Details of Drug Off-Target (DOT)

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

• DOT Name: Ubiquitin carboxyl-terminal hydrolase isozyme L1
• Synonyms: UCH-L1; EC 3.4.19.12; Neuron cytoplasmic protein 9.5; PGP 9.5; PGP9.5; Ubiquitin thioesterase L1
• Gene Name: UCHL1
• Related Disease:
  Early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome
  Spastic paraplegia 79A, autosomal dominant, with ataxia
  Parkinson disease 5, autosomal dominant, susceptibility to
• UniProt ID: UCHL1_HUMAN
• PDB ID: 2ETL; 2LEN; 3IFW; 3IRT; 3KVF; 3KW5; 4DM9; 4JKJ; 7ZM0; 8DY8; 8EDE
• EC Number: 3.4.19.12
• Pfam ID: PF01088
• Sequence:
  MQLKPMEINPEMLNKVLSRLGVAGQWRFVDVLGLEEESLGSVPAPACALLLLFPLTAQHE
  NFRKKQIEELKGQEVSPKVYFMKQTIGNSCGTIGLIHAVANNQDKLGFEDGSVLKQFLSE
  TEKMSPEDRAKCFEKNEAIQAAHDAVAQEGQCRVDDKVNFHFILFNNVDGHLYELDGRMP
  FPVNHGASSEDTLLKDAAKVCREFTEREQGEVRFSAVALCKAA
• Function: Deubiquitinase that plays a role in the regulation of several processes such as maintenance of synaptic function, cardiac function, inflammatory response or osteoclastogenesis. Abrogates the ubiquitination of multiple proteins including WWTR1/TAZ, EGFR, HIF1A and beta-site amyloid precursor protein cleaving enzyme 1/BACE1. In addition, recognizes and hydrolyzes a peptide bond at the C-terminal glycine of ubiquitin to maintain a stable pool of monoubiquitin that is a key requirement for the ubiquitin-proteasome and the autophagy-lysosome pathways. Regulates amyloid precursor protein/APP processing by promoting BACE1 degradation resulting in decreased amyloid beta production. Plays a role in the immune response by regulating the ability of MHC I molecules to reach cross-presentation compartments competent for generating Ag-MHC I complexes. Mediates the 'Lys-48'-linked deubiquitination of the transcriptional coactivator WWTR1/TAZ leading to its stabilization and inhibition of osteoclastogenesis. Deubiquitinates and stabilizes epidermal growth factor receptor EGFR to prevent its degradation and to activate its downstream mediators. Modulates oxidative activity in skeletal muscle by regulating key mitochondrial oxidative proteins. Enhances the activity of hypoxia-inducible factor 1-alpha/HIF1A by abrogateing its VHL E3 ligase-mediated ubiquitination and consequently inhibiting its degradation.
• Tissue Specificity: Found in neuronal cell bodies and processes throughout the neocortex (at protein level). Expressed in neurons and cells of the diffuse neuroendocrine system and their tumors. Weakly expressed in ovary. Down-regulated in brains from Parkinson disease and Alzheimer disease patients.
• KEGG Pathway:
  Parkinson disease (hsa05012)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway: UCH proteinases (R-HSA-5689603)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome	DIS6KYWB	Strong	Autosomal recessive	[1]
Spastic paraplegia 79A, autosomal dominant, with ataxia	DISHC9PJ	Strong	Autosomal dominant	[2]
Parkinson disease 5, autosomal dominant, susceptibility to	DIS1771N	Limited	Autosomal dominant	[3]

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Ubiquitin carboxyl-terminal hydrolase isozyme L1 affects the response to substance of Fluorouracil.	[23]
Mitomycin	DMH0ZJE	Approved	Ubiquitin carboxyl-terminal hydrolase isozyme L1 affects the response to substance of Mitomycin.	[23]
Topotecan	DMP6G8T	Approved	Ubiquitin carboxyl-terminal hydrolase isozyme L1 affects the response to substance of Topotecan.	[23]
Mitoxantrone	DMM39BF	Approved	Ubiquitin carboxyl-terminal hydrolase isozyme L1 affects the response to substance of Mitoxantrone.	[23]
PEITC	DMOMN31	Phase 2	Ubiquitin carboxyl-terminal hydrolase isozyme L1 affects the binding of PEITC.	[24]

18 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 Ubiquitin carboxyl-terminal hydrolase isozyme L1.	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ubiquitin carboxyl-terminal hydrolase isozyme L1.	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ubiquitin carboxyl-terminal hydrolase isozyme L1.	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ubiquitin carboxyl-terminal hydrolase isozyme L1.	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Ubiquitin carboxyl-terminal hydrolase isozyme L1.	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ubiquitin carboxyl-terminal hydrolase isozyme L1.	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ubiquitin carboxyl-terminal hydrolase isozyme L1.	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Ubiquitin carboxyl-terminal hydrolase isozyme L1.	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ubiquitin carboxyl-terminal hydrolase isozyme L1.	[12]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Ubiquitin carboxyl-terminal hydrolase isozyme L1.	[13]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Ubiquitin carboxyl-terminal hydrolase isozyme L1.	[14]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Ubiquitin carboxyl-terminal hydrolase isozyme L1.	[15]
Lidocaine	DML4ZOT	Approved	Lidocaine decreases the expression of Ubiquitin carboxyl-terminal hydrolase isozyme L1.	[16]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Ubiquitin carboxyl-terminal hydrolase isozyme L1.	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ubiquitin carboxyl-terminal hydrolase isozyme L1.	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ubiquitin carboxyl-terminal hydrolase isozyme L1.	[20]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Ubiquitin carboxyl-terminal hydrolase isozyme L1.	[21]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Ubiquitin carboxyl-terminal hydrolase isozyme L1.	[22]

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 increases the methylation of Ubiquitin carboxyl-terminal hydrolase isozyme L1.	[18]

References

• [1] Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration. Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3489-94. doi: 10.1073/pnas.1222732110. Epub 2013 Jan 28.
• [2] Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy. Genet Med. 2022 Oct;24(10):2079-2090. doi: 10.1016/j.gim.2022.07.006. Epub 2022 Aug 20.
• [3] Dopaminergic neuronal loss in transgenic mice expressing the Parkinson's disease-associated UCH-L1 I93M mutant. Neurochem Int. 2007 Jan;50(1):119-29. doi: 10.1016/j.neuint.2006.07.015. Epub 2006 Sep 11.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] Changes in gene expression profiles of multiple myeloma cells induced by arsenic trioxide (ATO): possible mechanisms to explain ATO resistance in vivo. Br J Haematol. 2005 Mar;128(5):636-44.
• [12] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [13] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [14] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [15] Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
• [16] Lidocaine prevents breast cancer growth by targeting neuronatin to inhibit nerve fibers formation. J Toxicol Sci. 2021;46(7):329-339. doi: 10.2131/jts.46.329.
• [17] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [18] 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.
• [19] 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.
• [20] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [21] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [22] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [23] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [24] Identification of potential protein targets of isothiocyanates by proteomics. Chem Res Toxicol. 2011 Oct 17;24(10):1735-43. doi: 10.1021/tx2002806. Epub 2011 Aug 26.