Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBU39Q1)

• DOT Name: Peptidyl-tRNA hydrolase 2, mitochondrial (PTRH2)
• Synonyms: PTH 2; EC 3.1.1.29; Bcl-2 inhibitor of transcription 1
• Gene Name: PTRH2
• Related Disease:
  Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1
  Pancreas disorder
  Breast cancer
  Breast carcinoma
  Esophageal adenocarcinoma
  Esophageal squamous cell carcinoma
  Lung adenocarcinoma
  Lung carcinoma
  Metastatic malignant neoplasm
  Non-small-cell lung cancer
  Oral cancer
  Peripheral neuropathy
  Polycystic ovarian syndrome
  Prostate cancer
  Prostate neoplasm
  Sensorineural hearing loss disorder
  Squamous cell carcinoma
  Congenital muscular dystrophy
  Duchenne muscular dystrophy
  Myopathy
  Obsolete infantile multisystem neurologic-endocrine-pancreatic disease
  Prediabetes syndrome
• UniProt ID: PTH2_HUMAN
• PDB ID: 1Q7S
• EC Number: 3.1.1.29
• Pfam ID: PF01981
• Sequence:
  MPSKSLVMEYLAHPSTLGLAVGVACGMCLGWSLRVCFGMLPKSKTSKTHTDTESEASILG
  DSGEYKMILVVRNDLKMGKGKVAAQCSHAAVSAYKQIQRRNPEMLKQWEYCGQPKVVVKA
  PDEETLIALLAHAKMLGLTVSLIQDAGRTQIAPGSQTVLGIGPGPADLIDKVTGHLKLY
• Function: The natural substrate for this enzyme may be peptidyl-tRNAs which drop off the ribosome during protein synthesis; Promotes caspase-independent apoptosis by regulating the function of two transcriptional regulators, AES and TLE1.
• Reactome Pathway: Ub-specific processing proteases (R-HSA-5689880)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1	DISANCCX	Definitive	Autosomal recessive	[1]
Pancreas disorder	DISDH7NI	Definitive	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Esophageal adenocarcinoma	DISODWFP	Strong	Altered Expression	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[3]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[4]
Lung carcinoma	DISTR26C	Strong	Biomarker	[4]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[6]
Oral cancer	DISLD42D	Strong	Biomarker	[7]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[8]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Altered Expression	[9]
Prostate cancer	DISF190Y	Strong	Biomarker	[10]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[10]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Genetic Variation	[8]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[3]
Congenital muscular dystrophy	DISKY7OY	moderate	Altered Expression	[11]
Duchenne muscular dystrophy	DISRQ3NV	moderate	Altered Expression	[11]
Myopathy	DISOWG27	moderate	Genetic Variation	[11]
Obsolete infantile multisystem neurologic-endocrine-pancreatic disease	DISGDVUY	Supportive	Autosomal recessive	[12]
Prediabetes syndrome	DISH2I53	Limited	Altered Expression	[13]

14 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 Peptidyl-tRNA hydrolase 2, mitochondrial (PTRH2).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Peptidyl-tRNA hydrolase 2, mitochondrial (PTRH2).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Peptidyl-tRNA hydrolase 2, mitochondrial (PTRH2).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Peptidyl-tRNA hydrolase 2, mitochondrial (PTRH2).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Peptidyl-tRNA hydrolase 2, mitochondrial (PTRH2).	[17]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Peptidyl-tRNA hydrolase 2, mitochondrial (PTRH2).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Peptidyl-tRNA hydrolase 2, mitochondrial (PTRH2).	[19]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Peptidyl-tRNA hydrolase 2, mitochondrial (PTRH2).	[20]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial decreases the expression of Peptidyl-tRNA hydrolase 2, mitochondrial (PTRH2).	[21]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium decreases the expression of Peptidyl-tRNA hydrolase 2, mitochondrial (PTRH2).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Peptidyl-tRNA hydrolase 2, mitochondrial (PTRH2).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Peptidyl-tRNA hydrolase 2, mitochondrial (PTRH2).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Peptidyl-tRNA hydrolase 2, mitochondrial (PTRH2).	[25]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Peptidyl-tRNA hydrolase 2, mitochondrial (PTRH2).	[27]

