Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN9Q07Y)

• DOT Name: Sentrin-specific protease 5 (SENP5)
• Synonyms: EC 3.4.22.-; Sentrin/SUMO-specific protease SENP5
• Gene Name: SENP5
• Related Disease:
  Cardiomyopathy
  Hepatocellular carcinoma
  Myopathy
  Squamous cell carcinoma
• UniProt ID: SENP5_HUMAN
• EC Number: 3.4.22.-
• Pfam ID: PF02902 ; PF19722
• Sequence:
  MKKQRKILWRKGIHLAFSEKWNTGFGGFKKFYFHQHLCILKAKLGRPVTWNRQLRHFQGR
  KKALQIQKTWIKDEPLCAKTKFNVATQNVSTLSSKVKRKDAKHFISSSKTLLRLQAEKLL
  SSAKNSDHEYCREKNLLKAVTDFPSNSALGQANGHRPRTDPQPSDFPMKFNGESQSPGES
  GTIVVTLNNHKRKGFCYGCCQGPEHHRNGGPLIPKKFQLNQHRRIKLSPLMMYEKLSMIR
  FRYRILRSQHFRTKSKVCKLRKAQRSWVQKVTGDHQETRRENGEGGSCSPFPSPEPKDPS
  CRHQPYFPDMDSSAVVKGTNSHVPDCHTKGSSFLGKELSLDEAFPDQQNGSATNAWDQSS
  CSSPKWECTELIHDIPLPEHRSNTMFISETEREIMTLGQENQTSSVSDDRVKLSVSGADT
  SVSSVDGPVSQKAVQNENSYQMEEDGSLKQSILSSELLDHPYCKSPLEAPLVCSGLKLEN
  QVGGGKNSQKASPVDDEQLSVCLSGFLDEVMKKYGSLVPLSEKEVLGRLKDVFNEDFSNR
  KPFINREITNYRARHQKCNFRIFYNKHMLDMDDLATLDGQNWLNDQVINMYGELIMDAVP
  DKVHFFNSFFHRQLVTKGYNGVKRWTKKVDLFKKSLLLIPIHLEVHWSLITVTLSNRIIS
  FYDSQGIHFKFCVENIRKYLLTEAREKNRPEFLQGWQTAVTKCIPQQKNDSDCGVFVLQY
  CKCLALEQPFQFSQEDMPRVRKRIYKELCECRLMD
• Function: Protease that catalyzes two essential functions in the SUMO pathway: processing of full-length SUMO3 to its mature form and deconjugation of SUMO2 and SUMO3 from targeted proteins. Has weak proteolytic activity against full-length SUMO1 or SUMO1 conjugates. Required for cell division.
• Reactome Pathway: SUMO is proteolytically processed (R-HSA-3065679)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Myopathy	DISOWG27	Strong	Biomarker	[1]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[3]

11 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 Sentrin-specific protease 5 (SENP5).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Sentrin-specific protease 5 (SENP5).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sentrin-specific protease 5 (SENP5).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sentrin-specific protease 5 (SENP5).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Sentrin-specific protease 5 (SENP5).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Sentrin-specific protease 5 (SENP5).	[5]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Sentrin-specific protease 5 (SENP5).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Sentrin-specific protease 5 (SENP5).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Sentrin-specific protease 5 (SENP5).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Sentrin-specific protease 5 (SENP5).	[14]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Sentrin-specific protease 5 (SENP5).	[15]

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 affects the methylation of Sentrin-specific protease 5 (SENP5).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Sentrin-specific protease 5 (SENP5).	[13]

References

• [1] SENP5, a SUMO isopeptidase, induces apoptosis and cardiomyopathy.J Mol Cell Cardiol. 2015 Jan;78:154-64. doi: 10.1016/j.yjmcc.2014.08.003. Epub 2014 Aug 12.
• [2] Saikosaponin-d Inhibits the Hepatoma Cells and Enhances Chemosensitivity Through SENP5-Dependent Inhibition of Gli1 SUMOylation Under Hypoxia.Front Pharmacol. 2019 Sep 20;10:1039. doi: 10.3389/fphar.2019.01039. eCollection 2019.
• [3] Overexpression of SENP5 in oral squamous cell carcinoma and its association with differentiation.Oncol Rep. 2008 Nov;20(5):1041-5.
• [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] 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.
• [6] 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.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [10] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [11] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [12] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [13] 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.
• [14] 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.
• [15] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.