Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUK054V)

• DOT Name: Probable tRNA(His) guanylyltransferase (THG1L)
• Synonyms: EC 2.7.7.79; Induced in high glucose-1; IHG-1; Interphase cytoplasmic foci protein 45; tRNA-histidine guanylyltransferase
• Gene Name: THG1L
• Related Disease:
  Deafness
  Cerebellar ataxia
  Renal fibrosis
  Spinocerebellar ataxia, autosomal recessive 28
  Diabetic kidney disease
  Nephropathy
• UniProt ID: THG1_HUMAN
• PDB ID: 3OTB; 3OTC; 3OTD; 3OTE; 7CV1
• EC Number: 2.7.7.79
• Pfam ID: PF04446 ; PF14413
• Sequence:
  MWGACKVKVHDSLATISITLRRYLRLGATMAKSKFEYVRDFEADDTCLAHCWVVVRLDGR
  NFHRFAEKHNFAKPNDSRALQLMTKCAQTVMEELEDIVIAYGQSDEYSFVFKRKTNWFKR
  RASKFMTHVASQFASSYVFYWRDYFEDQPLLYPPGFDGRVVVYPSNQTLKDYLSWRQADC
  HINNLYNTVFWALIQQSGLTPVQAQGRLQGTLAADKNEILFSEFNINYNNELPMYRKGTV
  LIWQKVDEVMTKEIKLPTEMEGKKMAVTRTRTKPVPLHCDIIGDAFWKEHPEILDEDS
• Function: Adds a GMP to the 5'-end of tRNA(His) after transcription and RNase P cleavage. This step is essential for proper recognition of the tRNA and for the fidelity of protein synthesis (Probable). Also functions as a guanyl-nucleotide exchange factor/GEF for the MFN1 and MFN2 mitofusins thereby regulating mitochondrial fusion. By regulating both mitochondrial dynamics and bioenergetic function, it contributes to cell survival following oxidative stress.
• Tissue Specificity: Expressed in many tissues.
• Reactome Pathway: tRNA modification in the nucleus and cytosol (R-HSA-6782315)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Deafness	DISKCLH4	Definitive	Biomarker	[1]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[2]
Renal fibrosis	DISMHI3I	Strong	Altered Expression	[3]
Spinocerebellar ataxia, autosomal recessive 28	DIS240OD	Strong	Autosomal recessive	[2]
Diabetic kidney disease	DISJMWEY	Disputed	Altered Expression	[4]
Nephropathy	DISXWP4P	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Probable tRNA(His) guanylyltransferase (THG1L).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Probable tRNA(His) guanylyltransferase (THG1L).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Probable tRNA(His) guanylyltransferase (THG1L).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Probable tRNA(His) guanylyltransferase (THG1L).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Probable tRNA(His) guanylyltransferase (THG1L).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Probable tRNA(His) guanylyltransferase (THG1L).	[12]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Probable tRNA(His) guanylyltransferase (THG1L).	[13]

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 Probable tRNA(His) guanylyltransferase (THG1L).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Probable tRNA(His) guanylyltransferase (THG1L).	[11]

References

• [1] Decreased Expression of TRPV4 Channels in HEI-OC1 Cells Induced by High Glucose Is Associated with Hearing Impairment.Yonsei Med J. 2018 Nov;59(9):1131-1137. doi: 10.3349/ymj.2018.59.9.1131.
• [2] A mutation in the THG1L gene in a family with cerebellar ataxia and developmental delay. Neurogenetics. 2016 Oct;17(4):219-225. doi: 10.1007/s10048-016-0487-z. Epub 2016 Jun 15.
• [3] IHG-1 amplifies TGF-1 signalling and mitochondrial biogenesis and is increased in diabetic kidney disease.Curr Opin Nephrol Hypertens. 2013 Jan;22(1):77-84. doi: 10.1097/MNH.0b013e32835b54b0.
• [4] Profibrotic IHG-1 complexes with renal disease associated HSPA5 and TRAP1 in mitochondria.Biochim Biophys Acta Mol Basis Dis. 2017 Apr;1863(4):896-906. doi: 10.1016/j.bbadis.2017.01.015. Epub 2017 Jan 20.
• [5] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] 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.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [13] Suppression subtractive hybridization identifies high glucose levels as a stimulus for expression of connective tissue growth factor and other genes in human mesangial cells. J Biol Chem. 1999 Feb 26;274(9):5830-4. doi: 10.1074/jbc.274.9.5830.