Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU52TXX)

• DOT Name: tRNA modification GTPase GTPBP3, mitochondrial (GTPBP3)
• Synonyms: GTP-binding protein 3; Mitochondrial GTP-binding protein 1
• Gene Name: GTPBP3
• Related Disease:
  Cardiac failure
  Combined oxidative phosphorylation defect type 23
  Congestive heart failure
  Hypertrophic cardiomyopathy
  Leigh syndrome
• UniProt ID: GTPB3_HUMAN
• Pfam ID: PF01926 ; PF12631 ; PF10396
• Sequence:
  MWRGLWTLAAQAARGPRRLCTRRSSGAPAPGSGATIFALSSGQGRCGIAVIRTSGPASGH
  ALRILTAPRDLPLARHASLRLLSDPRSGEPLDRALVLWFPGPQSFTGEDCVEFHVHGGPA
  VVSGVLQALGSVPGLRPAEAGEFTRRAFANGKLNLTEVEGLADLIHAETEAQRRQALRQL
  DGELGHLCRGWAETLTKALAHVEAYIDFGEDDNLEEGVLEQADIEVRALQVALGAHLRDA
  RRGQRLRSGVHVVVTGPPNAGKSSLVNLLSRKPVSIVSPEPGTTRDVLETPVDLAGFPVL
  LSDTAGLREGVGPVEQEGVRRARERLEQADLILAMLDASDLASPSSCNFLATVVASVGAQ
  SPSDSSQRLLLVLNKSDLLSPEGPGPGPDLPPHLLLSCLTGEGLDGLLEALRKELAAVCG
  DPSTDPPLLTRARHQHHLQGCLDALGHYKQSKDLALAAEALRVARGHLTRLTGGGGTEEI
  LDIIFQDFCVGK
• Function: GTPase involved in the 5-carboxymethylaminomethyl modification (mnm(5)s(2)U34) of the wobble uridine base in mitochondrial tRNAs.
• Tissue Specificity: Ubiquitously expressed.
• Reactome Pathway: tRNA modification in the mitochondrion (R-HSA-6787450)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac failure	DISDC067	Strong	Genetic Variation	[1]
Combined oxidative phosphorylation defect type 23	DISCKVY1	Strong	Autosomal recessive	[2]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[1]
Hypertrophic cardiomyopathy	DISQG2AI	moderate	Genetic Variation	[3]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of tRNA modification GTPase GTPBP3, mitochondrial (GTPBP3).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of tRNA modification GTPase GTPBP3, mitochondrial (GTPBP3).	[6]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of tRNA modification GTPase GTPBP3, mitochondrial (GTPBP3).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of tRNA modification GTPase GTPBP3, mitochondrial (GTPBP3).	[8]
Menadione	DMSJDTY	Approved	Menadione affects the expression of tRNA modification GTPase GTPBP3, mitochondrial (GTPBP3).	[9]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of tRNA modification GTPase GTPBP3, mitochondrial (GTPBP3).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of tRNA modification GTPase GTPBP3, mitochondrial (GTPBP3).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of tRNA modification GTPase GTPBP3, mitochondrial (GTPBP3).	[12]

References

• [1] Mutations in the Caenorhabditis elegans orthologs of human genes required for mitochondrial tRNA modification cause similar electron transport chain defects but different nuclear responses.PLoS Genet. 2017 Jul 21;13(7):e1006921. doi: 10.1371/journal.pgen.1006921. eCollection 2017 Jul.
• [2] Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy. Am J Hum Genet. 2014 Dec 4;95(6):708-20. doi: 10.1016/j.ajhg.2014.10.017. Epub 2014 Nov 26.
• [3] Deletion of Gtpbp3 in zebrafish revealed the hypertrophic cardiomyopathy manifested by aberrant mitochondrial tRNA metabolism.Nucleic Acids Res. 2019 Jun 4;47(10):5341-5355. doi: 10.1093/nar/gkz218.
• [4] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [8] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [9] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.