Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD57ILL)

• DOT Name: CCA tRNA nucleotidyltransferase 1, mitochondrial (TRNT1)
• Synonyms: EC 2.7.7.72; Mitochondrial tRNA nucleotidyl transferase, CCA-adding; mt CCA-adding enzyme; mt tRNA CCA-diphosphorylase; mt tRNA CCA-pyrophosphorylase; mt tRNA adenylyltransferase
• Gene Name: TRNT1
• Related Disease:
  Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome
  IRIDA syndrome
  Metabolic disorder
  Neonatal anemia
  Retinitis pigmentosa and erythrocytic microcytosis
  Thrombocytosis disease
  Cardiomyopathy
  Cataract
  Inherited retinal dystrophy
  Inherited sideroblastic anemia
  Retinitis pigmentosa
  Sideroblastic anemia
  Anemia
  Mycoses
• UniProt ID: TRNT1_HUMAN
• PDB ID: 1OU5; 4X4W
• EC Number: 2.7.7.72
• Pfam ID: PF01743 ; PF12627
• Sequence:
  MLRCLYHWHRPVLNRRWSRLCLPKQYLFTMKLQSPEFQSLFTEGLKSLTELFVKENHELR
  IAGGAVRDLLNGVKPQDIDFATTATPTQMKEMFQSAGIRMINNRGEKHGTITARLHEENF
  EITTLRIDVTTDGRHAEVEFTTDWQKDAERRDLTINSMFLGFDGTLFDYFNGYEDLKNKK
  VRFVGHAKQRIQEDYLRILRYFRFYGRIVDKPGDHDPETLEAIAENAKGLAGISGERIWV
  ELKKILVGNHVNHLIHLIYDLDVAPYIGLPANASLEEFDKVSKNVDGFSPKPVTLLASLF
  KVQDDVTKLDLRLKIAKEEKNLGLFIVKNRKDLIKATDSSDPLKPYQDFIIDSREPDATT
  RVCELLKYQGEHCLLKEMQQWSIPPFPVSGHDIRKVGISSGKEIGALLQQLREQWKKSGY
  QMEKDELLSYIKKT
• Function: Nucleotidyltransferase that catalyzes the addition and repair of the essential 3'-terminal CCA sequence in tRNAs, which is necessary for the attachment of amino acids to the 3' terminus of tRNA molecules, using CTP and ATP as substrates. tRNA 3'-terminal CCA addition is required both for tRNA processing and repair. Promotes tRNA repair and recycling downstream of the ribosome-associated quality control (RQC) pathway by mediating addition of the tRNA 3'-terminal CCA following cleavage by ANKZF1 and repair by ELAC1. Also involved in tRNA surveillance by mediating tandem CCA addition to generate a CCACCA at the 3' terminus of unstable tRNAs and tRNA-like transcripts. While stable tRNAs receive only 3'-terminal CCA, unstable tRNAs beginning with GG are marked with CCACCA and rapidly degraded. The structural flexibility of RNA controls the choice between CCA versus CCACCA addition: following the first CCA addition cycle, nucleotide-binding to the active site triggers a clockwise screw motion, producing torque on the RNA. This ejects stable RNAs, whereas unstable RNAs are refolded while bound to the enzyme and subjected to a second CCA catalytic cycle ; [Isoform 2]: Adds 2 C residues (CC-) to the 3' terminus of tRNA molecules instead of a complete CCA end as isoform 1 does (in vitro).
• Reactome Pathway:
  tRNA processing in the mitochondrion (R-HSA-6785470)
  tRNA processing in the nucleus (R-HSA-6784531)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome	DISP3KCS	Definitive	Autosomal recessive	[1]
IRIDA syndrome	DISPN8YW	Definitive	Genetic Variation	[2]
Metabolic disorder	DIS71G5H	Definitive	Biomarker	[3]
Neonatal anemia	DISPFC78	Definitive	Biomarker	[4]
Retinitis pigmentosa and erythrocytic microcytosis	DIS0RYCY	Definitive	Autosomal recessive	[5]
Thrombocytosis disease	DISNG0P4	Definitive	Genetic Variation	[2]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[6]
Cataract	DISUD7SL	Strong	Genetic Variation	[7]
Inherited retinal dystrophy	DISGGL77	Strong	Biomarker	[7]
Inherited sideroblastic anemia	DISLT2PU	Strong	Genetic Variation	[8]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[6]
Sideroblastic anemia	DIS4F3X1	Strong	Genetic Variation	[6]
Anemia	DISTVL0C	moderate	Altered Expression	[9]
Mycoses	DIS9K7PB	Disputed	Genetic Variation	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of CCA tRNA nucleotidyltransferase 1, mitochondrial (TRNT1).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of CCA tRNA nucleotidyltransferase 1, mitochondrial (TRNT1).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of CCA tRNA nucleotidyltransferase 1, mitochondrial (TRNT1).	[13]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of CCA tRNA nucleotidyltransferase 1, mitochondrial (TRNT1).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of CCA tRNA nucleotidyltransferase 1, mitochondrial (TRNT1).	[15]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of CCA tRNA nucleotidyltransferase 1, mitochondrial (TRNT1).	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of CCA tRNA nucleotidyltransferase 1, mitochondrial (TRNT1).	[17]
Marinol	DM70IK5	Approved	Marinol increases the expression of CCA tRNA nucleotidyltransferase 1, mitochondrial (TRNT1).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of CCA tRNA nucleotidyltransferase 1, mitochondrial (TRNT1).	[19]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of CCA tRNA nucleotidyltransferase 1, mitochondrial (TRNT1).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of CCA tRNA nucleotidyltransferase 1, mitochondrial (TRNT1).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of CCA tRNA nucleotidyltransferase 1, mitochondrial (TRNT1).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of CCA tRNA nucleotidyltransferase 1, mitochondrial (TRNT1).	[21]

