Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPAS5G8)

• DOT Name: Aprataxin (APTX)
• Synonyms: EC 3.6.1.71; EC 3.6.1.72; Forkhead-associated domain histidine triad-like protein; FHA-HIT
• Gene Name: APTX
• Related Disease:
  Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia
  Autosomal dominant optic atrophy, classic form
  Microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability
  Neoplasm
  Neuroblastoma
  Advanced cancer
  Amyotrophic lateral sclerosis
  Anaplastic astrocytoma
  Apraxia
  Ataxia-telangiectasia
  Ataxia-telangiectasia-like disorder
  Ataxia-telangiectasia-like disorder 1
  Cervical cancer
  Cervical carcinoma
  Charlevoix-Saguenay spastic ataxia
  Coenzyme Q10 deficiency
  Dystonia
  Familial isolated deficiency of vitamin E
  Friedreich's ataxia
  Isolated congenital microcephaly
  Marinesco-Sjogren syndrome
  Mitochondrial disease
  Multiple system atrophy
  Peripheral neuropathy
  Premature aging syndrome
  Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy
  Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2
  Carcinoma
  Choreatic disease
  Ocular motor apraxia, Cogan type
  Spinocerebellar ataxia type 14
  Acute myelogenous leukaemia
  Nervous system disease
• UniProt ID: APTX_HUMAN
• PDB ID: 3KT9; 4NDF; 4NDG; 4NDH; 4NDI; 6CVO; 6CVP; 6CVQ; 6CVR; 6CVS; 6CVT
• EC Number: 3.6.1.71; 3.6.1.72
• Pfam ID: PF11969 ; PF17913 ; PF16278
• Sequence:
  MSNVNLSVSDFWRVMMRVCWLVRQDSRHQRIRLPHLEAVVIGRGPETKITDKKCSRQQVQ
  LKAECNKGYVKVKQVGVNPTSIDSVVIGKDQEVKLQPGQVLHMVNELYPYIVEFEEEAKN
  PGLETHRKRKRSGNSDSIERDAAQEAEAGTGLEPGSNSGQCSVPLKKGKDAPIKKESLGH
  WSQGLKISMQDPKMQVYKDEQVVVIKDKYPKARYHWLVLPWTSISSLKAVAREHLELLKH
  MHTVGEKVIVDFAGSSKLRFRLGYHAIPSMSHVHLHVISQDFDSPCLKNKKHWNSFNTEY
  FLESQAVIEMVQEAGRVTVRDGMPELLKLPLRCHECQQLLPSIPQLKEHLRKHWTQ
• Function: DNA-binding protein involved in single-strand DNA break repair, double-strand DNA break repair and base excision repair. Resolves abortive DNA ligation intermediates formed either at base excision sites, or when DNA ligases attempt to repair non-ligatable breaks induced by reactive oxygen species. Catalyzes the release of adenylate groups covalently linked to 5'-phosphate termini, resulting in the production of 5'-phosphate termini that can be efficiently rejoined. Also able to hydrolyze adenosine 5'-monophosphoramidate (AMP-NH(2)) and diadenosine tetraphosphate (AppppA), but with lower catalytic activity. Likewise, catalyzes the release of 3'-linked guanosine (DNAppG) and inosine (DNAppI) from DNA, but has higher specific activity with 5'-linked adenosine (AppDNA).
• Tissue Specificity: Widely expressed; detected in liver, kidney and lymph node (at protein level) . Isoform 1 is highly expressed in the cerebral cortex and cerebellum, compared to isoform 2 (at protein level) . Widely expressed; detected throughout the brain, in liver, kidney, skeletal muscle, fibroblasts, lymphocytes and pancreas .
• KEGG Pathway: Base excision repair (hsa03410)
• BioCyc Pathway: MetaCyc:ENSG00000137074-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia	DIS8CFD7	Definitive	Autosomal recessive	[1]
Autosomal dominant optic atrophy, classic form	DISXUAV9	Definitive	Altered Expression	[2]
Microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability	DISFHDE1	Definitive	Genetic Variation	[3]
Neoplasm	DISZKGEW	Definitive	Altered Expression	[4]
Neuroblastoma	DISVZBI4	Definitive	Genetic Variation	[5]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[6]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Genetic Variation	[7]
Anaplastic astrocytoma	DISSBE0K	Strong	Biomarker	[8]
Apraxia	DISULX63	Strong	Genetic Variation	[9]
Ataxia-telangiectasia	DISP3EVR	Strong	Biomarker	[10]
Ataxia-telangiectasia-like disorder	DIS98DFM	Strong	Biomarker	[11]
Ataxia-telangiectasia-like disorder 1	DISKHZ2U	Strong	Biomarker	[11]
Cervical cancer	DISFSHPF	Strong	Biomarker	[12]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[12]
Charlevoix-Saguenay spastic ataxia	DISE8X81	Strong	Genetic Variation	[13]
Coenzyme Q10 deficiency	DIS1HGDF	Strong	Genetic Variation	[14]
Dystonia	DISJLFGW	Strong	Biomarker	[15]
Familial isolated deficiency of vitamin E	DIS53306	Strong	Genetic Variation	[13]
Friedreich's ataxia	DIS5DV35	Strong	Genetic Variation	[16]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[17]
Marinesco-Sjogren syndrome	DISKEU0B	Strong	Genetic Variation	[13]
Mitochondrial disease	DISKAHA3	Strong	Genetic Variation	[18]
Multiple system atrophy	DISASEYE	Strong	Biomarker	[19]
Peripheral neuropathy	DIS7KN5G	Strong	Biomarker	[20]
Premature aging syndrome	DIS51AGT	Strong	Biomarker	[21]
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy	DISISGZ2	Strong	Biomarker	[17]
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	DIS84UUI	Strong	Biomarker	[2]
Carcinoma	DISH9F1N	moderate	Biomarker	[22]
Choreatic disease	DISH8K3M	moderate	Biomarker	[23]
Ocular motor apraxia, Cogan type	DIS32GGL	moderate	Genetic Variation	[24]
Spinocerebellar ataxia type 14	DISMGAYN	moderate	Biomarker	[25]
Acute myelogenous leukaemia	DISCSPTN	Limited	Biomarker	[26]
Nervous system disease	DISJ7GGT	Limited	Genetic Variation	[27]

