Details of Drug Off-Target (DOT)

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

• DOT Name: Ubiquitin-like modifier-activating enzyme 1
• Synonyms: EC 6.2.1.45; Protein A1S9; Ubiquitin-activating enzyme E1
• Gene Name: UBA1
• Related Disease:
  Infantile-onset X-linked spinal muscular atrophy
  Inflammation
• UniProt ID: UBA1_HUMAN
• PDB ID: 4P22; 6DC6; 7PYV
• EC Number: 6.2.1.45
• Pfam ID: PF16191 ; PF16190 ; PF09358 ; PF00899 ; PF10585
• Sequence:
  MSSSPLSKKRRVSGPDPKPGSNCSPAQSVLSEVPSVPTNGMAKNGSEADIDEGLYSRQLY
  VLGHEAMKRLQTSSVLVSGLRGLGVEIAKNIILGGVKAVTLHDQGTAQWADLSSQFYLRE
  EDIGKNRAEVSQPRLAELNSYVPVTAYTGPLVEDFLSGFQVVVLTNTPLEDQLRVGEFCH
  NRGIKLVVADTRGLFGQLFCDFGEEMILTDSNGEQPLSAMVSMVTKDNPGVVTCLDEARH
  GFESGDFVSFSEVQGMVELNGNQPMEIKVLGPYTFSICDTSNFSDYIRGGIVSQVKVPKK
  ISFKSLVASLAEPDFVVTDFAKFSRPAQLHIGFQALHQFCAQHGRPPRPRNEEDAAELVA
  LAQAVNARALPAVQQNNLDEDLIRKLAYVAAGDLAPINAFIGGLAAQEVMKACSGKFMPI
  MQWLYFDALECLPEDKEVLTEDKCLQRQNRYDGQVAVFGSDLQEKLGKQKYFLVGAGAIG
  CELLKNFAMIGLGCGEGGEIIVTDMDTIEKSNLNRQFLFRPWDVTKLKSDTAAAAVRQMN
  PHIRVTSHQNRVGPDTERIYDDDFFQNLDGVANALDNVDARMYMDRRCVYYRKPLLESGT
  LGTKGNVQVVIPFLTESYSSSQDPPEKSIPICTLKNFPNAIEHTLQWARDEFEGLFKQPA
  ENVNQYLTDPKFVERTLRLAGTQPLEVLEAVQRSLVLQRPQTWADCVTWACHHWHTQYSN
  NIRQLLHNFPPDQLTSSGAPFWSGPKRCPHPLTFDVNNPLHLDYVMAAANLFAQTYGLTG
  SQDRAAVATFLQSVQVPEFTPKSGVKIHVSDQELQSANASVDDSRLEELKATLPSPDKLP
  GFKMYPIDFEKDDDSNFHMDFIVAASNLRAENYDIPSADRHKSKLIAGKIIPAIATTTAA
  VVGLVCLELYKVVQGHRQLDSYKNGFLNLALPFFGFSEPLAAPRHQYYNQEWTLWDRFEV
  QGLQPNGEEMTLKQFLDYFKTEHKLEITMLSQGVSMLYSFFMPAAKLKERLDQPMTEIVS
  RVSKRKLGRHVRALVLELCCNDESGEDVEVPYVRYTIR
• Function: Catalyzes the first step in ubiquitin conjugation to mark cellular proteins for degradation through the ubiquitin-proteasome system. Activates ubiquitin by first adenylating its C-terminal glycine residue with ATP, and thereafter linking this residue to the side chain of a cysteine residue in E1, yielding a ubiquitin-E1 thioester and free AMP. Essential for the formation of radiation-induced foci, timely DNA repair and for response to replication stress. Promotes the recruitment of TP53BP1 and BRCA1 at DNA damage sites.
• Tissue Specificity: Detected in erythrocytes (at protein level). Ubiquitous.
• KEGG Pathway:
  Ubiquitin mediated proteolysis (hsa04120)
  Parkinson disease (hsa05012)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Synthesis of active ubiquitin (R-HSA-8866652)
• BioCyc Pathway: MetaCyc:HS05465-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Infantile-onset X-linked spinal muscular atrophy	DIS574FL	Strong	X-linked	[1]
Inflammation	DISJUQ5T	No Known	Unknown	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Ubiquitin-like modifier-activating enzyme 1 affects the response to substance of Methotrexate.	[15]
Topotecan	DMP6G8T	Approved	Ubiquitin-like modifier-activating enzyme 1 affects the response to substance of Topotecan.	[15]

2 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 Ubiquitin-like modifier-activating enzyme 1.	[3]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Ubiquitin-like modifier-activating enzyme 1.	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ubiquitin-like modifier-activating enzyme 1.	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ubiquitin-like modifier-activating enzyme 1.	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ubiquitin-like modifier-activating enzyme 1.	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Ubiquitin-like modifier-activating enzyme 1.	[8]
Selenium	DM25CGV	Approved	Selenium increases the expression of Ubiquitin-like modifier-activating enzyme 1.	[9]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Ubiquitin-like modifier-activating enzyme 1.	[10]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Ubiquitin-like modifier-activating enzyme 1.	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ubiquitin-like modifier-activating enzyme 1.	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the expression of Ubiquitin-like modifier-activating enzyme 1.	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ubiquitin-like modifier-activating enzyme 1.	[12]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Ubiquitin-like modifier-activating enzyme 1.	[14]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin affects the binding of Ubiquitin-like modifier-activating enzyme 1.	[6]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Biotinylated quercetin as an intrinsic photoaffinity proteomics probe for the identification of quercetin target proteins. Bioorg Med Chem. 2011 Aug 15;19(16):4710-20. doi: 10.1016/j.bmc.2011.07.005. Epub 2011 Jul 13.
• [7] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [8] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [9] 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.
• [10] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [11] Benzo(a)pyrene exposure in utero exacerbates Parkinson's Disease (PD)-like -synucleinopathy in A53T human alpha-synuclein transgenic mice. Toxicol Appl Pharmacol. 2021 Sep 15;427:115658. doi: 10.1016/j.taap.2021.115658. Epub 2021 Jul 29.
• [12] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [13] 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.
• [14] Lipid Rafts Disruption Increases Ochratoxin A Cytotoxicity to Hepatocytes. J Biochem Mol Toxicol. 2016 Feb;30(2):71-9. doi: 10.1002/jbt.21738. Epub 2015 Aug 25.
• [15] 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.