Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO8J4VV)

• DOT Name: Sentrin-specific protease 1 (SENP1)
• Synonyms: EC 3.4.22.-; Sentrin/SUMO-specific protease SENP1
• Gene Name: SENP1
• UniProt ID: SENP1_HUMAN
• PDB ID: 2CKG; 2CKH; 2G4D; 2IY0; 2IY1; 2IYC; 2IYD; 2XPH; 2XRE; 6NNQ
• EC Number: 3.4.22.-
• Pfam ID: PF02902
• Sequence:
  MDDIADRMRMDAGEVTLVNHNSVFKTHLLPQTGFPEDQLSLSDQQILSSRQGHLDRSFTC
  STRSAAYNPSYYSDNPSSDSFLGSGDLRTFGQSANGQWRNSTPSSSSSLQKSRNSRSLYL
  ETRKTSSGLSNSFAGKSNHHCHVSAYEKSFPIKPVPSPSWSGSCRRSLLSPKKTQRRHVS
  TAEETVQEEEREIYRQLLQMVTGKQFTIAKPTTHFPLHLSRCLSSSKNTLKDSLFKNGNS
  CASQIIGSDTSSSGSASILTNQEQLSHSVYSLSSYTPDVAFGSKDSGTLHHPHHHHSVPH
  QPDNLAASNTQSEGSDSVILLKVKDSQTPTPSSTFFQAELWIKELTSVYDSRARERLRQI
  EEQKALALQLQNQRLQEREHSVHDSVELHLRVPLEKEIPVTVVQETQKKGHKLTDSEDEF
  PEITEEMEKEIKNVFRNGNQDEVLSEAFRLTITRKDIQTLNHLNWLNDEIINFYMNMLME
  RSKEKGLPSVHAFNTFFFTKLKTAGYQAVKRWTKKVDVFSVDILLVPIHLGVHWCLAVVD
  FRKKNITYYDSMGGINNEACRILLQYLKQESIDKKRKEFDTNGWQLFSKKSQEIPQQMNG
  SDCGMFACKYADCITKDRPINFTQQHMPYFRKRMVWEILHRKLL
• Function: Protease that catalyzes two essential functions in the SUMO pathway. The first is the hydrolysis of an alpha-linked peptide bond at the C-terminal end of the small ubiquitin-like modifier (SUMO) propeptides, SUMO1, SUMO2 and SUMO3 leading to the mature form of the proteins. The second is the deconjugation of SUMO1, SUMO2 and SUMO3 from targeted proteins, by cleaving an epsilon-linked peptide bond between the C-terminal glycine of the mature SUMO and the lysine epsilon-amino group of the target protein. Deconjugates SUMO1 from HIPK2. Deconjugates SUMO1 from HDAC1 and BHLHE40/DEC1, which decreases its transcriptional repression activity. Deconjugates SUMO1 from CLOCK, which decreases its transcriptional activation activity. Deconjugates SUMO2 from MTA1. Deconjugates SUMO1 from METTL3. Desumoylates CCAR2 which decreases its interaction with SIRT1. Deconjugates SUMO1 from GPS2.
• Tissue Specificity: Highly expressed in testis. Expressed at lower levels in thymus, pancreas, spleen, liver, ovary and small intestine.
• Reactome Pathway:
  RHOF GTPase cycle (R-HSA-9035034)
  SUMO is proteolytically processed (R-HSA-3065679)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Sentrin-specific protease 1 (SENP1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Sentrin-specific protease 1 (SENP1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sentrin-specific protease 1 (SENP1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sentrin-specific protease 1 (SENP1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sentrin-specific protease 1 (SENP1).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Sentrin-specific protease 1 (SENP1).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Sentrin-specific protease 1 (SENP1).	[8]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Sentrin-specific protease 1 (SENP1).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Sentrin-specific protease 1 (SENP1).	[11]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Sentrin-specific protease 1 (SENP1).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Sentrin-specific protease 1 (SENP1).	[14]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Sentrin-specific protease 1 (SENP1).	[16]

4 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 Sentrin-specific protease 1 (SENP1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Sentrin-specific protease 1 (SENP1).	[10]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Sentrin-specific protease 1 (SENP1).	[12]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Sentrin-specific protease 1 (SENP1).	[15]

References

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• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Quantitative proteomic analysis of HepG2 cells treated with quercetin suggests IQGAP1 involved in quercetin-induced regulation of cell proliferation and migration. OMICS. 2009 Apr;13(2):93-103. doi: 10.1089/omi.2008.0075.
• [8] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [9] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [10] 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.
• [11] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [12] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [13] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [14] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [15] 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.
• [16] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.