Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJT9T23)

• DOT Name: Aladin (AAAS)
• Synonyms: Adracalin
• Gene Name: AAAS
• Related Disease:
  Cerebellar degeneration
  Peroxisome biogenesis disorder
  Triple-A syndrome
  Type-1/2 diabetes
  Aarskog-Scott syndrome, X-linked
  Abdominal aortic aneurysm
  Achalasia
  Acute myelogenous leukaemia
  Adrenocortical insufficiency
  Arteriosclerosis
  Atherosclerosis
  Bone Paget disease
  Cardiovascular disease
  Dysautonomia
  Frontotemporal dementia
  Glucocorticoid deficiency 1
  Hereditary spastic paraplegia
  Inclusion body myopathy with Paget disease of bone and frontotemporal dementia
  Non-insulin dependent diabetes
  Obesity
  Pick disease
  Prostate cancer
  Prostate neoplasm
  Autonomic nervous system disorder
  Charcot-Marie-Tooth disease axonal type 2Q
  Hypoglycemia
  Metabolic disorder
  Motor neurone disease
  Parkinsonian disorder
  Peripheral sensory neuropathies
  Spastic ataxia
  Acute adrenal insufficiency
  Autosomal dominant polycystic kidney disease
  Neuroblastoma
  Rheumatoid arthritis
• UniProt ID: AAAS_HUMAN
• PDB ID: 7R5J; 7R5K
• Pfam ID: PF00400
• Sequence:
  MCSLGLFPPPPPRGQVTLYEHNNELVTGSSYESPPPDFRGQWINLPVLQLTKDPLKTPGR
  LDHGTRTAFIHHREQVWKRCINIWRDVGLFGVLNEIANSEEEVFEWVKTASGWALALCRW
  ASSLHGSLFPHLSLRSEDLIAEFAQVTNWSSCCLRVFAWHPHTNKFAVALLDDSVRVYNA
  SSTIVPSLKHRLQRNVASLAWKPLSASVLAVACQSCILIWTLDPTSLSTRPSSGCAQVLS
  HPGHTPVTSLAWAPSGGRLLSASPVDAAIRVWDVSTETCVPLPWFRGGGVTNLLWSPDGS
  KILATTPSAVFRVWEAQMWTCERWPTLSGRCQTGCWSPDGSRLLFTVLGEPLIYSLSFPE
  RCGEGKGCVGGAKSATIVADLSETTIQTPDGEERLGGEAHSMVWDPSGERLAVLMKGKPR
  VQDGKPVILLFRTRNSPVFELLPCGIIQGEPGAQPQLITFHPSFNKGALLSVGWSTGRIA
  HIPLYFVNAQFPRFSPVLGRAQEPPAGGGGSIHDLPLFTETSPTSAPWDPLPGPPPVLPH
  SPHSHL
• Function: Plays a role in the normal development of the peripheral and central nervous system. Required for the correct localization of aurora kinase AURKA and the microtubule minus end-binding protein NUMA1 as well as a subset of AURKA targets which ensures proper spindle formation and timely chromosome alignment.
• Tissue Specificity: Widely expressed . Particularly abundant in cerebellum, corpus callosum, adrenal gland, pituitary gland, gastrointestinal structures and fetal lung .
• KEGG Pathway: Nucleocytoplasmic transport (hsa03013)
• Reactome Pathway:
  Transport of the SLBP independent Mature mRNA (R-HSA-159227)
  Transport of the SLBP Dependant Mature mRNA (R-HSA-159230)
  Transport of Mature mRNA Derived from an Intronless Transcript (R-HSA-159231)
  Transport of Mature mRNA derived from an Intron-Containing Transcript (R-HSA-159236)
  Rev-mediated nuclear export of HIV RNA (R-HSA-165054)
  Transport of Ribonucleoproteins into the Host Nucleus (R-HSA-168271)
  NS1 Mediated Effects on Host Pathways (R-HSA-168276)
  Viral Messenger RNA Synthesis (R-HSA-168325)
  NEP/NS2 Interacts with the Cellular Export Machinery (R-HSA-168333)
  Regulation of Glucokinase by Glucokinase Regulatory Protein (R-HSA-170822)
  Nuclear import of Rev protein (R-HSA-180746)
  Vpr-mediated nuclear import of PICs (R-HSA-180910)
  snRNP Assembly (R-HSA-191859)
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)
  SUMOylation of ubiquitinylation proteins (R-HSA-3232142)
  Nuclear Pore Complex (NPC) Disassembly (R-HSA-3301854)
  Regulation of HSF1-mediated heat shock response (R-HSA-3371453)
  SUMOylation of SUMOylation proteins (R-HSA-4085377)
  SUMOylation of chromatin organization proteins (R-HSA-4551638)
  SUMOylation of RNA binding proteins (R-HSA-4570464)
  SUMOylation of DNA replication proteins (R-HSA-4615885)
  Transcriptional regulation by small RNAs (R-HSA-5578749)
  Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC) (R-HSA-5619107)
  tRNA processing in the nucleus (R-HSA-6784531)
  RHOA GTPase cycle (R-HSA-8980692)
  HCMV Early Events (R-HSA-9609690)
