Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1Y5IKN)

• DOT Name: Small ubiquitin-related modifier 2 (SUMO2)
• Synonyms: SUMO-2; HSMT3; SMT3 homolog 2; SUMO-3; Sentrin-2; Ubiquitin-like protein SMT3B; Smt3B
• Gene Name: SUMO2
• Related Disease:
  Carcinoma of liver and intrahepatic biliary tract
  Intervertebral disc degeneration
  Liver cancer
  Type-1 diabetes
  Alzheimer disease
  Autosomal dominant cerebellar ataxia type II
  Bacillary dysentery
  Bronchopulmonary dysplasia
  Cardiac failure
  Cardiomyopathy
  Cerebral infarction
  Congestive heart failure
  Cytomegalovirus infection
  Hepatocellular carcinoma
  Huntington disease
  Inflammatory bowel disease
  Neoplasm
  Osteoarthritis
  Promyelocytic leukaemia
  Stroke
  Basal cell nevus syndrome
  Bloom syndrome
  Progressive multifocal leukoencephalopathy
  Rheumatoid arthritis
  AIDS-related lymphoma
  Amyotrophic lateral sclerosis
  Kaposi sarcoma
  Lymphoma
• UniProt ID: SUMO2_HUMAN
• PDB ID: 1WM2; 1WM3; 1WZ0; 2AWT; 2CKH; 2D07; 2IO0; 2IO3; 2IYD; 2N1W; 2N9E; 2RPQ; 3UIN; 3UIO; 3ZO5; 4BKG; 4NPN; 5D2M; 5ELU; 5EQL; 5GHB; 5GHC; 6JXW; 6JXX; 7ZJV
• Pfam ID: PF11976
• Sequence:
  MADEKPKEGVKTENNDHINLKVAGQDGSVVQFKIKRHTPLSKLMKAYCERQGLSMRQIRF
  RFDGQPINETDTPAQLEMEDEDTIDVFQQQTGGVY
• Function: Ubiquitin-like protein that can be covalently attached to proteins as a monomer or as a lysine-linked polymer. Covalent attachment via an isopeptide bond to its substrates requires prior activation by the E1 complex SAE1-SAE2 and linkage to the E2 enzyme UBE2I, and can be promoted by an E3 ligase such as PIAS1-4, RANBP2, CBX4 or ZNF451. This post-translational modification on lysine residues of proteins plays a crucial role in a number of cellular processes such as nuclear transport, DNA replication and repair, mitosis and signal transduction. Polymeric SUMO2 chains are also susceptible to polyubiquitination which functions as a signal for proteasomal degradation of modified proteins. Plays a role in the regulation of sumoylation status of SETX.
• Tissue Specificity: Broadly expressed.
• KEGG Pathway:
  Nucleocytoplasmic transport (hsa03013)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  SUMO is conjugated to E1 (UBA2 (R-HSA-3065676)
  SUMO is transferred from E1 to E2 (UBE2I, UBC9) (R-HSA-3065678)
  SUMO is proteolytically processed (R-HSA-3065679)
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)
  SUMOylation of transcription factors (R-HSA-3232118)
  SUMOylation of transcription cofactors (R-HSA-3899300)
  SUMOylation of SUMOylation proteins (R-HSA-4085377)
  SUMOylation of intracellular receptors (R-HSA-4090294)
  SUMOylation of chromatin organization proteins (R-HSA-4551638)
  SUMOylation of RNA binding proteins (R-HSA-4570464)
  SUMOylation of DNA replication proteins (R-HSA-4615885)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  Formation of Incision Complex in GG-NER (R-HSA-5696395)
  Vitamin D (calciferol) metabolism (R-HSA-196791)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Definitive	Biomarker	[1]
Intervertebral disc degeneration	DISG3AIM	Definitive	Biomarker	[2]
Liver cancer	DISDE4BI	Definitive	Biomarker	[1]
Type-1 diabetes	DIS7HLUB	Definitive	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Autosomal dominant cerebellar ataxia type II	DIS0PM39	Strong	Biomarker	[4]
Bacillary dysentery	DISFZHKN	Strong	Biomarker	[5]
Bronchopulmonary dysplasia	DISO0BY5	Strong	Biomarker	[6]
Cardiac failure	DISDC067	Strong	Biomarker	[7]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[8]
Cerebral infarction	DISR1WNP	Strong	Biomarker	[9]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[10]
