Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ4ZJP5)

• DOT Name: E3 ubiquitin-protein ligase synoviolin (SYVN1)
• Synonyms: EC 2.3.2.27; RING-type E3 ubiquitin transferase synoviolin; Synovial apoptosis inhibitor 1
• Gene Name: SYVN1
• Related Disease: Schizophrenia
• UniProt ID: SYVN1_HUMAN
• PDB ID: 6A3Z
• EC Number: 2.3.2.27
• Pfam ID: PF13639
• Sequence:
  MFRTAVMMAASLALTGAVVAHAYYLKHQFYPTVVYLTKSSPSMAVLYIQAFVLVFLLGKV
  MGKVFFGQLRAAEMEHLLERSWYAVTETCLAFTVFRDDFSPRFVALFTLLLFLKCFHWLA
  EDRVDFMERSPNISWLFHCRIVSLMFLLGILDFLFVSHAYHSILTRGASVQLVFGFEYAI
  LMTMVLTIFIKYVLHSVDLQSENPWDNKAVYMLYTELFTGFIKVLLYMAFMTIMIKVHTF
  PLFAIRPMYLAMRQFKKAVTDAIMSRRAIRNMNTLYPDATPEELQAMDNVCIICREEMVT
  GAKRLPCNHIFHTSCLRSWFQRQQTCPTCRMDVLRASLPAQSPPPPEPADQGPPPAPHPP
  PLLPQPPNFPQGLLPPFPPGMFPLWPPMGPFPPVPPPPSSGEAVAPPSTSAAALSRPSGA
  ATTTAAGTSATAASATASGPGSGSAPEAGPAPGFPFPPPWMGMPLPPPFAFPPMPVPPAG
  FAGLTPEELRALEGHERQHLEARLQSLRNIHTLLDAAMLQINQYLTVLASLGPPRPATSV
  NSTEETATTVVAAASSTSIPSSEATTPTPGASPPAPEMERPPAPESVGTEEMPEDGEPDA
  AELRRRRLQKLESPVAH
• Function: E3 ubiquitin-protein ligase which accepts ubiquitin specifically from endoplasmic reticulum-associated UBC7 E2 ligase and transfers it to substrates, promoting their degradation. Component of the endoplasmic reticulum quality control (ERQC) system also called ER-associated degradation (ERAD) involved in ubiquitin-dependent degradation of misfolded endoplasmic reticulum proteins. Also promotes the degradation of normal but naturally short-lived proteins such as SGK. Protects cells from ER stress-induced apoptosis. Protects neurons from apoptosis induced by polyglutamine-expanded huntingtin (HTT) or unfolded GPR37 by promoting their degradation. Sequesters p53/TP53 in the cytoplasm and promotes its degradation, thereby negatively regulating its biological function in transcription, cell cycle regulation and apoptosis. Mediates the ubiquitination and subsequent degradation of cytoplasmic NFE2L1. During the early stage of B cell development, required for degradation of the pre-B cell receptor (pre-BCR) complex, hence supporting further differentiation into mature B cells.
• Tissue Specificity: Ubiquitously expressed, with highest levels in liver and kidney (at protein level). Up-regulated in synovial tissues from patients with rheumatoid arthritis (at protein level).
• KEGG Pathway:
  Ubiquitin mediated proteolysis (hsa04120)
  Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway:
  Hedgehog ligand biogenesis (R-HSA-5358346)
  Hh mutants are degraded by ERAD (R-HSA-5362768)
  ER Quality Control Compartment (ERQC) (R-HSA-901032)
  XBP1(S) activates chaperone genes (R-HSA-381038)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Schizophrenia	DISSRV2N	No Known	Unknown	[1]

11 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 synoviolin (SYVN1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase synoviolin (SYVN1).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of E3 ubiquitin-protein ligase synoviolin (SYVN1).	[4]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of E3 ubiquitin-protein ligase synoviolin (SYVN1).	[6]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of E3 ubiquitin-protein ligase synoviolin (SYVN1).	[7]
Sertraline	DM0FB1J	Approved	Sertraline increases the expression of E3 ubiquitin-protein ligase synoviolin (SYVN1).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of E3 ubiquitin-protein ligase synoviolin (SYVN1).	[9]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of E3 ubiquitin-protein ligase synoviolin (SYVN1).	[10]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of E3 ubiquitin-protein ligase synoviolin (SYVN1).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of E3 ubiquitin-protein ligase synoviolin (SYVN1).	[12]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of E3 ubiquitin-protein ligase synoviolin (SYVN1).	[13]

1 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 synoviolin (SYVN1).	[5]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [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] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [4] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [5] 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.
• [6] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [7] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [8] Sertraline induces endoplasmic reticulum stress in hepatic cells. Toxicology. 2014 Aug 1;322:78-88. doi: 10.1016/j.tox.2014.05.007. Epub 2014 May 24.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.
• [11] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [12] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [13] Lipid Rafts Disruption Increases Ochratoxin A Cytotoxicity to Hepatocytes. J Biochem Mol Toxicol. 2016 Feb;30(2):71-9. doi: 10.1002/jbt.21738. Epub 2015 Aug 25.