Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIA27P3)

• DOT Name: Ubiquitin-protein ligase E3A
• Synonyms: EC 2.3.2.26; E6AP ubiquitin-protein ligase; HECT-type ubiquitin transferase E3A; Human papillomavirus E6-associated protein; Oncogenic protein-associated protein E6-AP; Renal carcinoma antigen NY-REN-54
• Gene Name: UBE3A
• Related Disease: Angelman syndrome
• UniProt ID: UBE3A_HUMAN
• PDB ID: 1C4Z; 1D5F; 1EQX; 2KR1; 4GIZ; 4XR8; 6SJV; 6SLM; 6TGK; 6U19; 7Q41; 7QPB; 8ENP; 8EPT; 8R1F; 8R1G
• EC Number: 2.3.2.26
• Pfam ID: PF16558 ; PF00632
• Sequence:
  MEKLHQCYWKSGEPQSDDIEASRMKRAAAKHLIERYYHQLTEGCGNEACTNEFCASCPTF
  LRMDNNAAAIKALELYKINAKLCDPHPSKKGASSAYLENSKGAPNNSCSEIKMNKKGARI
  DFKDVTYLTEEKVYEILELCREREDYSPLIRVIGRVFSSAEALVQSFRKVKQHTKEELKS
  LQAKDEDKDEDEKEKAACSAAAMEEDSEASSSRIGDSSQGDNNLQKLGPDDVSVDIDAIR
  RVYTRLLSNEKIETAFLNALVYLSPNVECDLTYHNVYSRDPNYLNLFIIVMENRNLHSPE
  YLEMALPLFCKAMSKLPLAAQGKLIRLWSKYNADQIRRMMETFQQLITYKVISNEFNSRN
  LVNDDDAIVAASKCLKMVYYANVVGGEVDTNHNEEDDEEPIPESSELTLQELLGEERRNK
  KGPRVDPLETELGVKTLDCRKPLIPFEEFINEPLNEVLEMDKDYTFFKVETENKFSFMTC
  PFILNAVTKNLGLYYDNRIRMYSERRITVLYSLVQGQQLNPYLRLKVRRDHIIDDALVRL
  EMIAMENPADLKKQLYVEFEGEQGVDEGGVSKEFFQLVVEEIFNPDIGMFTYDESTKLFW
  FNPSSFETEGQFTLIGIVLGLAIYNNCILDVHFPMVVYRKLMGKKGTFRDLGDSHPVLYQ
  SLKDLLEYEGNVEDDMMITFQISQTDLFGNPMMYDLKENGDKIPITNENRKEFVNLYSDY
  ILNKSVEKQFKAFRRGFHMVTNESPLKYLFRPEEIELLICGSRNLDFQALEETTEYDGGY
  TRDSVLIREFWEIVHSFTDEQKRLFLQFTTGTDRAPVGGLGKLKMIIAKNGPDTERLPTS
  HTCFNVLLLPEYSSKEKLKERLLKAITYAKGFGML
• Function: E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and transfers it to its substrates. Several substrates have been identified including the BMAL1, ARC, LAMTOR1, RAD23A and RAD23B, MCM7 (which is involved in DNA replication), annexin A1, the PML tumor suppressor, and the cell cycle regulator CDKN1B. Additionally, may function as a cellular quality control ubiquitin ligase by helping the degradation of the cytoplasmic misfolded proteins. Finally, UBE3A also promotes its own degradation in vivo. Plays an important role in the regulation of the circadian clock: involved in the ubiquitination of the core clock component BMAL1, leading to its proteasomal degradation. Acts as transcriptional coactivator of progesterone receptor PGR upon progesterone hormone activation. Acts as a regulator of synaptic development by mediating ubiquitination and degradation of ARC. Required for synaptic remodeling in neurons by mediating ubiquitination and degradation of LAMTOR1, thereby limiting mTORC1 signaling and activity-dependent synaptic remodeling. Synergizes with WBP2 in enhancing PGR activity ; (Microbial infection) Catalyzes the high-risk human papilloma virus E6-mediated ubiquitination of p53/TP53, contributing to the neoplastic progression of cells infected by these viruses.
• KEGG Pathway:
  Ubiquitin mediated proteolysis (hsa04120)
  Human papillomavirus infection (hsa05165)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Angelman syndrome	DIS4QVXO	Definitive	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Ubiquitin-protein ligase E3A.	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ubiquitin-protein ligase E3A.	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ubiquitin-protein ligase E3A.	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ubiquitin-protein ligase E3A.	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ubiquitin-protein ligase E3A.	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Ubiquitin-protein ligase E3A.	[7]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Ubiquitin-protein ligase E3A.	[8]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Ubiquitin-protein ligase E3A.	[9]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Ubiquitin-protein ligase E3A.	[10]
Tubocurarine	DMBZIVP	Approved	Tubocurarine increases the expression of Ubiquitin-protein ligase E3A.	[10]
Mecamylamine	DMGQFYB	Approved	Mecamylamine decreases the expression of Ubiquitin-protein ligase E3A.	[10]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of Ubiquitin-protein ligase E3A.	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Ubiquitin-protein ligase E3A.	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Ubiquitin-protein ligase E3A.	[14]

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 Ubiquitin-protein ligase E3A.	[13]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] 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.
• [3] Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor alpha and enhancing changes in all-trans-retinoic acid-regulated gene expression. Cancer Res. 2005 Sep 1;65(17):7856-65. doi: 10.1158/0008-5472.CAN-05-1056.
• [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] 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.
• [6] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] 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.
• [8] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [9] Cannabidiol Modulates the Expression of Alzheimer's Disease-Related Genes in Mesenchymal Stem Cells. Int J Mol Sci. 2016 Dec 23;18(1):26. doi: 10.3390/ijms18010026.
• [10] Nicotine modulates the expression of a diverse set of genes in the neuronal SH-SY5Y cell line. J Biol Chem. 2003 May 2;278(18):15633-40.
• [11] 4-HPR modulates gene expression in ovarian cells. Int J Cancer. 2006 Sep 1;119(5):1005-13. doi: 10.1002/ijc.21797.
• [12] 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.
• [13] 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.
• [14] 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.