Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1P6ZIE)

• DOT Name: Auxilin (DNAJC6)
• Synonyms: EC 3.1.3.-; DnaJ homolog subfamily C member 6
• Gene Name: DNAJC6
• Related Disease:
  Autosomal recessive juvenile Parkinson disease 2
  Cowden disease
  Epilepsy
  Hepatocellular carcinoma
  Intellectual disability
  Juvenile onset Parkinson disease 19A
  Juvenile-onset Parkinson disease
  Myocardial infarction
  Neoplasm
  Obesity
  Parkinsonian disorder
  Schizophrenia
  Atypical juvenile parkinsonism
  Young-onset Parkinson disease
  Dilated cardiomyopathy
  Venous thromboembolism
• UniProt ID: AUXI_HUMAN
• EC Number: 3.1.3.-
• Pfam ID: PF10409
• Sequence:
  MKDSENKGASSPDMEPSYGGGLFDMVKGGAGRLFSNLKDNLKDTLKDTSSRVIQSVTSYT
  KGDLDFTYVTSRIIVMSFPLDNVDIGFRNQVDDIRSFLDSRHLDHYTVYNLSPKSYRTAK
  FHSRVSECSWPIRQAPSLHNLFAVCRNMYNWLLQNPKNVCVVHCLDGRAASSILVGAMFI
  FCNLYSTPGPAIRLLYAKRPGIGLSPSHRRYLGYMCDLLADKPYRPHFKPLTIKSITVSP
  IPFFNKQRNGCRPYCDVLIGETKIYSTCTDFERMKEYRVQDGKIFIPLNITVQGDVVVSM
  YHLRSTIGSRLQAKVTNTQIFQLQFHTGFIPLDTTVLKFTKPELDACDVPEKYPQLFQVT
  LDVELQPHDKVIDLTPPWEHYCTKDVNPSILFSSHQEHQDTLALGGQAPIDIPPDNPRHY
  GQSGFFASLCWQDQKSEKSFCEEDHAALVNQESEQSDDELLTLSSPHGNANGDKPHGVKK
  PSKKQQEPAAPPPPEDVDLLGLEGSAMSNSFSPPAAPPTNSELLSDLFGGGGAAGPTQAG
  QSGVEDVFHPSGPASTQSTPRRSATSTSASPTLRVGEGATFDPFGAPSKPSGQDLLGSFL
  NTSSASSDPFLQPTRSPSPTVHASSTPAVNIQPDVSGGWDWHAKPGGFGMGSKSAATSPT
  GSSHGTPTHQSKPQTLDPFADLGTLGSSSFASKPTTPTGLGGGFPPLSSPQKASPQPMGG
  GWQQGGAYNWQQPQPKPQPSMPHSSPQNRPNYNVSFSAMPGGQNERGKGSSNLEGKQKAA
  DFEDLLSGQGFNAHKDKKGPRTIAEMRKEEMAKEMDPEKLKILEWIEGKERNIRALLSTM
  HTVLWAGETKWKPVGMADLVTPEQVKKVYRKAVLVVHPDKATGQPYEQYAKMIFMELNDA
  WSEFENQGQKPLY
• Function: May act as a protein phosphatase and/or a lipid phosphatase. Co-chaperone that recruits HSPA8/HSC70 to clathrin-coated vesicles (CCVs) and promotes the ATP-dependent dissociation of clathrin from CCVs and participates in clathrin-mediated endocytosis of synaptic vesicles and their recycling and also in intracellular trafficking. Firstly, binds tightly to the clathrin cages, at a ratio of one DNAJC6 per clathrin triskelion. The HSPA8:ATP complex then binds to the clathrin-auxilin cage, initially at a ratio of one HSPA8 per triskelion leading to ATP hydrolysis stimulation and causing a conformational change in the HSPA8. This cycle is repeated three times to drive to a complex containing the clathrin-auxilin cage associated to three HSPA8:ADP complex. The ATP hydrolysis of the third HSPA8:ATP complex leads to a concerted dismantling of the cage into component triskelia. Then, dissociates from the released triskelia and be recycled to initiate another cycle of HSPA8's recruitment. Also acts during the early steps of clathrin-coated vesicle (CCV) formation through its interaction with the GTP bound form of DNM1.
• Tissue Specificity: Expressed in various brain regions, including cerebellum, corpus callosum, cortex, striatum, brainstem, pons, putamen, spinal cord and substantia nigra. Very low expression in non-neural tissues such as leukocytes, liver, adipose tissue, skeletal muscle and bone marrow.
• KEGG Pathway: Endocytosis (hsa04144)
• Reactome Pathway:
  Golgi Associated Vesicle Biogenesis (R-HSA-432722)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  Lysosome Vesicle Biogenesis (R-HSA-432720)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive juvenile Parkinson disease 2	DISNSTD1	Strong	Genetic Variation	[1]
Cowden disease	DISMYKCE	Strong	Biomarker	[2]
Epilepsy	DISBB28L	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Intellectual disability	DISMBNXP	Strong	Biomarker	[3]
Juvenile onset Parkinson disease 19A	DISKIOCW	Strong	Autosomal recessive	[5]
Juvenile-onset Parkinson disease	DISNT5BI	Strong	Genetic Variation	[6]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Obesity	DIS47Y1K	Strong	Genetic Variation	[9]
Parkinsonian disorder	DISHGY45	Strong	Genetic Variation	[10]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[11]
Atypical juvenile parkinsonism	DISYXFE3	Supportive	Autosomal recessive	[12]
Young-onset Parkinson disease	DIS05LFS	Supportive	Autosomal recessive	[1]
Dilated cardiomyopathy	DISX608J	Limited	Biomarker	[13]
Venous thromboembolism	DISUR7CR	Limited	Biomarker	[14]

