Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT18HFX5)

• DOT Name: SUMO-activating enzyme subunit 1 (SAE1)
• Synonyms: Ubiquitin-like 1-activating enzyme E1A
• Gene Name: SAE1
• Related Disease:
  Advanced cancer
  Idiopathic inflammatory myopathy
  Breast cancer
  Cleft lip/palate
  Exanthem
  Glioma
  Multiple sclerosis
  Myositis disease
  Neoplasm
• UniProt ID: SAE1_HUMAN
• PDB ID: 1Y8Q; 1Y8R; 3KYC; 3KYD; 6CWY; 6CWZ; 6XOG; 6XOH; 6XOI
• Pfam ID: PF00899
• Sequence:
  MVEKEEAGGGISEEEAAQYDRQIRLWGLEAQKRLRASRVLLVGLKGLGAEIAKNLILAGV
  KGLTMLDHEQVTPEDPGAQFLIRTGSVGRNRAEASLERAQNLNPMVDVKVDTEDIEKKPE
  SFFTQFDAVCLTCCSRDVIVKVDQICHKNSIKFFTGDVFGYHGYTFANLGEHEFVEEKTK
  VAKVSQGVEDGPDTKRAKLDSSETTMVKKKVVFCPVKEALEVDWSSEKAKAALKRTTSDY
  FLLQVLLKFRTDKGRDPSSDTYEEDSELLLQIRNDVLDSLGISPDLLPEDFVRYCFSEMA
  PVCAVVGGILAQEIVKALSQRDPPHNNFFFFDGMKGNGIVECLGPK
• Function: The heterodimer acts as an E1 ligase for SUMO1, SUMO2, SUMO3, and probably SUMO4. It mediates ATP-dependent activation of SUMO proteins followed by formation of a thioester bond between a SUMO protein and a conserved active site cysteine residue on UBA2/SAE2.
• Tissue Specificity: Expression level increases during S phase and drops in G2 phase (at protein level).
• KEGG Pathway: Ubiquitin mediated proteolysis (hsa04120)
• Reactome Pathway:
  SUMO is transferred from E1 to E2 (UBE2I, UBC9) (R-HSA-3065678)
  SUMO is conjugated to E1 (UBA2 (R-HSA-3065676)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Idiopathic inflammatory myopathy	DISGB1BZ	Definitive	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Cleft lip/palate	DIS14IG3	Strong	Biomarker	[3]
Exanthem	DISAFOQN	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Altered Expression	[5]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[6]
Myositis disease	DISCIXF0	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]

14 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 SUMO-activating enzyme subunit 1 (SAE1).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of SUMO-activating enzyme subunit 1 (SAE1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of SUMO-activating enzyme subunit 1 (SAE1).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of SUMO-activating enzyme subunit 1 (SAE1).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of SUMO-activating enzyme subunit 1 (SAE1).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of SUMO-activating enzyme subunit 1 (SAE1).	[13]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of SUMO-activating enzyme subunit 1 (SAE1).	[14]
Retigabine	DMGNYIH	Approved	Retigabine decreases the expression of SUMO-activating enzyme subunit 1 (SAE1).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of SUMO-activating enzyme subunit 1 (SAE1).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of SUMO-activating enzyme subunit 1 (SAE1).	[19]
EMODIN	DMAEDQG	Terminated	EMODIN decreases the expression of SUMO-activating enzyme subunit 1 (SAE1).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of SUMO-activating enzyme subunit 1 (SAE1).	[14]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of SUMO-activating enzyme subunit 1 (SAE1).	[21]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of SUMO-activating enzyme subunit 1 (SAE1).	[22]

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 SUMO-activating enzyme subunit 1 (SAE1).	[16]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of SUMO-activating enzyme subunit 1 (SAE1).	[18]

References

• [1] Identification of multiple cancer-associated myositis-specific autoantibodies in idiopathic inflammatory myopathies: a large longitudinal cohort study.Arthritis Res Ther. 2017 Nov 25;19(1):259. doi: 10.1186/s13075-017-1469-8.
• [2] A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis.Science. 2012 Jan 20;335(6066):348-53. doi: 10.1126/science.1212728. Epub 2011 Dec 8.
• [3] Array-CGH detection of a de novo 0.8Mb deletion in 19q13.32 associated with mental retardation, cardiac malformation, cleft lip and palate, hearing loss and multiple dysmorphic features.Eur J Med Genet. 2009 Jan-Feb;52(1):62-6. doi: 10.1016/j.ejmg.2008.09.007. Epub 2008 Oct 31.
• [4] Association Between Autoantibody Phenotype and Cutaneous Adverse Reactions to Hydroxychloroquine in Dermatomyositis.JAMA Dermatol. 2018 Oct 1;154(10):1199-1203. doi: 10.1001/jamadermatol.2018.2549.
• [5] SAE1 promotes human glioma progression through activating AKT SUMOylation-mediated signaling pathways.Cell Commun Signal. 2019 Jul 25;17(1):82. doi: 10.1186/s12964-019-0392-9.
• [6] Genetic overlap between multiple sclerosis and several cardiovascular disease risk factors.Mult Scler. 2016 Dec;22(14):1783-1793. doi: 10.1177/1352458516635873. Epub 2016 Feb 26.
• [7] Antibodies to small ubiquitin-like modifier activating enzyme are associated with a diagnosis of dermatomyositis: results from an unselected cohort.Immunol Res. 2018 Jun;66(3):431-436. doi: 10.1007/s12026-018-9006-7.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] 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.
• [10] 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.
• [11] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [12] 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.
• [13] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [14] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [15] The SUMO-specific protease SENP2 plays an essential role in the regulation of Kv7.2 and Kv7.3 potassium channels. J Biol Chem. 2021 Oct;297(4):101183. doi: 10.1016/j.jbc.2021.101183. Epub 2021 Sep 10.
• [16] 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.
• [17] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [18] 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.
• [19] 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.
• [20] Gene expression alteration during redox-dependent enhancement of arsenic cytotoxicity by emodin in HeLa cells. Cell Res. 2005 Jul;15(7):511-22.
• [21] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [22] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.