Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ322WE)

• DOT Name: Ubiquitin-like modifier-activating enzyme 5
• Synonyms: Ubiquitin-activating enzyme 5; ThiFP1; UFM1-activating enzyme; Ubiquitin-activating enzyme E1 domain-containing protein 1
• Gene Name: UBA5
• Related Disease:
  Developmental and epileptic encephalopathy, 44
  Undetermined early-onset epileptic encephalopathy
  Spinocerebellar ataxia, autosomal recessive 24
• UniProt ID: UBA5_HUMAN
• PDB ID: 3GUC; 3H8V; 5HKH; 5IA8; 5IAA; 5L95; 6H77; 6H78; 6H8C; 7NVK; 7NW1; 7OVC
• Pfam ID: PF00899
• Sequence:
  MAESVERLQQRVQELERELAQERSLQVPRSGDGGGGRVRIEKMSSEVVDSNPYSRLMALK
  RMGIVSDYEKIRTFAVAIVGVGGVGSVTAEMLTRCGIGKLLLFDYDKVELANMNRLFFQP
  HQAGLSKVQAAEHTLRNINPDVLFEVHNYNITTVENFQHFMDRISNGGLEEGKPVDLVLS
  CVDNFEARMTINTACNELGQTWMESGVSENAVSGHIQLIIPGESACFACAPPLVVAANID
  EKTLKREGVCAASLPTTMGVVAGILVQNVLKFLLNFGTVSFYLGYNAMQDFFPTMSMKPN
  PQCDDRNCRKQQEEYKKKVAALPKQEVIQEEEEIIHEDNEWGIELVSEVSEEELKNFSGP
  VPDLPEGITVAYTIPKKQEDSVTELTVEDSGESLEDLMAKMKNM
• Function: E1-like enzyme which specifically catalyzes the first step in ufmylation. Activates UFM1 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 UFM1-E1 thioester and free AMP. Activates UFM1 via a trans-binding mechanism, in which UFM1 interacts with distinct sites in both subunits of the UBA5 homodimer. Trans-binding also promotes stabilization of the UBA5 homodimer, and enhances ATP-binding. Transfer of UFM1 from UBA5 to the E2-like enzyme UFC1 also takes place using a trans mechanism. Ufmylation is involved in reticulophagy (also called ER-phagy) induced in response to endoplasmic reticulum stress. Ufmylation is essential for erythroid differentiation of both megakaryocytes and erythrocytes.
• Tissue Specificity: Widely expressed.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Developmental and epileptic encephalopathy, 44	DIS14WNV	Strong	Autosomal recessive	[1]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Supportive	Autosomal dominant	[1]
Spinocerebellar ataxia, autosomal recessive 24	DISPZONT	Limited	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Ubiquitin-like modifier-activating enzyme 5.	[3]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Ubiquitin-like modifier-activating enzyme 5.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ubiquitin-like modifier-activating enzyme 5.	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ubiquitin-like modifier-activating enzyme 5.	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ubiquitin-like modifier-activating enzyme 5.	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Ubiquitin-like modifier-activating enzyme 5.	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ubiquitin-like modifier-activating enzyme 5.	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Ubiquitin-like modifier-activating enzyme 5.	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Ubiquitin-like modifier-activating enzyme 5.	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ubiquitin-like modifier-activating enzyme 5.	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ubiquitin-like modifier-activating enzyme 5.	[13]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Ubiquitin-like modifier-activating enzyme 5.	[14]

References

• [1] Biallelic Variants in UBA5 Link Dysfunctional UFM1?Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy. Am J Hum Genet. 2016 Sep 1;99(3):683-694. doi: 10.1016/j.ajhg.2016.06.020. Epub 2016 Aug 18.
• [2] UBA5 Mutations Cause a New Form of Autosomal Recessive Cerebellar Ataxia. PLoS One. 2016 Feb 12;11(2):e0149039. doi: 10.1371/journal.pone.0149039. eCollection 2016.
• [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] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] 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.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] Comparison of quantitation methods in proteomics to define relevant toxicological information on AhR activation of HepG2 cells by BaP. Toxicology. 2021 Jan 30;448:152652. doi: 10.1016/j.tox.2020.152652. Epub 2020 Dec 2.
• [11] 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.
• [12] 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.
• [13] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [14] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.