References

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• [2] Genotype/phenotype correlations of childhood-onset congenital sideroblastic anaemia in a European cohort.Br J Haematol. 2019 Nov;187(4):530-542. doi: 10.1111/bjh.16100. Epub 2019 Jul 23.
• [3] TRNT1 deficiency: clinical, biochemical and molecular genetic features.Orphanet J Rare Dis. 2016 Jul 2;11(1):90. doi: 10.1186/s13023-016-0477-0.
• [4] SIFD as a novel cause of severe fetal hydrops and neonatal anaemia with iron loading and marked extramedullary haemopoiesis.J Clin Pathol. 2018 Mar;71(3):275-278. doi: 10.1136/jclinpath-2017-204698. Epub 2017 Oct 21.
• [5] Biallelic TRNT1 variants in a child with B cell immunodeficiency, periodic fever and developmental delay without sideroblastic anemia (SIFD variant). Immunol Lett. 2020 Sep;225:64-65. doi: 10.1016/j.imlet.2020.06.012. Epub 2020 Jun 24.
• [6] Atypical SIFD with novel TRNT1 mutations: a case study on the pathogenesis of B-cell deficiency.Int J Hematol. 2019 Apr;109(4):382-389. doi: 10.1007/s12185-019-02614-0. Epub 2019 Feb 13.
• [7] Expanding the Phenotype of TRNT1-Related Immunodeficiency to Include Childhood Cataract and Inner Retinal Dysfunction.JAMA Ophthalmol. 2016 Sep 1;134(9):1049-53. doi: 10.1001/jamaophthalmol.2015.5833.
• [8] In vitro studies of disease-linked variants of human tRNA nucleotidyltransferase reveal decreased thermal stability and altered catalytic activity.Biochim Biophys Acta Proteins Proteom. 2018 Apr;1866(4):527-540. doi: 10.1016/j.bbapap.2018.02.002. Epub 2018 Feb 16.
• [9] Hypomorphic mutations in TRNT1 cause retinitis pigmentosa with erythrocytic microcytosis. Hum Mol Genet. 2016 Jan 1;25(1):44-56. doi: 10.1093/hmg/ddv446. Epub 2015 Oct 22.
• [10] Genotyping bacterial and fungal pathogens using sequence variation in the gene for the CCA-adding enzyme.BMC Microbiol. 2016 Mar 18;16:47. doi: 10.1186/s12866-016-0670-2.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] 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.
• [13] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [14] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [15] 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.
• [16] 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.
• [17] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [18] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [21] 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.
• [22] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.