2 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 increases the methylation of Peptidyl-tRNA hydrolase 2, mitochondrial (PTRH2).	[22]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Peptidyl-tRNA hydrolase 2, mitochondrial (PTRH2).	[26]

References

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• [2] TLE1 is an anoikis regulator and is downregulated by Bit1 in breast cancer cells.Mol Cancer Res. 2012 Nov;10(11):1482-95. doi: 10.1158/1541-7786.MCR-12-0144. Epub 2012 Sep 4.
• [3] Preliminary evaluation for Bit1 as a potential biomarker for squamous cell carcinoma and adenocarcinoma of esophagus.Tumour Biol. 2017 May;39(5):1010428317708267. doi: 10.1177/1010428317708267.
• [4] The anoikis effector Bit1 displays tumor suppressive function in lung cancer cells.PLoS One. 2014 Jul 8;9(7):e101564. doi: 10.1371/journal.pone.0101564. eCollection 2014.
• [5] Bit1 in anoikis resistance and tumor metastasis.Cancer Lett. 2013 Jun 10;333(2):147-51. doi: 10.1016/j.canlet.2013.01.043. Epub 2013 Jan 31.
• [6] Downregulation of Bit1 expression promotes growth, anoikis resistance, and transformation of immortalized human bronchial epithelial cells via Erk activation-dependent suppression of E-cadherin.Biochem Biophys Res Commun. 2018 Jan 1;495(1):1240-1248. doi: 10.1016/j.bbrc.2017.11.126. Epub 2017 Nov 21.
• [7] Bit1 Regulates Cell Migration and Survival in Oral Squamous CellCarcinoma.J Oral Maxillofac Surg. 2017 Mar 23:S0278-2391(17)30345-2. doi: 10.1016/j.joms.2017.03.027. Online ahead of print.
• [8] Homozygous mutation in PTRH2 gene causes progressive sensorineural deafness and peripheral neuropathy.Am J Med Genet A. 2017 Apr;173(4):1051-1055. doi: 10.1002/ajmg.a.38140.
• [9] Bit1-a potential positive regulator of epithelial-mesenchymal transition in lens epithelial cells.Graefes Arch Clin Exp Ophthalmol. 2016 Jul;254(7):1311-8. doi: 10.1007/s00417-016-3357-3. Epub 2016 Apr 28.
• [10] Global analysis of differentially expressed genes in androgen-independent prostate cancer.Prostate Cancer Prostatic Dis. 2007;10(2):167-74. doi: 10.1038/sj.pcan.4500933. Epub 2007 Jan 2.
• [11] PTRH2 gene mutation causes progressive congenital skeletal muscle pathology.Hum Mol Genet. 2017 Apr 15;26(8):1458-1464. doi: 10.1093/hmg/ddx048.
• [12] Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness. Ann Clin Transl Neurol. 2014 Dec;1(12):1024-35. doi: 10.1002/acn3.149. Epub 2014 Dec 3.
• [13] Prediabetes is Characterized by Higher FGF23 Levels and Higher Prevalence of Vitamin D Deficiency Compared to Normal Glucose Tolerance Subjects.Horm Metab Res. 2019 Feb;51(2):106-111. doi: 10.1055/a-0813-3164. Epub 2018 Dec 20.
• [14] 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.
• [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] 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.
• [17] 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.
• [18] [Construction of subtracted cDNA library in human Jurkat T cell line induced by arsenic trioxide in vitro]. Zhonghua Yu Fang Yi Xue Za Zhi. 2003 Nov;37(6):403-7.
• [19] 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.
• [20] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [21] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [22] 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.
• [23] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [24] 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.
• [25] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [26] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [27] Lipid Rafts Disruption Increases Ochratoxin A Cytotoxicity to Hepatocytes. J Biochem Mol Toxicol. 2016 Feb;30(2):71-9. doi: 10.1002/jbt.21738. Epub 2015 Aug 25.