  HCMV Late Events (R-HSA-9610379)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebellar degeneration	DISPBCM3	Definitive	Biomarker	[1]
Peroxisome biogenesis disorder	DISBQ6QJ	Definitive	Genetic Variation	[2]
Triple-A syndrome	DISCOH2J	Definitive	Autosomal recessive	[3]
Type-1/2 diabetes	DISIUHAP	Definitive	Altered Expression	[4]
Aarskog-Scott syndrome, X-linked	DISNHV62	Strong	Genetic Variation	[5]
Abdominal aortic aneurysm	DISD06OF	Strong	Biomarker	[6]
Achalasia	DISK845N	Strong	Genetic Variation	[7]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[8]
Adrenocortical insufficiency	DISZ0CPT	Strong	Genetic Variation	[9]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[10]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[10]
Bone Paget disease	DISIPS4V	Strong	Genetic Variation	[11]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[12]
Dysautonomia	DISF4MT6	Strong	Genetic Variation	[13]
Frontotemporal dementia	DISKYHXL	Strong	Genetic Variation	[11]
Glucocorticoid deficiency 1	DISCTX0T	Strong	Biomarker	[5]
Hereditary spastic paraplegia	DISGZQV1	Strong	Biomarker	[14]
Inclusion body myopathy with Paget disease of bone and frontotemporal dementia	DISK4S94	Strong	Genetic Variation	[11]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[12]
Obesity	DIS47Y1K	Strong	Biomarker	[15]
Pick disease	DISP6X50	Strong	Genetic Variation	[11]
Prostate cancer	DISF190Y	Strong	Biomarker	[16]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[16]
Autonomic nervous system disorder	DIS6JLTA	moderate	Genetic Variation	[13]
Charcot-Marie-Tooth disease axonal type 2Q	DISM66KB	moderate	Biomarker	[17]
Hypoglycemia	DISRCKR7	moderate	Genetic Variation	[18]
Metabolic disorder	DIS71G5H	moderate	Biomarker	[15]
Motor neurone disease	DISUHWUI	moderate	Genetic Variation	[13]
Parkinsonian disorder	DISHGY45	moderate	Biomarker	[19]
Peripheral sensory neuropathies	DISYWI6M	moderate	Genetic Variation	[20]
Spastic ataxia	DISIRRA9	moderate	Biomarker	[19]
Acute adrenal insufficiency	DIS66YLV	Limited	Genetic Variation	[21]
Autosomal dominant polycystic kidney disease	DISBHWUI	Limited	Genetic Variation	[22]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[23]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Paraquat	DMR8O3X	Investigative	Aladin (AAAS) affects the response to substance of Paraquat.	[32]

5 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 Aladin (AAAS).	[25]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Aladin (AAAS).	[26]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Aladin (AAAS).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Aladin (AAAS).	[29]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Aladin (AAAS).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Aladin (AAAS).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Aladin (AAAS).	[30]

References

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• [2] The peroxisomal AAA ATPase complex prevents pexophagy and development of peroxisome biogenesis disorders.Autophagy. 2017 May 4;13(5):868-884. doi: 10.1080/15548627.2017.1291470.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] 2-Aminoadipic acid protects against obesity and diabetes.J Endocrinol. 2019 Nov;243(2):111-123. doi: 10.1530/JOE-19-0157.
• [5] Heterogeneity in the molecular basis of ACTH resistance syndrome.Eur J Endocrinol. 2008 Jul;159(1):61-8. doi: 10.1530/EJE-08-0079. Epub 2008 Apr 21.
• [6] Notch -secretase inhibitor dibenzazepine attenuates angiotensin II-induced abdominal aortic aneurysm in ApoE knockout mice by multiple mechanisms.PLoS One. 2013 Dec 16;8(12):e83310. doi: 10.1371/journal.pone.0083310. eCollection 2013.
• [7] Triple A or Allgrove syndrome. A case report with ophthalmic abnormalities and a novel mutation in the AAAS gene.Ophthalmic Genet. 2009 Mar;30(1):45-9. doi: 10.1080/13816810802502962.