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 Aprataxin (APTX).	[28]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Aprataxin (APTX).	[29]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Aprataxin (APTX).	[30]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Aprataxin (APTX).	[31]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Aprataxin (APTX).	[33]

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 decreases the methylation of Aprataxin (APTX).	[32]

References

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• [2] Diminished OPA1 expression and impaired mitochondrial morphology and homeostasis in Aprataxin-deficient cells.Nucleic Acids Res. 2019 May 7;47(8):4086-4110. doi: 10.1093/nar/gkz083.
• [3] Genetic analysis of undiagnosed ataxia-telangiectasia-like disorders.Brain Dev. 2019 Feb;41(2):150-157. doi: 10.1016/j.braindev.2018.09.007. Epub 2018 Oct 6.
• [4] Aprataxin tumor levels predict response of colorectal cancer patients to irinotecan-based treatment.Clin Cancer Res. 2010 Apr 15;16(8):2375-82. doi: 10.1158/1078-0432.CCR-09-3275. Epub 2010 Apr 6.
• [5] Lack of aprataxin impairs mitochondrial functions via downregulation of the APE1/NRF1/NRF2 pathway.Hum Mol Genet. 2015 Aug 15;24(16):4516-29. doi: 10.1093/hmg/ddv183. Epub 2015 May 14.
• [6] Rap GTPase Interactor: A Potential Marker for Cancer Prognosis Following Kidney Transplantation.Front Oncol. 2019 Aug 7;9:737. doi: 10.3389/fonc.2019.00737. eCollection 2019.
• [7] A genome-wide association study on amyotrophic lateral sclerosis in the Taiwanese Han population.Biomark Med. 2016 Jun;10(6):597-611. doi: 10.2217/bmm.15.115. Epub 2015 Nov 18.
• [8] 1p/19q codeletion and IDH1/2 mutation identified a subtype of anaplastic oligoastrocytomas with prognosis as favorable as anaplastic oligodendrogliomas.Neuro Oncol. 2013 Jun;15(6):775-82. doi: 10.1093/neuonc/not027. Epub 2013 Mar 13.
• [9] A novel mutation of aprataxin associated with ataxia ocular apraxia type 1: phenotypical and genotypical characterization.J Neurol Sci. 2007 Sep 15;260(1-2):219-24. doi: 10.1016/j.jns.2007.05.015. Epub 2007 Jun 18.
• [10] Comparing ataxias with oculomotor apraxia: a multimodal study of AOA1, AOA2 and AT focusing on video-oculography and alpha-fetoprotein.Sci Rep. 2017 Nov 10;7(1):15284. doi: 10.1038/s41598-017-15127-9.
• [11] Spinocerebellar ataxia with ocular motor apraxia and DNA repair.Neuropathology. 2006 Aug;26(4):361-7. doi: 10.1111/j.1440-1789.2006.00741.x.
• [12] miR-424 acts as a tumor radiosensitizer by targeting aprataxin in cervical cancer.Oncotarget. 2016 Nov 22;7(47):77508-77515. doi: 10.18632/oncotarget.12716.
• [13] Epidemiological, clinical, paraclinical and molecular study of a cohort of 102 patients affected with autosomal recessive progressive cerebellar ataxia from Alsace, Eastern France: implications for clinical management.Neurogenetics. 2010 Feb;11(1):1-12. doi: 10.1007/s10048-009-0196-y. Epub 2009 May 14.