Cytomegalovirus infection	DISCEMGC	Strong	Altered Expression	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[12]
Huntington disease	DISQPLA4	Strong	Biomarker	[13]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[14]
Neoplasm	DISZKGEW	Strong	Altered Expression	[12]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[15]
Promyelocytic leukaemia	DISYGG13	Strong	Biomarker	[16]
Stroke	DISX6UHX	Strong	Biomarker	[9]
Basal cell nevus syndrome	DIST8BC2	moderate	Altered Expression	[17]
Bloom syndrome	DISKXQ7J	moderate	Genetic Variation	[18]
Progressive multifocal leukoencephalopathy	DISX02WS	moderate	Biomarker	[19]
Rheumatoid arthritis	DISTSB4J	moderate	Altered Expression	[20]
AIDS-related lymphoma	DISSLRAU	Limited	Biomarker	[21]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Genetic Variation	[22]
Kaposi sarcoma	DISC1H1Z	Limited	Biomarker	[23]
Lymphoma	DISN6V4S	Limited	Biomarker	[24]

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 Small ubiquitin-related modifier 2 (SUMO2).	[25]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Small ubiquitin-related modifier 2 (SUMO2).	[26]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Small ubiquitin-related modifier 2 (SUMO2).	[27]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Small ubiquitin-related modifier 2 (SUMO2).	[28]
Selenium	DM25CGV	Approved	Selenium increases the expression of Small ubiquitin-related modifier 2 (SUMO2).	[29]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Small ubiquitin-related modifier 2 (SUMO2).	[30]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Small ubiquitin-related modifier 2 (SUMO2).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Small ubiquitin-related modifier 2 (SUMO2).	[31]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Small ubiquitin-related modifier 2 (SUMO2).	[32]

References

• [1] SUMOylation regulates LKB1 localization and its oncogenic activity in liver cancer.EBioMedicine. 2019 Feb;40:406-421. doi: 10.1016/j.ebiom.2018.12.031. Epub 2018 Dec 26.
• [2] Silencing SUMO2 promotes protection against degradation and apoptosis of nucleus pulposus cells through p53 signaling pathway in intervertebral disc degeneration.Biosci Rep. 2018 Jun 29;38(3):BSR20171523. doi: 10.1042/BSR20171523. Print 2018 Jun 29.
• [3] Polymorphisms of small ubiquitin-related modifier genes are associated with risk of Alzheimer's disease in Korean: A case-control study.J Neurol Sci. 2016 May 15;364:122-7. doi: 10.1016/j.jns.2016.03.023. Epub 2016 Mar 19.
• [4] SUMOylation by SUMO2 is implicated in the degradation of misfolded ataxin-7 via RNF4 in SCA7 models.Dis Model Mech. 2019 Jan 11;12(1):dmm036145. doi: 10.1242/dmm.036145.
• [5] Sumoylation controls host anti-bacterial response to the gut invasive pathogen Shigella flexneri.EMBO Rep. 2014 Sep;15(9):965-72. doi: 10.15252/embr.201338386. Epub 2014 Aug 5.
• [6] Attenuated SUMOylation of sirtuin 1 in premature neonates with bronchopulmonary dysplasia.Mol Med Rep. 2018 Jan;17(1):1283-1288. doi: 10.3892/mmr.2017.8012. Epub 2017 Nov 8.
• [7] Involvement of activated SUMO-2 conjugation in cardiomyopathy.Biochim Biophys Acta. 2015 Jul;1852(7):1388-99. doi: 10.1016/j.bbadis.2015.03.013. Epub 2015 Apr 6.
• [8] Sumoylation-independent activation of Calcineurin-NFAT-signaling via SUMO2 mediates cardiomyocyte hypertrophy.Sci Rep. 2016 Oct 21;6:35758. doi: 10.1038/srep35758.
• [9] Hypothermia exerts early neuroprotective effects involving protein conjugation of SUMO?/3 in a rat model of middle cerebral artery occlusion.Mol Med Rep. 2017 Sep;16(3):3217-3223. doi: 10.3892/mmr.2017.6994. Epub 2017 Jul 15.
