Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ4KKOO)

• DOT Name: Selenocysteine-specific elongation factor (EEFSEC)
• Synonyms: EC 3.6.5.-; Elongation factor sec; Eukaryotic elongation factor, selenocysteine-tRNA-specific
• Gene Name: EEFSEC
• Related Disease:
  Hypospadias
  Nasopharyngeal carcinoma
  Prostate cancer
  Prostate carcinoma
  Chronic obstructive pulmonary disease
  Endometrial carcinoma
  Asthma
• UniProt ID: SELB_HUMAN
• PDB ID: 5IZK; 5IZL; 5IZM; 7ZJW
• EC Number: 3.6.5.-
• Pfam ID: PF21131 ; PF21208 ; PF00009 ; PF03144
• Sequence:
  MAGRRVNVNVGVLGHIDSGKTALARALSTTASTAAFDKQPQSRERGITLDLGFSCFSVPL
  PARLRSSLPEFQAAPEAEPEPGEPLLQVTLVDCPGHASLIRTIIGGAQIIDLMMLVIDVT
  KGMQTQSAECLVIGQIACQKLVVVLNKIDLLPEGKRQAAIDKMTKKMQKTLENTKFRGAP
  IIPVAAKPGGPEAPETEAPQGIPELIELLTSQISIPTRDPSGPFLMSVDHCFSIKGQGTV
  MTGTILSGSISLGDSVEIPALKVVKKVKSMQMFHMPITSAMQGDRLGICVTQFDPKLLER
  GLVCAPESLHTVHAALISVEKIPYFRGPLQTKAKFHITVGHETVMGRLMFFSPAPDNFDQ
  EPILDSFNFSQEYLFQEQYLSKDLTPAVTDNDEADKKAGQATEGHCPRQQWALVEFEKPV
  TCPRLCLVIGSRLDADIHTNTCRLAFHGILLHGLEDRNYADSFLPRLKVYKLKHKHGLVE
  RAMDDYSVIGRSLFKKETNIQLFVGLKVHLSTGELGIIDSAFGQSGKFKIHIPGGLSPES
  KKILTPALKKRARAGRGEATRQEESAERSEPSQHVVLSLTFKRYVFDTHKRMVQSP
• Function: Translation factor required for the incorporation of the rare amino acid selenocysteine encoded by UGA codons. Replaces the eRF1-eRF3-GTP ternary complex for the insertion of selenocysteine directed by the UGA codon. Insertion of selenocysteine at UGA codons is mediated by SECISBP2 and EEFSEC: SECISBP2 (1) specifically binds the SECIS sequence once the 80S ribosome encounters an in-frame UGA codon and (2) contacts the RPS27A/eS31 of the 40S ribosome before ribosome stalling. (3) GTP-bound EEFSEC then delivers selenocysteinyl-tRNA(Sec) to the 80S ribosome and adopts a preaccommodated state conformation. (4) After GTP hydrolysis, EEFSEC dissociates from the assembly, selenocysteinyl-tRNA(Sec) accommodates, and peptide bond synthesis and selenoprotein elongation occur.
• Reactome Pathway: Selenocysteine synthesis (R-HSA-2408557)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypospadias	DIS48CCP	Strong	Genetic Variation	[1]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Genetic Variation	[2]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[3]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[4]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Genetic Variation	[5]
Endometrial carcinoma	DISXR5CY	moderate	Genetic Variation	[6]
Asthma	DISW9QNS	Limited	Genetic Variation	[7]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Selenocysteine-specific elongation factor (EEFSEC) decreases the response to substance of Arsenic trioxide.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Selenocysteine-specific elongation factor (EEFSEC).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Selenocysteine-specific elongation factor (EEFSEC).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Selenocysteine-specific elongation factor (EEFSEC).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Selenocysteine-specific elongation factor (EEFSEC).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Selenocysteine-specific elongation factor (EEFSEC).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Selenocysteine-specific elongation factor (EEFSEC).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Selenocysteine-specific elongation factor (EEFSEC).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Selenocysteine-specific elongation factor (EEFSEC).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Selenocysteine-specific elongation factor (EEFSEC).	[16]

References

• [1] Genome-wide association analyses identify variants in developmental genes associated with hypospadias.Nat Genet. 2014 Sep;46(9):957-63. doi: 10.1038/ng.3063. Epub 2014 Aug 10.
• [2] A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci.Nat Genet. 2010 Jul;42(7):599-603. doi: 10.1038/ng.601. Epub 2010 May 30.
• [3] Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility.Nat Genet. 2009 Oct;41(10):1122-6. doi: 10.1038/ng.448. Epub 2009 Sep 20.
• [4] Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.Nat Genet. 2018 Jul;50(7):928-936. doi: 10.1038/s41588-018-0142-8. Epub 2018 Jun 11.
• [5] Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations.Nat Genet. 2019 Mar;51(3):494-505. doi: 10.1038/s41588-018-0342-2. Epub 2019 Feb 25.
• [6] Identification of nine new susceptibility loci for endometrial cancer.Nat Commun. 2018 Aug 9;9(1):3166. doi: 10.1038/s41467-018-05427-7.
• [7] Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct.Am J Hum Genet. 2019 Apr 4;104(4):665-684. doi: 10.1016/j.ajhg.2019.02.022. Epub 2019 Mar 28.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [12] 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.
• [13] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [16] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [17] Functional Profiling Identifies Determinants of Arsenic Trioxide Cellular Toxicity. Toxicol Sci. 2019 May 1;169(1):108-121. doi: 10.1093/toxsci/kfz024.