Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKYG33W)

• DOT Name: E3 ubiquitin-protein ligase TRIM9 (TRIM9)
• Synonyms: EC 2.3.2.27; RING finger protein 91; RING-type E3 ubiquitin transferase TRIM9; Tripartite motif-containing protein 9
• Gene Name: TRIM9
• Related Disease:
  Respiratory syncytial virus infection
  Bone disease
  Clear cell renal carcinoma
  Narcolepsy
  Non-small-cell lung cancer
  Psychotic disorder
  Renal cell carcinoma
  Adult glioblastoma
  Glioblastoma multiforme
  Lewy body dementia
  Myasthenia gravis
  Parkinson disease
• UniProt ID: TRIM9_HUMAN
• PDB ID: 2DB8; 7B2S
• EC Number: 2.3.2.27
• Pfam ID: PF00041 ; PF00622 ; PF00643 ; PF00097
• Sequence:
  MEEMEEELKCPVCGSFYREPIILPCSHNLCQACARNILVQTPESESPQSHRAAGSGVSDY
  DYLDLDKMSLYSEADSGYGSYGGFASAPTTPCQKSPNGVRVFPPAMPPPATHLSPALAPV
  PRNSCITCPQCHRSLILDDRGLRGFPKNRVLEGVIDRYQQSKAAALKCQLCEKAPKEATV
  MCEQCDVFYCDPCRLRCHPPRGPLAKHRLVPPAQGRVSRRLSPRKVSTCTDHELENHSMY
  CVQCKMPVCYQCLEEGKHSSHEVKALGAMWKLHKSQLSQALNGLSDRAKEAKEFLVQLRN
  MVQQIQENSVEFEACLVAQCDALIDALNRRKAQLLARVNKEHEHKLKVVRDQISHCTVKL
  RQTTGLMEYCLEVIKENDPSGFLQISDALIRRVHLTEDQWGKGTLTPRMTTDFDLSLDNS
  PLLQSIHQLDFVQVKASSPVPATPILQLEECCTHNNSATLSWKQPPLSTVPADGYILELD
  DGNGGQFREVYVGKETMCTVDGLHFNSTYNARVKAFNKTGVSPYSKTLVLQTSEVAWFAF
  DPGSAHSDIILSNDNLTVTCSSYDDRVVLGKTGFSKGIHYWELTVDRYDNHPDPAFGVAR
  MDVMKDVMLGKDDKAWAMYVDNNRSWFMHNNSHTNRTEGGITKGATIGVLLDLNRKNLTF
  FINDEQQGPIAFDNVEGLFFPAVSLNRNVQVTLHTGLPVPDFYSSRASIA
• Function: E3 ubiquitin-protein ligase which ubiquitinates itself in cooperation with an E2 enzyme UBE2D2/UBC4 and serves as a targeting signal for proteasomal degradation. May play a role in regulation of neuronal functions and may also participate in the formation or breakdown of abnormal inclusions in neurodegenerative disorders. May act as a regulator of synaptic vesicle exocytosis by controlling the availability of SNAP25 for the SNARE complex formation.
• Tissue Specificity: Brain. Highly expressed in the cerebral cortex (at protein level). Severely decreased in the affected brain areas in Parkinson disease and dementia with Lewy bodies.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Respiratory syncytial virus infection	DIS7FWHY	Definitive	Biomarker	[1]
Bone disease	DISE1F82	Strong	Biomarker	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[3]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[5]
Psychotic disorder	DIS4UQOT	Strong	Genetic Variation	[6]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[3]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[7]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[7]
Lewy body dementia	DISAE66J	Limited	Biomarker	[8]
Myasthenia gravis	DISELRCI	Limited	Biomarker	[9]
Parkinson disease	DISQVHKL	Limited	Biomarker	[8]

12 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 E3 ubiquitin-protein ligase TRIM9 (TRIM9).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase TRIM9 (TRIM9).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of E3 ubiquitin-protein ligase TRIM9 (TRIM9).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of E3 ubiquitin-protein ligase TRIM9 (TRIM9).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of E3 ubiquitin-protein ligase TRIM9 (TRIM9).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of E3 ubiquitin-protein ligase TRIM9 (TRIM9).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of E3 ubiquitin-protein ligase TRIM9 (TRIM9).	[17]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of E3 ubiquitin-protein ligase TRIM9 (TRIM9).	[18]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of E3 ubiquitin-protein ligase TRIM9 (TRIM9).	[16]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of E3 ubiquitin-protein ligase TRIM9 (TRIM9).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of E3 ubiquitin-protein ligase TRIM9 (TRIM9).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of E3 ubiquitin-protein ligase TRIM9 (TRIM9).	[22]

2 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-protein ligase TRIM9 (TRIM9).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of E3 ubiquitin-protein ligase TRIM9 (TRIM9).	[20]

References

• [1] Cost-utility analysis of Palivizumab for Respiratory Syncytial Virus infection prophylaxis in preterm infants: update based on the clinical evidence in Spain.BMC Infect Dis. 2017 Oct 17;17(1):687. doi: 10.1186/s12879-017-2803-0.
• [2] External Validation and Optimization of the SPRING Model for Prediction of Survival After Surgical Treatment of Bone Metastases of the Extremities.Clin Orthop Relat Res. 2018 Aug;476(8):1591-1599. doi: 10.1097/01.blo.0000534678.44152.ee.
• [3] HNF4alpha reduces proliferation of kidney cells and affects genes deregulated in renal cell carcinoma.Oncogene. 2005 Sep 22;24(42):6418-31. doi: 10.1038/sj.onc.1208794.
• [4] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [5] TRIM59 Promotes the Proliferation and Migration of Non-Small Cell Lung Cancer Cells by Upregulating Cell Cycle Related Proteins.PLoS One. 2015 Nov 24;10(11):e0142596. doi: 10.1371/journal.pone.0142596. eCollection 2015.
• [6] Genome-wide association study of atypical psychosis.Am J Med Genet B Neuropsychiatr Genet. 2013 Oct;162B(7):679-86. doi: 10.1002/ajmg.b.32164.
• [7] Mutual Stabilization between TRIM9 Short Isoform and MKK6 Potentiates p38 Signaling to Synergistically Suppress Glioblastoma Progression.Cell Rep. 2018 Apr 17;23(3):838-851. doi: 10.1016/j.celrep.2018.03.096.
• [8] TRIM9, a novel brain-specific E3 ubiquitin ligase, is repressed in the brain of Parkinson's disease and dementia with Lewy bodies.Neurobiol Dis. 2010 May;38(2):210-8. doi: 10.1016/j.nbd.2010.01.007. Epub 2010 Jan 18.
• [9] MicroRNA-653 Inhibits Thymocyte Proliferation and Induces Thymocyte Apoptosis in Mice with Autoimmune Myasthenia Gravis by Downregulating TRIM9.Neuroimmunomodulation. 2019;26(1):7-18. doi: 10.1159/000494802. Epub 2019 Jan 31.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [13] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [14] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [15] 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.
• [16] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [17] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [18] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [19] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [20] 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.
• [21] 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.
• [22] 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.