Details of Drug Off-Target (DOT)

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

• DOT Name: E3 ubiquitin-protein ligase TRIM17 (TRIM17)
• Synonyms: EC 2.3.2.27; RING finger protein 16; RING-type E3 ubiquitin transferase TRIM17; Testis RING finger protein; Tripartite motif-containing protein 17
• Gene Name: TRIM17
• Related Disease:
  Parkinson disease
  Gastric cancer
  Stomach cancer
  X-linked Opitz G/BBB syndrome
• UniProt ID: TRI17_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF00622 ; PF00643 ; PF13445
• Sequence:
  MEAVELARKLQEEATCSICLDYFTDPVMTTCGHNFCRACIQLSWEKARGKKGRRKRKGSF
  PCPECREMSPQRNLLPNRLLTKVAEMAQQHPGLQKQDLCQEHHEPLKLFCQKDQSPICVV
  CRESREHRLHRVLPAEEAVQGYKLKLEEDMEYLREQITRTGNLQAREEQSLAEWQGKVKE
  RRERIVLEFEKMNLYLVEEEQRLLQALETEEEETASRLRESVACLDRQGHSLELLLLQLE
  ERSTQGPLQMLQDMKEPLSRKNNVSVQCPEVAPPTRPRTVCRVPGQIEVLRGFLEDVVPD
  ATSAYPYLLLYESRQRRYLGSSPEGSGFCSKDRFVAYPCAVGQTAFSSGRHYWEVGMNIT
  GDALWALGVCRDNVSRKDRVPKCPENGFWVVQLSKGTKYLSTFSALTPVMLMEPPSHMGI
  FLDFEAGEVSFYSVSDGSHLHTYSQATFPGPLQPFFCLGAPKSGQMVISTVTMWVKG
• Function: E3 ubiquitin ligase that plays important roles in the regulation of neuronal apoptosis, selective autophagy or cell proliferation. Stimulates the degradation of kinetochore ZW10 interacting protein ZWINT in a proteasome-dependent manner, leading to negative regulation of cell proliferation. Inhibits autophagic degradation of diverse known targets while contributing to autophagy of midbodies. Autophagy-inhibitory activity involves MCL1, which TRIM17 assembles into complexes with the key autophagy regulator BECN1. Controls neuronal apoptosis by mediating ubiquitination and degradation of MCL1 to initiate neuronal death. In addition, regulates NFAT transcription factors NFATC3 and NFATC4 activities by preventing their nuclear localization, thus inhibiting their transcriptional activities. Decreases TRIM41-mediated degradation of ZSCAN2 thereby stimulating alpha-synuclein/SNCA transcription in neuronal cells. Prevents the E3 ubiquitin-ligase activity of TRIM28 and its interaction with anti-apoptotic BCL2A1, blocking TRIM28 from ubiquitinating BCL2A1.
• Tissue Specificity: Almost exclusively in the testis.
• Reactome Pathway: Interferon gamma signaling (R-HSA-877300)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Parkinson disease	DISQVHKL	Definitive	Biomarker	[1]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[2]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[2]
X-linked Opitz G/BBB syndrome	DISQ14EC	Disputed	Genetic Variation	[3]

2 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 E3 ubiquitin-protein ligase TRIM17 (TRIM17).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of E3 ubiquitin-protein ligase TRIM17 (TRIM17).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Rofecoxib	DM3P5DA	Approved	Rofecoxib affects the expression of E3 ubiquitin-protein ligase TRIM17 (TRIM17).	[5]

References

• [1] The E3Ubiquitin Ligases TRIM17 and TRIM41 Modulate -Synuclein Expression by Regulating ZSCAN21.Cell Rep. 2018 Nov 27;25(9):2484-2496.e9. doi: 10.1016/j.celrep.2018.11.002.
• [2] The cellular level of TRIM31, an RBCC protein overexpressed in gastric cancer, is regulated by multiple mechanisms including the ubiquitin-proteasome system.Cell Biol Int. 2011 Jul;35(7):657-61. doi: 10.1042/CBI20100772.
• [3] New mutations in MID1 provide support for loss of function as the cause of X-linked Opitz syndrome. Hum Mol Genet. 2000 Oct 12;9(17):2553-62. doi: 10.1093/hmg/9.17.2553.
• [4] 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.
• [5] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [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.