Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT35SG1R)

• DOT Name: E3 ubiquitin/ISG15 ligase TRIM25 (TRIM25)
• Synonyms: EC 6.3.2.n3; Estrogen-responsive finger protein; RING finger protein 147; RING-type E3 ubiquitin transferase; EC 2.3.2.27; RING-type E3 ubiquitin transferase TRIM25; Tripartite motif-containing protein 25; Ubiquitin/ISG15-conjugating enzyme TRIM25; Zinc finger protein 147
• Gene Name: TRIM25
• Related Disease:
  Attention deficit hyperactivity disorder
  Breast neoplasm
  Colon carcinoma
  Endometrium neoplasm
  Estrogen-receptor positive breast cancer
  Gastric adenocarcinoma
  Gastric cancer
  Hemolytic-uremic syndrome
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Influenza
  Lung adenocarcinoma
  Measles
  Metabolic disorder
  Neoplasm
  Non-small-cell lung cancer
  Periodontal disease
  Prostate cancer
  Prostate carcinoma
  Stomach cancer
  Adenocarcinoma
  Advanced cancer
  leukaemia
  Leukemia
  Metastatic malignant neoplasm
  Plasma cell myeloma
  Breast cancer
  Colorectal carcinoma
  Lung cancer
  Lung carcinoma
  Middle East Respiratory Syndrome (MERS)
  Severe acute respiratory syndrome (SARS)
• UniProt ID: TRI25_HUMAN
• PDB ID: 4CFG; 4LTB; 5EYA; 5FER; 5NT1; 5NT2; 6FLM; 6FLN
• EC Number: 2.3.2.27; 6.3.2.n3
• Pfam ID: PF13765 ; PF00622 ; PF13445
• Sequence:
  MAELCPLAEELSCSICLEPFKEPVTTPCGHNFCGSCLNETWAVQGSPYLCPQCRAVYQAR
  PQLHKNTVLCNVVEQFLQADLAREPPADVWTPPARASAPSPNAQVACDHCLKEAAVKTCL
  VCMASFCQEHLQPHFDSPAFQDHPLQPPVRDLLRRKCSQHNRLREFFCPEHSECICHICL
  VEHKTCSPASLSQASADLEATLRHKLTVMYSQINGASRALDDVRNRQQDVRMTANRKVEQ
  LQQEYTEMKALLDASETTSTRKIKEEEKRVNSKFDTIYQILLKKKSEIQTLKEEIEQSLT
  KRDEFEFLEKASKLRGISTKPVYIPEVELNHKLIKGIHQSTIDLKNELKQCIGRLQEPTP
  SSGDPGEHDPASTHKSTRPVKKVSKEEKKSKKPPPVPALPSKLPTFGAPEQLVDLKQAGL
  EAAAKATSSHPNSTSLKAKVLETFLAKSRPELLEYYIKVILDYNTAHNKVALSECYTVAS
  VAEMPQNYRPHPQRFTYCSQVLGLHCYKKGIHYWEVELQKNNFCGVGICYGSMNRQGPES
  RLGRNSASWCVEWFNTKISAWHNNVEKTLPSTKATRVGVLLNCDHGFVIFFAVADKVHLM
  YKFRVDFTEALYPAFWVFSAGATLSICSPK
• Function: Functions as a ubiquitin E3 ligase and as an ISG15 E3 ligase. Involved in innate immune defense against viruses by mediating ubiquitination of RIGI and IFIH1. Mediates 'Lys-63'-linked polyubiquitination of the RIGI N-terminal CARD-like region and may play a role in signal transduction that leads to the production of interferons in response to viral infection. Mediates 'Lys-63'-linked polyubiquitination of IFIH1. Promotes ISGylation of 14-3-3 sigma (SFN), an adapter protein implicated in the regulation of a large spectrum signaling pathway. Mediates estrogen action in various target organs. Mediates the ubiquitination and subsequent proteasomal degradation of ZFHX3. Plays a role in promoting the restart of stalled replication forks via interaction with the KHDC3L-OOEP scaffold and subsequent ubiquitination of BLM, resulting in the recruitment and retainment of BLM at DNA replication forks. Plays an essential role in the antiviral activity of ZAP/ZC3HAV1; an antiviral protein which inhibits the replication of certain viruses. Mechanistically, mediates 'Lys-63'-linked polyubiquitination of ZAP/ZC3HAV1 that is required for its optimal binding to target mRNA. Mediates also the ubiquitination of various substrates implicated in stress granule formation, nonsense-mediated mRNA decay, nucleoside synthesis and mRNA translation and stability.
• Tissue Specificity: Expressed in breast tumors (at protein level). Ubiquitous.
• KEGG Pathway:
  NF-kappa B sig.ling pathway (hsa04064)
  RIG-I-like receptor sig.ling pathway (hsa04622)
  Influenza A (hsa05164)
• Reactome Pathway:
  DDX58/IFIH1-mediated induction of interferon-alpha/beta (R-HSA-168928)
  Termination of translesion DNA synthesis (R-HSA-5656169)
  Ovarian tumor domain proteases (R-HSA-5689896)
  Interferon gamma signaling (R-HSA-877300)
  TRAF3-dependent IRF activation pathway (R-HSA-918233)
  TRAF6 mediated IRF7 activation (R-HSA-933541)
  TRAF6 mediated NF-kB activation (R-HSA-933542)
  NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 (R-HSA-933543)
  Negative regulators of DDX58/IFIH1 signaling (R-HSA-936440)
  SARS-CoV-1 activates/modulates innate immune responses (R-HSA-9692916)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  PKR-mediated signaling (R-HSA-9833482)
  ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[2]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
Endometrium neoplasm	DIS6OS2L	Strong	Biomarker	[4]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Altered Expression	[5]
Gastric adenocarcinoma	DISWWLTC	Strong	Biomarker	[6]
Gastric cancer	DISXGOUK	Strong	Biomarker	[6]
Hemolytic-uremic syndrome	DISSCBGW	Strong	CausalMutation	[7]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[9]
Influenza	DIS3PNU3	Strong	Genetic Variation	[10]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[11]
Measles	DISXSUID	Strong	Genetic Variation	[12]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[14]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[15]
Periodontal disease	DISJQHVN	Strong	Biomarker	[16]
Prostate cancer	DISF190Y	Strong	Altered Expression	[17]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[17]
Stomach cancer	DISKIJSX	Strong	Biomarker	[6]
Adenocarcinoma	DIS3IHTY	moderate	Altered Expression	[18]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[19]
leukaemia	DISS7D1V	moderate	Biomarker	[20]
Leukemia	DISNAKFL	moderate	Biomarker	[20]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[21]
Plasma cell myeloma	DIS0DFZ0	moderate	Altered Expression	[22]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[23]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[3]
Lung cancer	DISCM4YA	Limited	Biomarker	[24]
Lung carcinoma	DISTR26C	Limited	Biomarker	[24]
Middle East Respiratory Syndrome (MERS)	DIS5VPYU	Limited	Biomarker	[25]
Severe acute respiratory syndrome (SARS)	DISYW14W	Limited	Biomarker	[25]

