Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC7QMYA)

• DOT Name: Ubiquitin-fold modifier 1
• Gene Name: UFM1
• Related Disease:
  Leukodystrophy, hypomyelinating, 14
  Hypomyelinating leukodystrophy 6
• UniProt ID: UFM1_HUMAN
• PDB ID: 1WXS; 5HKH; 5IA7; 5IA8; 5IAA; 5L95; 6H77; 7W3N
• Pfam ID: PF03671
• Sequence:
  MSKVSFKITLTSDPRLPYKVLSVPESTPFTAVLKFAAEEFKVPAATSAIITNDGIGINPA
  QTAGNVFLKHGSELRIIPRDRVGSC
• Function: Ubiquitin-like modifier which can be covalently attached via an isopeptide bond to lysine residues of substrate proteins as a monomer or a lysine-linked polymer. The so-called ufmylation, requires the UFM1-activating E1 enzyme UBA5, the UFM1-conjugating E2 enzyme UFC1, and the UFM1-ligase E3 enzyme UFL1. Ufmylation is involved in reticulophagy (also called ER-phagy) induced in response to endoplasmic reticulum stress. Ufmylation of TRIP4 regulates nuclear receptors-mediated transcription.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leukodystrophy, hypomyelinating, 14	DISSN2H6	Strong	Autosomal recessive	[1]
Hypomyelinating leukodystrophy 6	DIS774EP	Supportive	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Ubiquitin-fold modifier 1.	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ubiquitin-fold modifier 1.	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ubiquitin-fold modifier 1.	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ubiquitin-fold modifier 1.	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Ubiquitin-fold modifier 1.	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ubiquitin-fold modifier 1.	[7]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Ubiquitin-fold modifier 1.	[8]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Ubiquitin-fold modifier 1.	[9]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Ubiquitin-fold modifier 1.	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ubiquitin-fold modifier 1.	[11]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Ubiquitin-fold modifier 1.	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ubiquitin-fold modifier 1.	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Ubiquitin-fold modifier 1.	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ubiquitin-fold modifier 1.	[15]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Ubiquitin-fold modifier 1.	[16]

References

• [1] UFM1 founder mutation in the Roma population causes recessive variant of H-ABC. Neurology. 2017 Oct 24;89(17):1821-1828. doi: 10.1212/WNL.0000000000004578. Epub 2017 Sep 20.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] 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.
• [7] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [8] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [9] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [10] Differentially expressed genes in the prostate cancer cell line LNCaP after exposure to androgen and anti-androgen. Cancer Genet Cytogenet. 2006 Apr 15;166(2):130-8. doi: 10.1016/j.cancergencyto.2005.09.012.
• [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] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [13] 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.
• [14] 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.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] 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.