Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHFD7J1)

• DOT Name: Putative E3 ubiquitin-protein ligase UBR7
• Synonyms: EC 2.3.2.27; N-recognin-7; RING-type E3 ubiquitin transferase UBR7
• Gene Name: UBR7
• Related Disease:
  Li-Campeau syndrome
  Intellectual disability
• UniProt ID: UBR7_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF02207
• Sequence:
  MAGAEGAAGRQSELEPVVSLVDVLEEDEELENEACAVLGGSDSEKCSYSQGSVKRQALYA
  CSTCTPEGEEPAGICLACSYECHGSHKLFELYTKRNFRCDCGNSKFKNLECKLLPDKAKV
  NSGNKYNDNFFGLYCICKRPYPDPEDEIPDEMIQCVVCEDWFHGRHLGAIPPESGDFQEM
  VCQACMKRCSFLWAYAAQLAVTKISTEDDGLVRNIDGIGDQEVIKPENGEHQDSTLKEDV
  PEQGKDDVREVKVEQNSEPCAGSSSESDLQTVFKNESLNAESKSGCKLQELKAKQLIKKD
  TATYWPLNWRSKLCTCQDCMKMYGDLDVLFLTDEYDTVLAYENKGKIAQATDRSDPLMDT
  LSSMNRVQQVELICEYNDLKTELKDYLKRFADEGTVVKREDIQQFFEEFQSKKRRRVDGM
  QYYCS
• Function: E3 ubiquitin-protein ligase which is a component of the N-end rule pathway. Recognizes and binds to proteins bearing specific N-terminal residues that are destabilizing according to the N-end rule, leading to their ubiquitination and subsequent degradation.
• Tissue Specificity: Expressed in sperm (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Li-Campeau syndrome	DIS7K6CD	Strong	Autosomal recessive	[1]
Intellectual disability	DISMBNXP	Limited	Autosomal recessive	[2]

11 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 Putative E3 ubiquitin-protein ligase UBR7.	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Putative E3 ubiquitin-protein ligase UBR7.	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Putative E3 ubiquitin-protein ligase UBR7.	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Putative E3 ubiquitin-protein ligase UBR7.	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Putative E3 ubiquitin-protein ligase UBR7.	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Putative E3 ubiquitin-protein ligase UBR7.	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Putative E3 ubiquitin-protein ligase UBR7.	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Putative E3 ubiquitin-protein ligase UBR7.	[9]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Putative E3 ubiquitin-protein ligase UBR7.	[10]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Putative E3 ubiquitin-protein ligase UBR7.	[14]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Putative E3 ubiquitin-protein ligase UBR7.	[15]

3 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 decreases the methylation of Putative E3 ubiquitin-protein ligase UBR7.	[11]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Putative E3 ubiquitin-protein ligase UBR7.	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Putative E3 ubiquitin-protein ligase UBR7.	[13]

References

• [1] UBR7 functions with UBR5 in the Notch signaling pathway and is involved in a neurodevelopmental syndrome with epilepsy, ptosis, and hypothyroidism. Am J Hum Genet. 2021 Jan 7;108(1):134-147. doi: 10.1016/j.ajhg.2020.11.018. Epub 2020 Dec 18.
• [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] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [11] 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.
• [12] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [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] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [15] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.