Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2L4STK)

• DOT Name: E3 ubiquitin-protein ligase TRIM48 (TRIM48)
• Synonyms: EC 2.3.2.27; RING finger protein 101; Tripartite motif-containing protein 48
• Gene Name: TRIM48
• Related Disease:
  Adult glioblastoma
  Glioblastoma multiforme
• UniProt ID: TRI48_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF00643 ; PF15227
• Sequence:
  MSRRIIVGTLQRTQRNMNSGISQVFQRELTCPICMNYFIDPVTIDCGHSFCRPCFYLNWQ
  DIPILTQCFECIKTIQQRNLKTNIRLKKMASLARKASLWLFLSSEEQMCGIHRETKKMFC
  EVDRSLLCLLCSSSQEHRYHRHCPAEWAAEEHWEKLLKKMQSLWEKACENQRNLNVETTR
  ISHWKAFGDILYRSESVLLHMPQPLNLALRAGPITGLRDRLNQF
• Function: E3 ubiquitin-protein ligase which promotes K48-linked polyubiquitination of protein methyltransferase PRMT1, leading to PRMT1 degradation. This suppresses methylation of the PRMT1 substrate MAP3K5/ASK1, promoting its activation and increasing MAP3K5-dependent cell death induced by oxidative stress. TRIM48-mediated ubiquitination of PRMT1 also suppresses methylation of FOXO1 by PRMT1, leading to inhibition of FOXO1 transcriptional activity.
• Reactome Pathway: Interferon gamma signaling (R-HSA-877300)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Altered Expression	[1]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of E3 ubiquitin-protein ligase TRIM48 (TRIM48).	[2]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of E3 ubiquitin-protein ligase TRIM48 (TRIM48).	[3]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of E3 ubiquitin-protein ligase TRIM48 (TRIM48).	[3]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of E3 ubiquitin-protein ligase TRIM48 (TRIM48).	[4]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of E3 ubiquitin-protein ligase TRIM48 (TRIM48).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of E3 ubiquitin-protein ligase TRIM48 (TRIM48).	[6]

References

• [1] Overexpression of Tripartite Motif-Containing 48 (TRIM48) Inhibits Growth of Human Glioblastoma Cells by Suppressing Extracellular Signal Regulated Kinase 1/2 (ERK1/2) Pathway.Med Sci Monit. 2019 Nov 8;25:8422-8429. doi: 10.12659/MSM.916024.
• [2] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [3] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [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] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [6] 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.