• [8] The AAA+ATPase RUVBL2 is essential for the oncogenic function of c-MYB in acute myeloid leukemia.Leukemia. 2019 Dec;33(12):2817-2829. doi: 10.1038/s41375-019-0495-8. Epub 2019 May 28.
• [9] Triple A syndrome: a novel compound heterozygous mutation in the AAAS gene in an Italian patient without adrenal insufficiency.J Neurol Sci. 2010 Mar 15;290(1-2):150-2. doi: 10.1016/j.jns.2009.12.005. Epub 2010 Jan 6.
• [10] Advanced Glycation End Products, Oxidation Products, and the Extent of Atherosclerosis During the VA Diabetes Trial and Follow-up Study.Diabetes Care. 2017 Apr;40(4):591-598. doi: 10.2337/dc16-1875. Epub 2017 Feb 1.
• [11] A conserved inter-domain communication mechanism regulates the ATPase activity of the AAA-protein Drg1.Sci Rep. 2017 Mar 17;7:44751. doi: 10.1038/srep44751.
• [12] Lysine pathway metabolites and the risk of type 2 diabetes and cardiovascular disease in the PREDIMED study: results from two case-cohort studies.Cardiovasc Diabetol. 2019 Nov 13;18(1):151. doi: 10.1186/s12933-019-0958-2.
• [13] Loss of the nucleoporin Aladin in central nervous system and fibroblasts of Allgrove Syndrome.Hum Mol Genet. 2019 Dec 1;28(23):3921-3927. doi: 10.1093/hmg/ddz236.
• [14] The Mitochondrial m-AAA Protease Prevents Demyelination and Hair Greying.PLoS Genet. 2016 Dec 2;12(12):e1006463. doi: 10.1371/journal.pgen.1006463. eCollection 2016 Dec.
• [15] 2-Aminoadipic acid (2-AAA) as a potential biomarker for insulin resistance in childhood obesity.Sci Rep. 2019 Sep 20;9(1):13610. doi: 10.1038/s41598-019-49578-z.
• [16] The bromodomain protein BRD4 regulates the KEAP1/NRF2-dependent oxidative stress response.Cell Death Dis. 2014 Apr 24;5(4):e1195. doi: 10.1038/cddis.2014.157.
• [17] DHTKD1 Deficiency Causes Charcot-Marie-Tooth Disease in Mice.Mol Cell Biol. 2018 Jun 14;38(13):e00085-18. doi: 10.1128/MCB.00085-18. Print 2018 Jul 1.
• [18] The diagnosis of adrenal insufficiency in a patient with Allgrove syndrome and a novel mutation in the ALADIN gene.Metabolism. 2005 Feb;54(2):200-5. doi: 10.1016/j.metabol.2004.08.013.
• [19] Concurrent AFG3L2 and SPG7 mutations associated with syndromic parkinsonism and optic atrophy with aberrant OPA1 processing and mitochondrial network fragmentation.Hum Mutat. 2018 Dec;39(12):2060-2071. doi: 10.1002/humu.23658. Epub 2018 Oct 10.
• [20] Case report of adult-onset Allgrove syndrome.Neurol Sci. 2007 Dec;28(6):331-5. doi: 10.1007/s10072-007-0848-3. Epub 2008 Jan 4.
• [21] Triple A syndrome: 32 years experience of a single centre (1977-2008).Eur J Pediatr. 2010 Nov;169(11):1323-8. doi: 10.1007/s00431-010-1222-7. Epub 2010 May 25.
• [22] Octreotide-LAR in later-stage autosomal dominant polycystic kidney disease (ALADIN 2): A randomized, double-blind, placebo-controlled, multicenter trial.PLoS Med. 2019 Apr 5;16(4):e1002777. doi: 10.1371/journal.pmed.1002777. eCollection 2019 Apr.
• [23] Deficiency of ALADIN impairs redox homeostasis in human adrenal cells and inhibits steroidogenesis.Endocrinology. 2013 Sep;154(9):3209-18. doi: 10.1210/en.2013-1241. Epub 2013 Jul 3.
• [24] AAA-ATPase p97 suppresses apoptotic and autophagy-associated cell death in rheumatoid arthritis synovial fibroblasts.Oncotarget. 2016 Sep 27;7(39):64221-64232. doi: 10.18632/oncotarget.11890.
• [25] 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.
• [26] 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.
• [27] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [28] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [29] 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.
• [30] 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.
• [31] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [32] Changes in differential gene expression in fibroblast cells from patients with triple A syndrome under oxidative stress. Horm Metab Res. 2013 Feb;45(2):102-8.