Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA3ALQO)

• DOT Name: E3 ubiquitin-protein ligase NEURL3 (NEURL3)
• Synonyms: EC 2.3.2.27; Lung-inducible neuralized-related C3CH4 RING domain protein; Neuralized-like protein 3; RING-type E3 ubiquitin transferase NEURL3
• Gene Name: NEURL3
• Related Disease:
  Hepatitis C virus infection
  Multiple sclerosis
  Zika virus infection
  Acute myelogenous leukaemia
• UniProt ID: NEUL3_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF07177 ; PF13920
• Sequence:
  MGAQLCFEANAKAPREALRFHAEAKGAQVRLDTRGCIAHRRTTFHDGIVFSQRPVRLGER
  VALRVLREESGWCGGLRVGFTRLDPACVSVPSLPPFLCPDLEEQSPTWAAVLPEGCALTG
  DLVRFWVDRRGCLFAKVNAGCRLLLREGVPVGAPLWAVMDVYGTTKAIELLDPTASRLPT
  PMPWDLSNKAVPEPKATPGEECAICFYHAANTRLVPCGHTYFCRYCAWRVFSDTAKCPVC
  RWQIEAVAPAQGPPALRVEEGS
• Function: E3 ubiquitin-protein ligase that plays a role in various biological processes such as lung development or innate immunity. Seems to utilize UBE2E1. Promotes innate antiviral response by catalyzing 'Lys-63'-linked ubiquitination of IRF7. Inhibits also hepatitis C virus assembly by directly binding to viral E1 envelope glycoprotein to disrupt its interaction with E2.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[1]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[2]
Zika virus infection	DISQUCTY	Strong	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[3]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of E3 ubiquitin-protein ligase NEURL3 (NEURL3).	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of E3 ubiquitin-protein ligase NEURL3 (NEURL3).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of E3 ubiquitin-protein ligase NEURL3 (NEURL3).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of E3 ubiquitin-protein ligase NEURL3 (NEURL3).	[7]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of E3 ubiquitin-protein ligase NEURL3 (NEURL3).	[8]
Malathion	DMXZ84M	Approved	Malathion increases the expression of E3 ubiquitin-protein ligase NEURL3 (NEURL3).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of E3 ubiquitin-protein ligase NEURL3 (NEURL3).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of E3 ubiquitin-protein ligase NEURL3 (NEURL3).	[8]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of E3 ubiquitin-protein ligase NEURL3 (NEURL3).	[11]

References

• [1] Neuralized E3 Ubiquitin Protein Ligase 3 Is an Inducible Antiviral Effector That Inhibits Hepatitis C Virus Assembly by Targeting Viral E1 Glycoprotein.J Virol. 2018 Oct 12;92(21):e01123-18. doi: 10.1128/JVI.01123-18. Print 2018 Nov 1.
• [2] Correlation between LincR-Gng2-5'and LincR-Epas1-3'as with the severity of multiple sclerosis in Egyptian patients.Int J Neurosci. 2020 May;130(5):515-521. doi: 10.1080/00207454.2019.1695610. Epub 2019 Dec 2.
• [3] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [4] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [5] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [6] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [7] 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.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [9] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [10] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [11] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.