Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT5UKSZ)

• DOT Name: Elongator complex protein 3 (ELP3)
• Synonyms: hELP3; EC 2.3.1.-; tRNA uridine(34) acetyltransferase
• Gene Name: ELP3
• Related Disease:
  Amyotrophic lateral sclerosis
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Invasive breast carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Riley-Day syndrome
  Advanced cancer
  Chronic obstructive pulmonary disease
  Intestinal neoplasm
  Polyp
  Invasive ductal breast carcinoma
• UniProt ID: ELP3_HUMAN
• EC Number: 2.3.1.-
• Pfam ID: PF04055 ; PF16199
• Sequence:
  MRQKRKGDLSPAELMMLTIGDVIKQLIEAHEQGKDIDLNKVKTKTAAKYGLSAQPRLVDI
  IAAVPPQYRKVLMPKLKAKPIRTASGIAVVAVMCKPHRCPHISFTGNICVYCPGGPDSDF
  EYSTQSYTGYEPTSMRAIRARYDPFLQTRHRIEQLKQLGHSVDKVEFIVMGGTFMALPEE
  YRDYFIRNLHDALSGHTSNNIYEAVKYSERSLTKCIGITIETRPDYCMKRHLSDMLTYGC
  TRLEIGVQSVYEDVARDTNRGHTVKAVCESFHLAKDSGFKVVAHMMPDLPNVGLERDIEQ
  FTEFFENPAFRPDGLKLYPTLVIRGTGLYELWKSGRYKSYSPSDLVELVARILALVPPWT
  RVYRVQRDIPMPLVSSGVEHGNLRELALARMKDLGIQCRDVRTREVGIQEIHHKVRPYQV
  ELVRRDYVANGGWETFLSYEDPDQDILIGLLRLRKCSEETFRFELGGGVSIVRELHVYGS
  VVPVSSRDPTKFQHQGFGMLLMEEAERIAREEHGSGKIAVISGVGTRNYYRKIGYRLQGP
  YMVKMLK
• Function: Catalytic tRNA acetyltransferase subunit of the elongator complex which is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine). In the elongator complex, acts as a tRNA uridine(34) acetyltransferase by mediating formation of carboxymethyluridine in the wobble base at position 34 in tRNAs. May also act as a protein lysine acetyltransferase by mediating acetylation of target proteins; such activity is however unclear in vivo and recent evidences suggest that ELP3 primarily acts as a tRNA acetyltransferase. Involved in neurogenesis: regulates the migration and branching of projection neurons in the developing cerebral cortex, through a process depending on alpha-tubulin acetylation. Required for acetylation of GJA1 in the developing cerebral cortex.
• Tissue Specificity: Expressed in the cerebellum and spinal motor neurons.
• Reactome Pathway: HATs acetylate histones (R-HSA-3214847)
• BioCyc Pathway: MetaCyc:HS05804-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[2]
Invasive breast carcinoma	DISANYTW	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[4]
Riley-Day syndrome	DISJZHNP	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[6]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[7]
Intestinal neoplasm	DISK0GUH	moderate	Biomarker	[6]
Polyp	DISRSLYF	moderate	Biomarker	[6]
Invasive ductal breast carcinoma	DIS43J58	Limited	Biomarker	[8]

6 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 Elongator complex protein 3 (ELP3).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Elongator complex protein 3 (ELP3).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Elongator complex protein 3 (ELP3).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Elongator complex protein 3 (ELP3).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Elongator complex protein 3 (ELP3).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Elongator complex protein 3 (ELP3).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Elongator complex protein 3 (ELP3).	[14]

References

• [1] Elongator subunit 3 (ELP3) modifies ALS through tRNA modification.Hum Mol Genet. 2018 Apr 1;27(7):1276-1289. doi: 10.1093/hmg/ddy043.
• [2] Elp3 links tRNA modification to IRES-dependent translation of LEF1 to sustain metastasis in breast cancer.J Exp Med. 2016 Oct 17;213(11):2503-2523. doi: 10.1084/jem.20160397. Epub 2016 Oct 10.
• [3] Elongator promotes the migration and invasion of hepatocellular carcinoma cell by the phosphorylation of AKT.Int J Biol Sci. 2018 Apr 5;14(5):518-530. doi: 10.7150/ijbs.23511. eCollection 2018.
• [4] Non-invasive profiling of protease-specific elastin turnover in lung cancer: biomarker potential.J Cancer Res Clin Oncol. 2019 Feb;145(2):383-392. doi: 10.1007/s00432-018-2799-x. Epub 2018 Nov 22.
• [5] The histone acetyltransferase Elp3 plays in active role in the control of synaptic bouton expansion and sleep in Drosophila.J Neurochem. 2010 Oct;115(2):493-504. doi: 10.1111/j.1471-4159.2010.06892.x. Epub 2010 Aug 24.
• [6] Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine.J Exp Med. 2015 Nov 16;212(12):2057-75. doi: 10.1084/jem.20142288. Epub 2015 Nov 2.
• [7] Lung tissue destruction by proteinase 3 and cathepsin G mediated elastin degradation is elevated in chronic obstructive pulmonary disease.Biochem Biophys Res Commun. 2018 Sep 10;503(3):1284-1290. doi: 10.1016/j.bbrc.2018.07.038. Epub 2018 Jul 11.
• [8] Promoter hypermethylation may be an important mechanism of the transcriptional inactivation of ARRDC3, GATA5, and ELP3 in invasive ductal breast carcinoma.Mol Cell Biochem. 2014 Nov;396(1-2):67-77. doi: 10.1007/s11010-014-2143-y. Epub 2014 Aug 23.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] 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.
• [14] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [15] 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.