Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0T3BLP)

• DOT Name: Elongator complex protein 6 (ELP6)
• Synonyms: Angiotonin-transactivated protein 1; Protein TMEM103
• Gene Name: ELP6
• Related Disease:
  Melanoma
  Type-1 diabetes
• UniProt ID: ELP6_HUMAN
• Pfam ID: PF09807
• Sequence:
  MFVELNNLLNTTPDRAEQGKLTLLCDAKTDGSFLVHHFLSFYLKANCKVCFVALIQSFSH
  YSIVGQKLGVSLTMARERGQLVFLEGLKSAVDVVFQAQKEPHPLQFLREANAGNLKPLFE
  FVREALKPVDSGEARWTYPVLLVDDLSVLLSLGMGAVAVLDFIHYCRATVCWELKGNMVV
  LVHDSGDAEDEENDILLNGLSHQSHLILRAEGLATGFCRDVHGQLRILWRRPSQPAVHRD
  QSFTYQYKIQDKSVSFFAKGMSPAVL
• Function: Component 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). The elongator complex catalyzes formation of carboxymethyluridine in the wobble base at position 34 in tRNAs. Involved in cell migration.
• Reactome Pathway: HATs acetylate histones (R-HSA-3214847)
• BioCyc Pathway: MetaCyc:ENSG00000163832-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Melanoma	DIS1RRCY	Strong	Biomarker	[1]
Type-1 diabetes	DIS7HLUB	moderate	Genetic Variation	[2]

12 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 6 (ELP6).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Elongator complex protein 6 (ELP6).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Elongator complex protein 6 (ELP6).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Elongator complex protein 6 (ELP6).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Elongator complex protein 6 (ELP6).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Elongator complex protein 6 (ELP6).	[8]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Elongator complex protein 6 (ELP6).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Elongator complex protein 6 (ELP6).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Elongator complex protein 6 (ELP6).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Elongator complex protein 6 (ELP6).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Elongator complex protein 6 (ELP6).	[12]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Elongator complex protein 6 (ELP6).	[13]

References

• [1] DERP6 (ELP5) and C3ORF75 (ELP6) regulate tumorigenicity and migration of melanoma cells as subunits of Elongator.J Biol Chem. 2012 Sep 21;287(39):32535-45. doi: 10.1074/jbc.M112.402727. Epub 2012 Aug 1.
• [2] Association of diabetic neuropathy with Na/K ATPase gene polymorphism.Diabetologia. 1997 May;40(5):506-11. doi: 10.1007/s001250050708.
• [3] 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.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] 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.
• [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] Synergistic effects of arsenic trioxide combined with ascorbic acid in human osteosarcoma MG-63 cells: a systems biology analysis. Eur Rev Med Pharmacol Sci. 2014;18(24):3877-88.
• [8] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [9] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] 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.
• [12] 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.
• [13] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.