Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP6VI99)

• DOT Name: E3 ubiquitin-protein ligase TRIM37 (TRIM37)
• Synonyms: EC 2.3.2.27; Mulibrey nanism protein; RING-type E3 ubiquitin transferase TRIM37; Tripartite motif-containing protein 37
• Gene Name: TRIM37
• Related Disease: Mulibrey nanism
• UniProt ID: TRI37_HUMAN
• PDB ID: 3LRQ
• EC Number: 2.3.2.27
• Pfam ID: PF00917 ; PF00643
• Sequence:
  MDEQSVESIAEVFRCFICMEKLRDARLCPHCSKLCCFSCIRRWLTEQRAQCPHCRAPLQL
  RELVNCRWAEEVTQQLDTLQLCSLTKHEENEKDKCENHHEKLSVFCWTCKKCICHQCALW
  GGMHGGHTFKPLAEIYEQHVTKVNEEVAKLRRRLMELISLVQEVERNVEAVRNAKDERVR
  EIRNAVEMMIARLDTQLKNKLITLMGQKTSLTQETELLESLLQEVEHQLRSCSKSELISK
  SSEILMMFQQVHRKPMASFVTTPVPPDFTSELVPSYDSATFVLENFSTLRQRADPVYSPP
  LQVSGLCWRLKVYPDGNGVVRGYYLSVFLELSAGLPETSKYEYRVEMVHQSCNDPTKNII
  REFASDFEVGECWGYNRFFRLDLLANEGYLNPQNDTVILRFQVRSPTFFQKSRDQHWYIT
  QLEAAQTSYIQQINNLKERLTIELSRTQKSRDLSPPDNHLSPQNDDALETRAKKSACSDM
  LLEGGPTTASVREAKEDEEDEEKIQNEDYHHELSDGDLDLDLVYEDEVNQLDGSSSSASS
  TATSNTEENDIDEETMSGENDVEYNNMELEEGELMEDAAAAGPAGSSHGYVGSSSRISRR
  THLCSAATSSLLDIDPLILIHLLDLKDRSSIENLWGLQPRPPASLLQPTASYSRKDKDQR
  KQQAMWRVPSDLKMLKRLKTQMAEVRCMKTDVKNTLSEIKSSSAASGDMQTSLFSADQAA
  LAACGTENSGRLQDLGMELLAKSSVANCYIRNSTNKKSNSPKPARSSVAGSLSLRRAVDP
  GENSRSKGDCQTLSEGSPGSSQSGSRHSSPRALIHGSIGDILPKTEDRQCKALDSDAVVV
  AVFSGLPAVEKRRKMVTLGANAKGGHLEGLQMTDLENNSETGELQPVLPEGASAAPEEGM
  SSDSDIECDTENEEQEEHTSVGGFHDSFMVMTQPPDEDTHSSFPDGEQIGPEDLSFNTDE
  NSGR
• Function: E3 ubiquitin-protein ligase required to prevent centriole reduplication. Probably acts by ubiquitinating positive regulators of centriole reduplication. Mediates monoubiquitination of 'Lys-119' of histone H2A (H2AK119Ub), a specific tag for epigenetic transcriptional repression: associates with some Polycomb group (PcG) multiprotein PRC2-like complex and mediates repression of target genes. Also acts as a positive regulator of peroxisome import by mediating monoubiquitination of PEX5 at 'Lys-472': monoubiquitination promotes PEX5 stabilitation by preventing its polyubiquitination and degradation by the proteasome. Has anti-HIV activity.
• Tissue Specificity: Ubiquitous . Highly expressed in testis, while it is weakly expressed in other tissues .
• KEGG Pathway: Ubiquitin mediated proteolysis (hsa04120)
• 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
Mulibrey nanism	DIS138YX	Definitive	Autosomal recessive	[1]

4 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 E3 ubiquitin-protein ligase TRIM37 (TRIM37).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of E3 ubiquitin-protein ligase TRIM37 (TRIM37).	[3]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of E3 ubiquitin-protein ligase TRIM37 (TRIM37).	[4]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of E3 ubiquitin-protein ligase TRIM37 (TRIM37).	[7]

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 E3 ubiquitin-protein ligase TRIM37 (TRIM37).	[5]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of E3 ubiquitin-protein ligase TRIM37 (TRIM37).	[6]

References

• [1] 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.
• [2] 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.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [5] 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.
• [6] 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.
• [7] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.