Details of Drug Off-Target (DOT)

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

• DOT Name: Sentrin-specific protease 2 (SENP2)
• Synonyms: EC 3.4.22.-; Axam2; SMT3-specific isopeptidase 2; Smt3ip2; Sentrin/SUMO-specific protease SENP2
• Gene Name: SENP2
• Related Disease:
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Bladder cancer
  Cardiomyopathy
  Hepatocellular carcinoma
  Metabolic disorder
  Metastatic malignant neoplasm
  Neoplasm
  Non-insulin dependent diabetes
  Obesity
  Triple negative breast cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Ventricular septal defect
  Breast cancer
  Breast carcinoma
  Osteoarthritis
  Bone osteosarcoma
  Epstein barr virus infection
  Osteosarcoma
  Small lymphocytic lymphoma
• UniProt ID: SENP2_HUMAN
• PDB ID: 1TGZ; 1TH0; 2IO0; 2IO1; 2IO2; 2IO3; 3ZO5; 5AEK
• EC Number: 3.4.22.-
• Pfam ID: PF02902
• Sequence:
  MYRWLVRILGTIFRFCDRSVPPARALLKRRRSDSTLFSTVDTDEIPAKRPRLDCFIHQVK
  NSLYNAASLFGFPFQLTTKPMVTSACNGTRNVAPSGEVFSNSSSCELTGSGSWNNMLKLG
  NKSPNGISDYPKIRVTVTRDQPRRVLPSFGFTLNSEGCNRRPGGRRHSKGNPESSLMWKP
  QEQAVTEMISEESGKGLRRPHCTVEEGVQKEEREKYRKLLERLKESGHGNSVCPVTSNYH
  SSQRSQMDTLKTKGWGEEQNHGVKTTQFVPKQYRLVETRGPLCSLRSEKRCSKGKITDTE
  TMVGIRFENESRRGYQLEPDLSEEVSARLRLGSGSNGLLRRKVSIIETKEKNCSGKERDR
  RTDDLLELTEDMEKEISNALGHGPQDEILSSAFKLRITRGDIQTLKNYHWLNDEVINFYM
  NLLVERNKKQGYPALHVFSTFFYPKLKSGGYQAVKRWTKGVNLFEQEIILVPIHRKVHWS
  LVVIDLRKKCLKYLDSMGQKGHRICEILLQYLQDESKTKRNSDLNLLEWTHHSMKPHEIP
  QQLNGSDCGMFTCKYADYISRDKPITFTQHQMPLFRKKMVWEILHQQLL
• 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. May down-regulate CTNNB1 levels and thereby modulate the Wnt pathway. Deconjugates SUMO2 from MTA1. Plays a dynamic role in adipogenesis by desumoylating and promoting the stabilization of CEBPB. Acts as a regulator of the cGAS-STING pathway by catalyzing desumoylation of CGAS and STING1 during the late phase of viral infection.
• KEGG Pathway:
  Nucleocytoplasmic transport (hsa03013)
  Wnt sig.ling pathway (hsa04310)
• Reactome Pathway: SUMO is proteolytically processed (R-HSA-3065679)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[3]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[6]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[7]
Obesity	DIS47Y1K	Strong	Biomarker	[8]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[9]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[3]
Ventricular septal defect	DISICO41	Strong	Altered Expression	[4]
Breast cancer	DIS7DPX1	moderate	Genetic Variation	[10]
Breast carcinoma	DIS2UE88	moderate	Genetic Variation	[10]
Osteoarthritis	DIS05URM	moderate	Altered Expression	[11]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[5]
Epstein barr virus infection	DISOO0WT	Limited	Biomarker	[12]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[5]
Small lymphocytic lymphoma	DIS30POX	Limited	Biomarker	[1]

9 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 2 (SENP2).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sentrin-specific protease 2 (SENP2).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Sentrin-specific protease 2 (SENP2).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Sentrin-specific protease 2 (SENP2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Sentrin-specific protease 2 (SENP2).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Sentrin-specific protease 2 (SENP2).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Sentrin-specific protease 2 (SENP2).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Sentrin-specific protease 2 (SENP2).	[21]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Sentrin-specific protease 2 (SENP2).	[22]

1 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 decreases the methylation of Sentrin-specific protease 2 (SENP2).	[17]

References

• [1] SENP2 exerts an antitumor effect on chronic lymphocytic leukemia cells through the inhibition of the Notch and NFB signaling pathways.Int J Oncol. 2019 Feb;54(2):455-466. doi: 10.3892/ijo.2018.4635. Epub 2018 Nov 14.
• [2] SUMO-specific protease 2 (SENP2) suppresses keratinocyte migration by targeting NDR1 for de-SUMOylation.FASEB J. 2019 Jan;33(1):163-174. doi: 10.1096/fj.201800353R. Epub 2018 Jul 3.
• [3] SENP2 suppresses epithelial-mesenchymal transition of bladder cancer cells through deSUMOylation of TGF-RI.Mol Carcinog. 2017 Oct;56(10):2332-2341. doi: 10.1002/mc.22687. Epub 2017 Jun 30.
• [4] Enhanced desumoylation in murine hearts by overexpressed SENP2 leads to congenital heart defects and cardiac dysfunction.J Mol Cell Cardiol. 2012 Mar;52(3):638-49. doi: 10.1016/j.yjmcc.2011.11.011. Epub 2011 Dec 1.
• [5] SUMO-specific protease 2 (SENP2) functions as a tumor suppressor in osteosarcoma via SOX9 degradation.Exp Ther Med. 2018 Dec;16(6):5359-5365. doi: 10.3892/etm.2018.6838. Epub 2018 Oct 9.
• [6] SUMO-Specific Protease 2 (SENP2) Is an Important Regulator of Fatty Acid Metabolism in Skeletal Muscle.Diabetes. 2015 Jul;64(7):2420-31. doi: 10.2337/db15-0115. Epub 2015 Mar 17.
• [7] Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.Nat Genet. 2018 Apr;50(4):559-571. doi: 10.1038/s41588-018-0084-1. Epub 2018 Apr 9.
• [8] Senp2 regulates adipose lipid storage by de-SUMOylation of Setdb1.J Mol Cell Biol. 2018 Jun 1;10(3):258-266. doi: 10.1093/jmcb/mjx055.
• [9] The role of sentrin-specific protease 2 substrate recognition in TGF--induced tumorigenesis.Sci Rep. 2018 Jun 28;8(1):9786. doi: 10.1038/s41598-018-28103-8.
• [10] Association of SENPs single-nucleotide polymorphism and breast cancer in Chinese population.Medicine (Baltimore). 2019 Feb;98(6):e14168. doi: 10.1097/MD.0000000000014168.
• [11] Desumoylation of aggrecan and collagen II facilitates degradation via aggrecanases in IL-1-mediated osteoarthritis.J Pain Res. 2019 Jul 12;12:2145-2153. doi: 10.2147/JPR.S194306. eCollection 2019.
• [12] The Epstein-Barr Virus Oncoprotein, LMP1, Regulates the Function of SENP2, a SUMO-protease.Sci Rep. 2019 Jul 2;9(1):9523. doi: 10.1038/s41598-019-45825-5.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] 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.
• [15] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [16] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [17] 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.
• [18] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [19] 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.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [22] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.