Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLKKKA5)

• DOT Name: E3 ubiquitin ligase TRIM40 (TRIM40)
• Synonyms: EC 2.3.2.27; Probable E3 NEDD8-protein ligase; RING finger protein 35
• Gene Name: TRIM40
• Related Disease:
  Irritant contact dermatitis
  Rheumatoid arthritis
  Type-1 diabetes
  Nervous system disease
• UniProt ID: TRI40_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF00097
• Sequence:
  MIPLQKDNQEEGVCPICQESLKEAVSTNCGHLFCRVCLTQHVEKASASGVFCCPLCRKPC
  SEEVLGTGYICPNHQKRVCRFCEESRLLLCVECLVSPEHMSHHELTIENALSHYKERLNR
  RSRKLRKDIAELQRLKAQQEKKLQALQFQVDHGNHRLEAGPESQHQTREQLGALPQQWLG
  QLEHMPAEAARILDISRAVTQLRSLVIDLERTAKELDTNTLKNAGDLLNRSAPQKLEVIY
  PQLEKGVSELLLQPPQKL
• Function: E3 ubiquitin-protein ligase that plays a role in the limitation of the innate immune response. Mediates inhibition of the RLR signaling pathway by ubiquitinating RIGI and IFIH1 receptors, leading to their proteasomal degradation. Promotes also the neddylation of IKBKG/NEMO, stabilizing NFKBIA, and thereby inhibiting of NF-kappa-B nuclear translocation and activation.
• Tissue Specificity: Highly expressed in normal gastrointestinal epithelia but that is down-regulated in gastrointestinal carcinomas and chronic inflammatory lesions of the gastrointestinal tract.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Irritant contact dermatitis	DIS62JY3	Strong	Biomarker	[1]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[2]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[3]
Nervous system disease	DISJ7GGT	Disputed	Biomarker	[4]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of E3 ubiquitin ligase TRIM40 (TRIM40).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of E3 ubiquitin ligase TRIM40 (TRIM40).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of E3 ubiquitin ligase TRIM40 (TRIM40).	[7]

References

• [1] Association of MHC region SNPs with irritant susceptibility in healthcare workers. J Immunotoxicol. 2016 Sep;13(5):738-44. doi: 10.3109/1547691X.2016.1173135. Epub 2016 Jun 3.
• [2] REL, encoding a member of the NF-kappaB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis.Nat Genet. 2009 Jul;41(7):820-3. doi: 10.1038/ng.395. Epub 2009 Jun 7.
• [3] A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene.Nature. 2007 Aug 2;448(7153):591-4. doi: 10.1038/nature06010. Epub 2007 Jul 15.
• [4] Atlas of human diseases influenced by genetic variants with extreme allele frequency differences.Hum Genet. 2017 Jan;136(1):39-54. doi: 10.1007/s00439-016-1734-y. Epub 2016 Oct 3.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] 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.
• [7] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.