Int. 2018 Jan;112:108-113. doi: 10.1016/j.neuint.2017.11.008. Epub 2017 Nov 21.
• [4] Parkinson disease related ATP13A2 evolved early in animal evolution.PLoS One. 2018 Mar 5;13(3):e0193228. doi: 10.1371/journal.pone.0193228. eCollection 2018.
• [5] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [6] Clinical and ultrastructural findings in an ataxic variant of Kufor-Rakeb syndrome.Folia Neuropathol. 2019;57(3):285-294. doi: 10.5114/fn.2019.88459.
• [7] Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78). Brain. 2017 Feb;140(2):287-305. doi: 10.1093/brain/aww307.
• [8] Partial loss of ATP13A2 causes selective gliosis independent of robust lipofuscinosis.Mol Cell Neurosci. 2018 Oct;92:17-26. doi: 10.1016/j.mcn.2018.05.009. Epub 2018 Jun 1.
• [9] Rare causes of dystonia parkinsonism.Curr Neurol Neurosci Rep. 2010 Nov;10(6):431-9. doi: 10.1007/s11910-010-0136-0.
• [10] Identification of novel loci for pediatric cholestatic liver disease defined by KIF12, PPM1F, USP53, LSR, and WDR83OS pathogenic variants. Genet Med. 2019 May;21(5):1164-1172. doi: 10.1038/s41436-018-0288-x. Epub 2018 Sep 25.
• [11] Successful treatment of psychosis in a patient with Kufor-Rakeb syndrome with low dose aripiprazole: a case report.Neurocase. 2019 Jun-Aug;25(3-4):133-137. doi: 10.1080/13554794.2019.1625928. Epub 2019 Jun 24.
• [12] Glucocerebrosidase mutations alter the endoplasmic reticulum and lysosomes in Lewy body disease.J Neurochem. 2012 Oct;123(2):298-309. doi: 10.1111/j.1471-4159.2012.07879.x. Epub 2012 Aug 22.
• [13] The Parkinson-associated human P5B-ATPase ATP13A2 modifies lipid homeostasis.Biochim Biophys Acta Biomembr. 2019 Oct 1;1861(10):182993. doi: 10.1016/j.bbamem.2019.05.015. Epub 2019 May 24.
• [14] Iron dysregulation in movement disorders.Neurobiol Dis. 2012 Apr;46(1):1-18. doi: 10.1016/j.nbd.2011.12.054. Epub 2012 Jan 12.
• [15] Excess iron harms the brain: the syndromes of neurodegeneration with brain iron accumulation (NBIA).J Neural Transm (Vienna). 2013 Apr;120(4):695-703. doi: 10.1007/s00702-012-0922-8. Epub 2012 Dec 2.
• [16] ATP13A2 missense variant in Australian Cattle Dogs with late onset neuronal ceroid lipofuscinosis.Mol Genet Metab. 2019 May;127(1):95-106. doi: 10.1016/j.ymgme.2018.11.015. Epub 2019 Mar 27.
• [17] Overlapping expression patterns and functions of three paralogous P5B ATPases in Caenorhabditis elegans.PLoS One. 2018 Mar 16;13(3):e0194451. doi: 10.1371/journal.pone.0194451. eCollection 2018.
• [18] Mutations in ATP13A2 (PARK9) are associated with an amyotrophic lateral sclerosis-like phenotype, implicating this locus in further phenotypic expansion.Hum Genomics. 2019 Apr 16;13(1):19. doi: 10.1186/s40246-019-0203-9.
• [19] Novel ATP13A2 (PARK9) homozygous mutation in a family with marked phenotype variability.Neurogenetics. 2011 Feb;12(1):33-9. doi: 10.1007/s10048-010-0259-0. Epub 2010 Sep 21.
• [20] Overexpression of human Atp13a2Isoform-1 protein protects cells against manganese and starvation-induced toxicity.PLoS One. 2019 Aug 8;14(8):e0220849. doi: 10.1371/journal.pone.0220849. eCollection 2019.
• [21] ATP13A2 (PARK9) polymorphisms influence the neurotoxic effects of manganese.Neurotoxicology. 2012 Aug;33(4):697-702. doi: 10.1016/j.neuro.2012.01.007. Epub 2012 Jan 20.
• [22] Mutation of the parkinsonism gene ATP13A2 causes neuronal ceroid-lipofuscinosis. Hum Mol Genet. 2012 Jun 15;21(12):2646-50. doi: 10.1093/hmg/dds089. Epub 2012 Mar 2.
• [23] Low doses of paraquat and polyphenols prolong life span and locomotor activity in knock-down parkin Drosophila melanogaster exposed to oxidative stress stimuli: implication in autosomal recessive juvenile parkinsonism.Gene. 2013 Jan 10;512(2):355-63. doi: 10.1016/j.gene.2012.09.120. Epub 2012 Oct 6.
• [24] Genetic and phenotypic characterization of complex hereditary spastic paraplegia.Brain. 2016 Jul;139(Pt 7):1904-18. doi: 10.1093/brain/aww111. Epub 2016 May 23.
• [25] ATP13A2/PARK9 regulates endo-/lysosomal cargo sorting and proteostasis through a novel PI(3, 5)P2-mediated scaffolding function.Hum Mol Genet. 2017 May 1;26(9):1656-1669. doi: 10.1093/hmg/ddx070.
• [26] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [27] 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.
• [28] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [29] 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.
• [30] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [31] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [32] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [33] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [34] Characterization of cellular protective effects of ATP13A2/PARK9 expression and alterations resulting from pathogenic mutants. J Neurosci Res. 2012 Dec;90(12):2306-16. doi: 10.1002/jnr.23112. Epub 2012 Jul 30.
• [35] CHO cells expressing the human P?-ATPase ATP13A2 are more sensitive to the toxic effects of herbicide paraquat. Neurochem Int. 2012 Feb;60(3):243-8. doi: 10.1016/j.neuint.2012.01.002. Epub 2012 Jan 12.