Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9LZUX6)

• DOT Name: Ubiquitin carboxyl-terminal hydrolase 27
• Synonyms: EC 3.4.19.12; Deubiquitinating enzyme 27; Ubiquitin carboxyl-terminal hydrolase 22-like; Ubiquitin thioesterase 27; Ubiquitin-specific-processing protease 27; X-linked ubiquitin carboxyl-terminal hydrolase 27
• Gene Name: USP27X
• Related Disease:
  Intellectual disability, autosomal dominant 40
  Intellectual disability, X-linked 105
  Non-syndromic X-linked intellectual disability
  X-linked intellectual disability
• UniProt ID: UBP27_HUMAN
• EC Number: 3.4.19.12
• Pfam ID: PF00443
• Sequence:
  MCKDYVYDKDIEQIAKEEQGEALKLQASTSTEVSHQQCSVPGLGEKFPTWETTKPELELL
  GHNPRRRRITSSFTIGLRGLINLGNTCFMNCIVQALTHTPILRDFFLSDRHRCEMPSPEL
  CLVCEMSSLFRELYSGNPSPHVPYKLLHLVWIHARHLAGYRQQDAHEFLIAALDVLHRHC
  KGDDVGKAANNPNHCNCIIDQIFTGGLQSDVTCQACHGVSTTIDPCWDISLDLPGSCTSF
  WPMSPGRESSVNGESHIPGITTLTDCLRRFTRPEHLGSSAKIKCGSCQSYQESTKQLTMN
  KLPVVACFHFKRFEHSAKQRRKITTYISFPLELDMTPFMASSKESRMNGQLQLPTNSGNN
  ENKYSLFAVVNHQGTLESGHYTSFIRHHKDQWFKCDDAVITKASIKDVLDSEGYLLFYHK
  QVLEHESEKVKEMNTQAY
• Function: Deubiquitinase involved in innate antiviral immunity by mediating deubiquitination of CGAS and RIGI. Negatively regulates RIGI by mediating 'Lys-63'-linked deubiquitination of RIGI, inhibiting type I interferon signaling. Also regulates 'Lys-63'-linked ubiquitination level of MDA5/IFIH1. Acts as a positive regulator of the cGAS-STING pathway by catalyzing 'Lys-48'-linked deubiquitination of CGAS, thereby promoting its stabilization. Can reduce the levels of BCL2L11/BIM ubiquitination and stabilize BCL2L11 in response to the RAF-MAPK-degradation signal. By acting on BCL2L11 levels, may counteract the anti-apoptotic effects of MAPK activity.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, autosomal dominant 40	DISAI0IH	Strong	X-linked recessive	[1]
Intellectual disability, X-linked 105	DISNMINM	Strong	X-linked	[1]
Non-syndromic X-linked intellectual disability	DIS71AI3	Supportive	X-linked	[1]
X-linked intellectual disability	DISYJBY3	Limited	X-linked	[2]

1 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 Ubiquitin carboxyl-terminal hydrolase 27.	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Malathion	DMXZ84M	Approved	Malathion increases the expression of Ubiquitin carboxyl-terminal hydrolase 27.	[4]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Ubiquitin carboxyl-terminal hydrolase 27.	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ubiquitin carboxyl-terminal hydrolase 27.	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ubiquitin carboxyl-terminal hydrolase 27.	[7]

References

• [1] X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes. Mol Psychiatry. 2016 Jan;21(1):133-48. doi: 10.1038/mp.2014.193. Epub 2015 Feb 3.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [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] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [5] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [6] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [7] 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.