• [10] SUMOylation in cardiac disorders - a review.Eur Rev Med Pharmacol Sci. 2017 Apr;21(7):1583-1587.
• [11] Small ubiquitin-related modifier (SUMO) pathway-mediated enhancement of human cytomegalovirus replication correlates with a recruitment of SUMO-1/3 proteins to viral replication compartments.J Gen Virol. 2013 Jun;94(Pt 6):1373-1384. doi: 10.1099/vir.0.051078-0. Epub 2013 Feb 13.
• [12] Small ubiquitin-related modifier 2/3 interacts with p65 and stabilizes it in the cytoplasm in HBV-associated hepatocellular carcinoma.BMC Cancer. 2015 Oct 12;15:675. doi: 10.1186/s12885-015-1665-3.
• [13] SUMO-2 and PIAS1 modulate insoluble mutant huntingtin protein accumulation.Cell Rep. 2013 Jul 25;4(2):362-75. doi: 10.1016/j.celrep.2013.06.034. Epub 2013 Jul 18.
• [14] A nanogel based oral gene delivery system targeting SUMOylation machinery to combat gut inflammation.Nanoscale. 2019 Mar 14;11(11):4970-4986. doi: 10.1039/c8nr09599j.
• [15] 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.
• [16] Kaposi's sarcoma-associated herpesvirus K-Rta exhibits SUMO-targeting ubiquitin ligase (STUbL) like activity and is essential for viral reactivation.PLoS Pathog. 2013;9(8):e1003506. doi: 10.1371/journal.ppat.1003506. Epub 2013 Aug 22.
• [17] Down-regulation of SMT3A gene expression in association with DNA synthesis induction after X-ray irradiation in nevoid basal cell carcinoma syndrome (NBCCS) cells.Mutat Res. 2005 Oct 15;578(1-2):327-32. doi: 10.1016/j.mrfmmm.2005.06.027.
• [18] Small ubiquitin-related modifier (SUMO) binding determines substrate recognition and paralog-selective SUMO modification.J Biol Chem. 2008 Oct 24;283(43):29405-15. doi: 10.1074/jbc.M803632200. Epub 2008 Aug 15.
• [19] Solubility changes of promyelocytic leukemia (PML) and SUMO monomers and dynamics of PML nuclear body proteins in arsenite-treated cells.Toxicol Appl Pharmacol. 2018 Dec 1;360:150-159. doi: 10.1016/j.taap.2018.10.001. Epub 2018 Oct 5.
• [20] Role of small ubiquitin-like modifier proteins-1 (SUMO-1) in regulating migration and invasion of fibroblast-like synoviocytes from patients with rheumatoid arthritis.Exp Cell Res. 2019 Feb 1;375(1):52-61. doi: 10.1016/j.yexcr.2018.12.011. Epub 2018 Dec 15.
• [21] Identification of viral SIM-SUMO2-interaction inhibitors for treating primary effusion lymphoma.PLoS Pathog. 2019 Dec 12;15(12):e1008174. doi: 10.1371/journal.ppat.1008174. eCollection 2019 Dec.
• [22] SUMO3 modification accelerates the aggregation of ALS-linked SOD1 mutants.PLoS One. 2014 Jun 27;9(6):e101080. doi: 10.1371/journal.pone.0101080. eCollection 2014.
• [23] SUMO modification of a heterochromatin histone demethylase JMJD2A enables viral gene transactivation and viral replication.PLoS Pathog. 2017 Feb 17;13(2):e1006216. doi: 10.1371/journal.ppat.1006216. eCollection 2017 Feb.
• [24] Epstein-Barr Virus Latent Membrane Protein-1 Induces the Expression of SUMO-1 and SUMO-2/3 in LMP1-positive Lymphomas and Cells.Sci Rep. 2019 Jan 18;9(1):208. doi: 10.1038/s41598-018-36312-4.
• [25] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [26] 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.
• [27] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [28] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [29] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [30] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [31] 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.
• [32] Molecular targets of chloropicrin in human airway epithelial cells. Toxicol In Vitro. 2017 Aug;42:247-254.