17 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/ISG15 ligase TRIM25 (TRIM25).	[26]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin/ISG15 ligase TRIM25 (TRIM25).	[27]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of E3 ubiquitin/ISG15 ligase TRIM25 (TRIM25).	[28]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of E3 ubiquitin/ISG15 ligase TRIM25 (TRIM25).	[29]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin/ISG15 ligase TRIM25 (TRIM25).	[30]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of E3 ubiquitin/ISG15 ligase TRIM25 (TRIM25).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of E3 ubiquitin/ISG15 ligase TRIM25 (TRIM25).	[32]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of E3 ubiquitin/ISG15 ligase TRIM25 (TRIM25).	[33]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of E3 ubiquitin/ISG15 ligase TRIM25 (TRIM25).	[34]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of E3 ubiquitin/ISG15 ligase TRIM25 (TRIM25).	[35]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of E3 ubiquitin/ISG15 ligase TRIM25 (TRIM25).	[36]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of E3 ubiquitin/ISG15 ligase TRIM25 (TRIM25).	[28]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of E3 ubiquitin/ISG15 ligase TRIM25 (TRIM25).	[37]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of E3 ubiquitin/ISG15 ligase TRIM25 (TRIM25).	[4]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of E3 ubiquitin/ISG15 ligase TRIM25 (TRIM25).	[39]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of E3 ubiquitin/ISG15 ligase TRIM25 (TRIM25).	[42]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of E3 ubiquitin/ISG15 ligase TRIM25 (TRIM25).	[43]

4 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 affects the methylation of E3 ubiquitin/ISG15 ligase TRIM25 (TRIM25).	[38]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of E3 ubiquitin/ISG15 ligase TRIM25 (TRIM25).	[40]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of E3 ubiquitin/ISG15 ligase TRIM25 (TRIM25).	[41]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of E3 ubiquitin/ISG15 ligase TRIM25 (TRIM25).	[40]

References

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• [2] Estrogen-responsive RING finger protein controls breast cancer growth.J Steroid Biochem Mol Biol. 2003 Jun;85(2-5):101-4. doi: 10.1016/s0960-0760(03)00209-7.
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