Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXJ39JG)

• DOT Name: SUMO-activating enzyme subunit 2
• Synonyms: EC 2.3.2.-; Anthracycline-associated resistance ARX; Ubiquitin-like 1-activating enzyme E1B; Ubiquitin-like modifier-activating enzyme 2
• Gene Name: UBA2
• Related Disease:
  ACCES syndrome
  Multiple congenital anomalies/dysmorphic syndrome
• UniProt ID: SAE2_HUMAN
• PDB ID: 1Y8Q; 1Y8R; 2PX9; 3KYC; 3KYD; 4W5V; 5FQ2; 6CWY; 6CWZ; 6XOG; 6XOH; 6XOI
• EC Number: 2.3.2.-
• Pfam ID: PF00899 ; PF14732 ; PF16195
• Sequence:
  MALSRGLPRELAEAVAGGRVLVVGAGGIGCELLKNLVLTGFSHIDLIDLDTIDVSNLNRQ
  FLFQKKHVGRSKAQVAKESVLQFYPKANIVAYHDSIMNPDYNVEFFRQFILVMNALDNRA
  ARNHVNRMCLAADVPLIESGTAGYLGQVTTIKKGVTECYECHPKPTQRTFPGCTIRNTPS
  EPIHCIVWAKYLFNQLFGEEDADQEVSPDRADPEAAWEPTEAEARARASNEDGDIKRIST
  KEWAKSTGYDPVKLFTKLFKDDIRYLLTMDKLWRKRKPPVPLDWAEVQSQGEETNASDQQ
  NEPQLGLKDQQVLDVKSYARLFSKSIETLRVHLAEKGDGAELIWDKDDPSAMDFVTSAAN
  LRMHIFSMNMKSRFDIKSMAGNIIPAIATTNAVIAGLIVLEGLKILSGKIDQCRTIFLNK
  QPNPRKKLLVPCALDPPNPNCYVCASKPEVTVRLNVHKVTVLTLQDKIVKEKFAMVAPDV
  QIEDGKGTILISSEEGETEANNHKKLSEFGIRNGSRLQADDFLQDYTLLINILHSEDLGK
  DVEFEVVGDAPEKVGPKQAEDAAKSITNGSDDGAQPSTSTAQEQDDVLIVDSDEEDSSNN
  ADVSEEERSRKRKLDEKENLSAKRSRIEQKEELDDVIALD
• 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.
• 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

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
ACCES syndrome	DISOTYGN	Strong	Autosomal dominant	[1]
Multiple congenital anomalies/dysmorphic syndrome	DIS0LF2K	Strong	Autosomal dominant	[2]

8 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 SUMO-activating enzyme subunit 2.	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of SUMO-activating enzyme subunit 2.	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of SUMO-activating enzyme subunit 2.	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of SUMO-activating enzyme subunit 2.	[6]
Aspirin	DM672AH	Approved	Aspirin increases the expression of SUMO-activating enzyme subunit 2.	[7]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of SUMO-activating enzyme subunit 2.	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of SUMO-activating enzyme subunit 2.	[10]
1,6-hexamethylene diisocyanate	DMLB3RT	Investigative	1,6-hexamethylene diisocyanate affects the expression of SUMO-activating enzyme subunit 2.	[11]

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 affects the methylation of SUMO-activating enzyme subunit 2.	[9]

References

• [1] Cutis Aplasia as a clinical hallmark for the syndrome associated with 19q13.11 deletion: the possible role for UBA2 gene. Mol Cytogenet. 2015 Mar 26;8:21. doi: 10.1186/s13039-015-0123-x. eCollection 2015.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [8] Sumoylation of eukaryotic elongation factor 2 is vital for protein stability and anti-apoptotic activity in lung adenocarcinoma cells. Cancer Sci. 2011 Aug;102(8):1582-9. doi: 10.1111/j.1349-7006.2011.01975.x. Epub 2011 Jun 23.
• [9] 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.
• [10] 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.
• [11] Gene profiles of THP-1 macrophages after in vitro exposure to respiratory (non-)sensitizing chemicals: identification of discriminating genetic markers and pathway analysis. Toxicol In Vitro. 2009 Sep;23(6):1151-62. doi: 10.1016/j.tiv.2009.06.007. Epub 2009 Jun 13.