Details of Drug Off-Target (DOT)

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

• DOT Name: Selenocysteine insertion sequence-binding protein 2 (SECISBP2)
• Synonyms: SECIS-binding protein 2
• Gene Name: SECISBP2
• Related Disease:
  Myopathy
  Thyroid hormone metabolism, abnormal 1
  Neurodevelopmental disorder
  Osteoarthritis
  Obsolete short stature-delayed bone age due to thyroid hormone metabolism deficiency
  Colorectal carcinoma
  Inborn disorder of amino acid metabolism
  Thyroid hormone metabolism, abnormal
• UniProt ID: SEBP2_HUMAN
• PDB ID: 7ZJW; 7ZJX
• Pfam ID: PF01248
• Sequence:
  MASEGPREPESEGIKLSADVKPFVPRFAGLNVAWLESSEACVFPSSAATYYPFVQEPPVT
  EQKIYTEDMAFGASTFPPQYLSSEITLHPYAYSPYTLDSTQNVYSVPGSQYLYNQPSCYR
  GFQTVKHRNENTCPLPQEMKALFKKKTYDEKKTYDQQKFDSERADGTISSEIKSARGSHH
  LSIYAENSLKSDGYHKRTDRKSRIIAKNVSTSKPEFEFTTLDFPELQGAENNMSEIQKQP
  KWGPVHSVSTDISLLREVVKPAAVLSKGEIVVKNNPNESVTANAATNSPSCTRELSWTPM
  GYVVRQTLSTELSAAPKNVTSMINLKTIASSADPKNVSIPSSEALSSDPSYNKEKHIIHP
  TQKSKASQGSDLEQNEASRKNKKKKEKSTSKYEVLTVQEPPRIEDAEEFPNLAVASERRD
  RIETPKFQSKQQPQDNFKNNVKKSQLPVQLDLGGMLTALEKKQHSQHAKQSSKPVVVSVG
  AVPVLSKECASGERGRRMSQMKTPHNPLDSSAPLMKKGKQREIPKAKKPTSLKKIILKER
  QERKQRLQENAVSPAFTSDDTQDGESGGDDQFPEQAELSGPEGMDELISTPSVEDKSEEP
  PGTELQRDTEASHLAPNHTTFPKIHSRRFRDYCSQMLSKEVDACVTDLLKELVRFQDRMY
  QKDPVKAKTKRRLVLGLREVLKHLKLKKLKCVIISPNCEKIQSKGGLDDTLHTIIDYACE
  QNIPFVFALNRKALGRSLNKAVPVSVVGIFSYDGAQDQFHKMVELTVAARQAYKTMLENV
  QQELVGEPRPQAPPSLPTQGPSCPAEDGPPALKEKEEPHYIEIWKKHLEAYSGCTLELEE
  SLEASTSQMMNLNL
• Function: mRNA-binding protein that binds to the SECIS (selenocysteine insertion sequence) element present in the 3'-UTR of mRNAs encoding selenoproteins and facilitates the incorporation of the rare amino acid selenocysteine. 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.
• Tissue Specificity: Expressed at high levels in testis.
• Reactome Pathway: Selenocysteine synthesis (R-HSA-2408557)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Myopathy	DISOWG27	Strong	Genetic Variation	[1]
Thyroid hormone metabolism, abnormal 1	DISSKL8K	Strong	Autosomal recessive	[2]
Neurodevelopmental disorder	DIS372XH	moderate	Biomarker	[3]
Osteoarthritis	DIS05URM	moderate	Altered Expression	[4]
Obsolete short stature-delayed bone age due to thyroid hormone metabolism deficiency	DISMRWQY	Supportive	Autosomal recessive	[2]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[5]
Inborn disorder of amino acid metabolism	DISFWXCM	Limited	Biomarker	[2]
Thyroid hormone metabolism, abnormal	DISKXWH5	Limited	Genetic Variation	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Selenocysteine insertion sequence-binding protein 2 (SECISBP2) decreases the response to substance of Arsenic trioxide.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Selenocysteine insertion sequence-binding protein 2 (SECISBP2).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Selenocysteine insertion sequence-binding protein 2 (SECISBP2).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Selenocysteine insertion sequence-binding protein 2 (SECISBP2).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Selenocysteine insertion sequence-binding protein 2 (SECISBP2).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Selenocysteine insertion sequence-binding protein 2 (SECISBP2).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Selenocysteine insertion sequence-binding protein 2 (SECISBP2).	[12]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Selenocysteine insertion sequence-binding protein 2 (SECISBP2).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Selenocysteine insertion sequence-binding protein 2 (SECISBP2).	[15]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Selenocysteine insertion sequence-binding protein 2 (SECISBP2).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Selenocysteine insertion sequence-binding protein 2 (SECISBP2).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Selenocysteine insertion sequence-binding protein 2 (SECISBP2).	[14]

References

• [1] Post-transcriptional control of selenoprotein biosynthesis.Curr Protein Pept Sci. 2012 Jun;13(4):337-46. doi: 10.2174/138920312801619448.
• [2] Mutations in SECISBP2 result in abnormal thyroid hormone metabolism. Nat Genet. 2005 Nov;37(11):1247-52. doi: 10.1038/ng1654. Epub 2005 Oct 16.
• [3] Why 21? The significance of selenoproteins for human health revealed by inborn errors of metabolism.FASEB J. 2016 Nov;30(11):3669-3681. doi: 10.1096/fj.201600424. Epub 2016 Jul 29.
• [4] The hsa-miR-181a-5p reduces oxidation resistance by controlling SECISBP2 in osteoarthritis.BMC Musculoskelet Disord. 2018 Oct 5;19(1):355. doi: 10.1186/s12891-018-2273-6.
• [5] Genetic variants in selenoprotein genes increase risk of colorectal cancer.Carcinogenesis. 2010 Jun;31(6):1074-9. doi: 10.1093/carcin/bgq076. Epub 2010 Apr 8.
• [6] A Novel Homozygous Selenocysteine Insertion Sequence Binding Protein 2 (SECISBP2, SBP2) Gene Mutation in a Turkish Boy.Thyroid. 2018 Sep;28(9):1221-1223. doi: 10.1089/thy.2018.0015. Epub 2018 Aug 2.
• [7] 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.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [11] 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.
• [12] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [13] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [14] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [15] 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.
• [16] Oxidative Stress Triggers Body-Wide Skipping of Multiple Exons of the Spinal Muscular Atrophy Gene. PLoS One. 2016 Apr 25;11(4):e0154390. doi: 10.1371/journal.pone.0154390. eCollection 2016.
• [17] Functional Profiling Identifies Determinants of Arsenic Trioxide Cellular Toxicity. Toxicol Sci. 2019 May 1;169(1):108-121. doi: 10.1093/toxsci/kfz024.