13 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 Auxilin (DNAJC6).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Auxilin (DNAJC6).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Auxilin (DNAJC6).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Auxilin (DNAJC6).	[18]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Auxilin (DNAJC6).	[21]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Auxilin (DNAJC6).	[21]
Nefazodone	DM4ZS8M	Approved	Nefazodone increases the expression of Auxilin (DNAJC6).	[22]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Auxilin (DNAJC6).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Auxilin (DNAJC6).	[25]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Auxilin (DNAJC6).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Auxilin (DNAJC6).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Auxilin (DNAJC6).	[29]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Auxilin (DNAJC6).	[30]

6 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 Auxilin (DNAJC6).	[19]
Triclosan	DMZUR4N	Approved	Triclosan increases the methylation of Auxilin (DNAJC6).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Auxilin (DNAJC6).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Auxilin (DNAJC6).	[28]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Auxilin (DNAJC6).	[31]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Auxilin (DNAJC6).	[32]

References

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• [3] Homozygous deletion of an 80 kb region comprising part of DNAJC6 and LEPR genes on chromosome 1P31.3 is associated with early onset obesity, mental retardation and epilepsy.Mol Genet Metab. 2012 Jul;106(3):345-50. doi: 10.1016/j.ymgme.2012.04.026. Epub 2012 May 10.
• [4] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
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• [6] DNAJC6 promotes hepatocellular carcinoma progression through induction of epithelial-mesenchymal transition.Biochem Biophys Res Commun. 2014 Dec 12;455(3-4):298-304. doi: 10.1016/j.bbrc.2014.11.011. Epub 2014 Nov 13.
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• [9] DNAJC6 is responsible for juvenile parkinsonism with phenotypic variability.Parkinsonism Relat Disord. 2013 Mar;19(3):320-4. doi: 10.1016/j.parkreldis.2012.11.006. Epub 2012 Dec 2.
• [10] DNAJC proteins and pathways to parkinsonism.FEBS J. 2019 Aug;286(16):3080-3094. doi: 10.1111/febs.14936. Epub 2019 Jun 20.
• [11] Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.Eur Arch Psychiatry Clin Neurosci. 2009 Apr;259(3):151-63. doi: 10.1007/s00406-008-0847-2. Epub 2009 Jan 22.
• [12] A deleterious mutation in DNAJC6 encoding the neuronal-specific clathrin-uncoating co-chaperone auxilin, is associated with juvenile parkinsonism. PLoS One. 2012;7(5):e36458. doi: 10.1371/journal.pone.0036458. Epub 2012 May 1.
• [13] Identification of circular RNAs with host gene-independent expression in human model systems for cardiac differentiation and disease.J Mol Cell Cardiol. 2017 Aug;109:48-56. doi: 10.1016/j.yjmcc.2017.06.015. Epub 2017 Jul 1.
• [14] A genome-wide association study of the Protein C anticoagulant pathway.PLoS One. 2011;6(12):e29168. doi: 10.1371/journal.pone.0029168. Epub 2011 Dec 28.
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• [16] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [17] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [18] 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.
• [19] 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.
• [20] Pregnancy exposure to synthetic phenols and placental DNA methylation - An epigenome-wide association study in male infants from the EDEN cohort. Environ Pollut. 2021 Dec 1;290:118024. doi: 10.1016/j.envpol.2021.118024. Epub 2021 Aug 21.
• [21] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [22] Robustness testing and optimization of an adverse outcome pathway on cholestatic liver injury. Arch Toxicol. 2020 Apr;94(4):1151-1172. doi: 10.1007/s00204-020-02691-9. Epub 2020 Mar 10.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] 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.
• [25] Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myelogenous leukemia cells. Mol Cancer Ther. 2014 May;13(5):1142-54.
• [26] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [31] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [32] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.