Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYN8S27)

• DOT Name: Putative E3 ubiquitin-protein ligase UNKL
• Synonyms: EC 2.3.2.-; RING finger protein unkempt-like; Zinc finger CCCH domain-containing protein 5-like
• Gene Name: UNKL
• Related Disease: Tourette syndrome
• UniProt ID: UNKL_HUMAN
• EC Number: 2.3.2.-
• Pfam ID: PF13920 ; PF00642 ; PF18384
• Sequence:
  MPSVSKAAAAALSGSPPQTEKPTHYRYLKEFRTEQCPLFSQHKCAQHRPFTCFHWHFLNQ
  RRRRPLRRRDGTFNYSPDVYCSKYNEATGVCPDGDECPYLHRTTGDTERKYHLRYYKTGT
  CIHETDARGHCVKNGLHCAFAHGPLDLRPPVCDVRELQAQEALQNGQLGGGEGVPDLQPG
  VLASQAMIEKILSEDPRWQDANFVLGSYKTEQCPKPPRLCRQGYACPHYHNSRDRRRNPR
  RFQYRSTPCPSVKHGDEWGEPSRCDGGDGCQYCHSRTEQQFHPESTKCNDMRQTGYCPRG
  PFCAFAHVEKSLGMVNEWGCHDLHLTSPSSTGSGQPGNAKRRDSPAEGGPRGSEQDSKQN
  HLAVFAAVHPPAPSVSSSVASSLASSAGSGSSSPTALPAPPARALPLGPASSTVEAVLGS
  ALDLHLSNVNIASLEKDLEEQDGHDLGAAGPRSLAGSAPVAIPGSLPRAPSLHSPSSAST
  SPLGSLSQPLPGPVGSSAMTPPQQPPPLRSEPGTLGSAASSYSPLGLNGVPGSIWDFVSG
  SFSPSPSPILSAGPPSSSSASPNGAELARVRRQLDEAKRKIRQWEESWQQVKQVCDAWQR
  EAQEAKERARVADSDRQLALQKKEEVEAQVIFQLRAKQCVACRERAHGAVLRPCQHHILC
  EPCAATAPECPYCKGQPLQW
• Function: May participate in a protein complex showing an E3 ligase activity regulated by RAC1. Ubiquitination is directed towards itself and possibly other substrates, such as SMARCD2/BAF60b. Intrinsic E3 ligase activity has not been proven.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Tourette syndrome	DISX9D54	No Known	Unknown	[1]

3 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 Putative E3 ubiquitin-protein ligase UNKL.	[2]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the methylation of Putative E3 ubiquitin-protein ligase UNKL.	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Putative E3 ubiquitin-protein ligase UNKL.	[10]

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 Putative E3 ubiquitin-protein ligase UNKL.	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Putative E3 ubiquitin-protein ligase UNKL.	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Putative E3 ubiquitin-protein ligase UNKL.	[5]
Marinol	DM70IK5	Approved	Marinol increases the expression of Putative E3 ubiquitin-protein ligase UNKL.	[7]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Putative E3 ubiquitin-protein ligase UNKL.	[8]
Cidofovir	DMA13GD	Approved	Cidofovir affects the expression of Putative E3 ubiquitin-protein ligase UNKL.	[9]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Putative E3 ubiquitin-protein ligase UNKL.	[9]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of Putative E3 ubiquitin-protein ligase UNKL.	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Putative E3 ubiquitin-protein ligase UNKL.	[11]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Putative E3 ubiquitin-protein ligase UNKL.	[12]

References

• [1] De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Neuron. 2017 May 3;94(3):486-499.e9. doi: 10.1016/j.neuron.2017.04.024.
• [2] 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.
• [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] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Association of Arsenic Exposure with Whole Blood DNA Methylation: An Epigenome-Wide Study of Bangladeshi Adults. Environ Health Perspect. 2019 May;127(5):57011. doi: 10.1289/EHP3849. Epub 2019 May 28.
• [7] 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.
• [8] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [9] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [10] 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.
• [11] 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.
• [12] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.