Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVLF4G5)

• DOT Name: Ubiquitin carboxyl-terminal hydrolase MINDY-1 (MINDY1)
• Synonyms: EC 3.4.19.12; Deubiquitinating enzyme MINDY-1; Protein FAM63A
• Gene Name: MINDY1
• Related Disease: Non-insulin dependent diabetes
• UniProt ID: MINY1_HUMAN
• PDB ID: 5JKN; 5JQS; 5MN9; 6TUV; 6TXB; 6Y6R; 6YJG; 6Z90
• EC Number: 3.4.19.12
• Pfam ID: PF04424
• Sequence:
  MEYHQPEDPAPGKAGTAEAVIPENHEVLAGPDEHPQDTDARDADGEAREREPADQALLPS
  QCGDNLESPLPEASSAPPGPTLGTLPEVETIRACSMPQELPQSPRTRQPEPDFYCVKWIP
  WKGEQTPIITQSTNGPCPLLAIMNILFLQWKVKLPPQKEVITSDELMAHLGNCLLSIKPQ
  EKSEGLQLNFQQNVDDAMTVLPKLATGLDVNVRFTGVSDFEYTPECSVFDLLGIPLYHGW
  LVDPQSPEAVRAVGKLSYNQLVERIITCKHSSDTNLVTEGLIAEQFLETTAAQLTYHGLC
  ELTAAAKEGELSVFFRNNHFSTMTKHKSHLYLLVTDQGFLQEEQVVWESLHNVDGDSCFC
  DSDFHLSHSLGKGPGAEGGSGSPETQLQVDQDYLIALSLQQQQPRGPLGLTDLELAQQLQ
  QEEYQQQQAAQPVRMRTRVLSLQGRGATSGRPAGERRQRPKHESDCILL
• Function: Hydrolase that can specifically remove 'Lys-48'-linked conjugated ubiquitin from proteins. Has exodeubiquitinase activity and has a preference for long polyubiquitin chains. May play a regulatory role at the level of protein turnover.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[1]

14 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 carboxyl-terminal hydrolase MINDY-1 (MINDY1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ubiquitin carboxyl-terminal hydrolase MINDY-1 (MINDY1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ubiquitin carboxyl-terminal hydrolase MINDY-1 (MINDY1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ubiquitin carboxyl-terminal hydrolase MINDY-1 (MINDY1).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ubiquitin carboxyl-terminal hydrolase MINDY-1 (MINDY1).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Ubiquitin carboxyl-terminal hydrolase MINDY-1 (MINDY1).	[7]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Ubiquitin carboxyl-terminal hydrolase MINDY-1 (MINDY1).	[6]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ubiquitin carboxyl-terminal hydrolase MINDY-1 (MINDY1).	[8]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Ubiquitin carboxyl-terminal hydrolase MINDY-1 (MINDY1).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Ubiquitin carboxyl-terminal hydrolase MINDY-1 (MINDY1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ubiquitin carboxyl-terminal hydrolase MINDY-1 (MINDY1).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ubiquitin carboxyl-terminal hydrolase MINDY-1 (MINDY1).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Ubiquitin carboxyl-terminal hydrolase MINDY-1 (MINDY1).	[15]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Ubiquitin carboxyl-terminal hydrolase MINDY-1 (MINDY1).	[16]

2 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 increases the methylation of Ubiquitin carboxyl-terminal hydrolase MINDY-1 (MINDY1).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Ubiquitin carboxyl-terminal hydrolase MINDY-1 (MINDY1).	[12]

References

• [1] Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.Nat Genet. 2018 Apr;50(4):559-571. doi: 10.1038/s41588-018-0084-1. Epub 2018 Apr 9.
• [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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [7] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] 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.