Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW5R7YD)

• DOT Name: Elongator complex protein 5 (ELP5)
• Synonyms: Dermal papilla-derived protein 6; S-phase 2 protein
• Gene Name: ELP5
• Related Disease:
  Melanoma
  Gallbladder cancer
  Gallbladder carcinoma
  Type-1/2 diabetes
• UniProt ID: ELP5_HUMAN
• Pfam ID: PF10483
• Sequence:
  MLDSLLALGGLVLLRDSVEWEGRSLLKALVKKSALCGEQVHILGCEVSEEEFREGFDSDI
  NNRLVYHDFFRDPLNWSKTEEAFPGGPLGALRAMCKRTDPVPVTIALDSLSWLLLRLPCT
  TLCQVLHAVSHQDSCPGDSSSVGKVSVLGLLHEELHGPGPVGALSSLAQTEVTLGGTMGQ
  ASAHILCRRPRQRPTDQTQWFSILPDFSLDLQEGPSVESQPYSDPHIPPVDPTTHLTFNL
  HLSKKEREARDSLILPFQFSSEKQQALLRPRPGQATSHIFYEPDAYDDLDQEDPDDDLDI
• 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.
• Tissue Specificity: Ubiquitously expressed with high levels in heart, brain, liver, skeletal muscle and testis.
• Reactome Pathway: HATs acetylate histones (R-HSA-3214847)
• BioCyc Pathway: MetaCyc:ENSG00000170291-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Melanoma	DIS1RRCY	Strong	Biomarker	[1]
Gallbladder cancer	DISXJUAF	Disputed	Biomarker	[2]
Gallbladder carcinoma	DISD6ACL	Disputed	Biomarker	[2]
Type-1/2 diabetes	DISIUHAP	Limited	Genetic Variation	[3]

9 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 5 (ELP5).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Elongator complex protein 5 (ELP5).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Elongator complex protein 5 (ELP5).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Elongator complex protein 5 (ELP5).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Elongator complex protein 5 (ELP5).	[8]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Elongator complex protein 5 (ELP5).	[9]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Elongator complex protein 5 (ELP5).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Elongator complex protein 5 (ELP5).	[11]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Elongator complex protein 5 (ELP5).	[12]

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] Genome-wide CRISPR screen identifies ELP5 as a determinant of gemcitabine sensitivity in gallbladder cancer.Nat Commun. 2019 Dec 2;10(1):5492. doi: 10.1038/s41467-019-13420-x.
• [3] A common variant in the CLDN7/ELP5 locus predicts adiponectin change with lifestyle intervention and improved fitness in obese individuals with diabetes.Physiol Genomics. 2015 Jun;47(6):215-24. doi: 10.1152/physiolgenomics.00109.2014. Epub 2015 Mar 10.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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.
• [7] 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.
• [8] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [9] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [10] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.