• [14] Coenzyme Q deficiency and cerebellar ataxia associated with an aprataxin mutation.Neurology. 2005 Feb 8;64(3):539-41. doi: 10.1212/01.WNL.0000150588.75281.58.
• [15] Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies.Brain. 2003 Dec;126(Pt 12):2761-72. doi: 10.1093/brain/awg283. Epub 2003 Sep 23.
• [16] Absence of aprataxin gene mutations in a Greek cohort with sporadic early onset ataxia and normal GAA triplets in frataxin gene.Neurol Sci. 2010 Jun;31(3):393-7. doi: 10.1007/s10072-009-0201-0. Epub 2009 Dec 2.
• [17] Neurological disorders associated with DNA strand-break processing enzymes.Mech Ageing Dev. 2017 Jan;161(Pt A):130-140. doi: 10.1016/j.mad.2016.07.009. Epub 2016 Jul 25.
• [18] A novel diagnostic tool reveals mitochondrial pathology in human diseases and aging.Aging (Albany NY). 2013 Mar;5(3):192-208. doi: 10.18632/aging.100546.
• [19] Aprataxin (APTX) gene mutations resembling multiple system atrophy.Parkinsonism Relat Disord. 2007 Apr;13(3):139-42. doi: 10.1016/j.parkreldis.2006.08.010. Epub 2006 Oct 27.
• [20] A novel nonsense mutation in the APTX gene associated with delayed DNA single-strand break removal fails to enhance sensitivity to different genotoxic agents.Hum Mutat. 2011 Apr;32(4):E2118-33. doi: 10.1002/humu.21464. Epub 2011 Feb 8.
• [21] Expression of a pathogenic mutation of SOD1 sensitizes aprataxin-deficient cells and mice to oxidative stress and triggers hallmarks of premature ageing.Hum Mol Genet. 2015 Feb 1;24(3):828-40. doi: 10.1093/hmg/ddu500. Epub 2014 Sep 30.
• [22] Targeting glutamine metabolism and the focal adhesion kinase additively inhibits the mammalian target of the rapamycin pathway in spheroid cancer stem-like properties of ovarian clear cell carcinoma invitro.Int J Oncol. 2017 Apr;50(4):1431-1438. doi: 10.3892/ijo.2017.3891. Epub 2017 Feb 23.
• [23] Atypical presentation of ataxia-oculomotor apraxia type 1.Dev Med Child Neurol. 2006 Jun;48(6):529-32. doi: 10.1017/S0012162206001113.
• [24] Genotype-phenotype correlations in early onset ataxia with ocular motor apraxia and hypoalbuminaemia.Brain. 2011 May;134(Pt 5):1387-99. doi: 10.1093/brain/awr069. Epub 2011 Apr 12.
• [25] Protein kinase C gamma, a protein causative for dominant ataxia, negatively regulates nuclear import of recessive-ataxia-related aprataxin.Hum Mol Genet. 2009 Oct 1;18(19):3533-43. doi: 10.1093/hmg/ddp298. Epub 2009 Jun 26.
• [26] The clinically relevant pharmacogenomic changes in acute myelogenous leukemia.Pharmacogenomics. 2012 Aug;13(11):1257-69. doi: 10.2217/pgs.12.102.
• [27] Neurodegeneration: nicked to death.Curr Biol. 2007 Jan 23;17(2):R55-8. doi: 10.1016/j.cub.2006.12.012.
• [28] 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.
• [29] 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.
• [30] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [31] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [32] 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.
• [33] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.