Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOAOS93)

• DOT Name: Peptidyl-tRNA hydrolase (PTRH1)
• Synonyms: PTH; EC 3.1.1.29
• Gene Name: PTRH1
• Related Disease:
  Bone osteosarcoma
  Chronic kidney disease
  Familial hypocalciuric hypercalcemia 1
  Hypercalcaemia
  Hyperparathyroidism
  Hyperphosphatemia
  Neoplasm
  Osteoarthritis
  Osteosarcoma
  Postmenopausal osteoporosis
  Thanatophoric dysplasia
  Thanatophoric dysplasia type 1
  Autoimmune polyendocrine syndrome type 1
  Hypoparathyroidism
  X-linked hypophosphatemic rickets
  Pseudohypoparathyroidism type 1B
  Hyperglycemia
  Osteoporosis
  Prediabetes syndrome
• UniProt ID: PTH_HUMAN
• EC Number: 3.1.1.29
• Pfam ID: PF01195
• Sequence:
  MRPGGFLGAGQRLSRAMSRCVLEPRPPGKRWMVAGLGNPGLPGTRHSVGMAVLGQLARRL
  GVAESWTRDRHCAADLALAPLGDAQLVLLRPRRLMNANGRSVARAAELFGLTAEEVYLVH
  DELDKPLGRLALKLGGSARGHNGVRSCISCLNSNAMPRLRVGIGRPAHPEAVQAHVLGCF
  SPAEQELLPLLLDRATDLILDHIRERSQGPSLGP
• Function: Peptidyl-tRNA hydrolase that cleaves nascent chains-tRNAs that are not stably fixed in the P-site of 60S ribosome-nascent chain complexes. Acts downstream of the ribosome-associated quality control (RQC) pathway to release non-ubiquitinated nascent chains from 60S and 80S ribosome-nascent chain complexes. Does not act on ubiquitinated nascent chains, which are cleaved by ANKZF1 for degradation.

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Strong	Biomarker	[1]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[2]
Familial hypocalciuric hypercalcemia 1	DISPW6O5	Strong	Biomarker	[3]
Hypercalcaemia	DISKQ2K7	Strong	Biomarker	[4]
Hyperparathyroidism	DIS4FVAT	Strong	Biomarker	[5]
Hyperphosphatemia	DISHW3R3	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Osteoarthritis	DIS05URM	Strong	Biomarker	[8]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[1]
Postmenopausal osteoporosis	DISS0RQZ	Strong	Biomarker	[9]
Thanatophoric dysplasia	DIS3S10R	Strong	Biomarker	[10]
Thanatophoric dysplasia type 1	DISLE7J4	Strong	Biomarker	[10]
Autoimmune polyendocrine syndrome type 1	DISWJP8J	moderate	Genetic Variation	[11]
Hypoparathyroidism	DISICS0V	moderate	Biomarker	[4]
X-linked hypophosphatemic rickets	DISFTLIR	moderate	Genetic Variation	[12]
Pseudohypoparathyroidism type 1B	DIS9LDXL	Disputed	Genetic Variation	[13]
Hyperglycemia	DIS0BZB5	Limited	Genetic Variation	[14]
Osteoporosis	DISF2JE0	Limited	Biomarker	[15]
Prediabetes syndrome	DISH2I53	Limited	Altered Expression	[16]

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 Peptidyl-tRNA hydrolase (PTRH1).	[17]

6 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 Peptidyl-tRNA hydrolase (PTRH1).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Peptidyl-tRNA hydrolase (PTRH1).	[19]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Peptidyl-tRNA hydrolase (PTRH1).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Peptidyl-tRNA hydrolase (PTRH1).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Peptidyl-tRNA hydrolase (PTRH1).	[22]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Peptidyl-tRNA hydrolase (PTRH1).	[23]

References

• [1] Knockdown of PTHR1 in osteosarcoma cells decreases invasion and growth and increases tumor differentiation in vivo.Oncogene. 2015 May 28;34(22):2922-33. doi: 10.1038/onc.2014.217. Epub 2014 Jul 21.
• [2] Chronic kidney disease and vitamin D metabolism in human bone marrow-derived MSCs.Ann N Y Acad Sci. 2017 Aug;1402(1):43-55. doi: 10.1111/nyas.13464.
• [3] Neonatal hypercalcemia.J Nephrol. 2003 Jul-Aug;16(4):606-8.
• [4] Advances in the treatment of hypoparathyroidism with PTH 1-34.Bone. 2019 Mar;120:535-541. doi: 10.1016/j.bone.2018.09.018. Epub 2018 Sep 21.
• [5] Catabolic Effects of Human PTH (1-34) on Bone: Requirement of Monocyte Chemoattractant Protein-1 in Murine Model of Hyperparathyroidism.Sci Rep. 2017 Nov 10;7(1):15300. doi: 10.1038/s41598-017-15563-7.
• [6] High-serum phosphate and parathyroid hormone distinctly regulate bone loss and vascular calcification in experimental chronic kidney disease.Nephrol Dial Transplant. 2019 Jun 1;34(6):934-941. doi: 10.1093/ndt/gfy287.
• [7] Ectopic production of parathyroid hormone by small cell lung cancer in a patient with hypercalcemia.J Clin Endocrinol Metab. 1989 May;68(5):976-81. doi: 10.1210/jcem-68-5-976.
• [8] Parathyroid hormone-(1-34) ameliorated knee osteoarthritis in rats via autophagy.J Appl Physiol (1985). 2018 May 1;124(5):1177-1185. doi: 10.1152/japplphysiol.00871.2017. Epub 2018 Jan 4.
• [9] In vivo and in vitro effects of PTH1-34 on osteogenic and adipogenic differentiation of human bone marrow-derived mesenchymal stem cells through regulating microRNA-155.J Cell Biochem. 2018 Apr;119(4):3220-3235. doi: 10.1002/jcb.26478. Epub 2018 Jan 2.
• [10] Intermittent PTH (1-34) injection rescues the retarded skeletal development and postnatal lethality of mice mimicking human achondroplasia and thanatophoric dysplasia.Hum Mol Genet. 2012 Sep 15;21(18):3941-55. doi: 10.1093/hmg/dds181. Epub 2012 May 24.
• [11] Long-Term Parathyroid Hormone 1-34 Replacement Therapy in Children with Hypoparathyroidism.J Pediatr. 2018 Dec;203:391-399.e1. doi: 10.1016/j.jpeds.2018.08.010.
• [12] Parathyroid hormone sensitivity in familial X-linked hypophosphatemic rickets.J Clin Endocrinol Metab. 1989 Aug;69(2):386-9. doi: 10.1210/jcem-69-2-386.
• [13] A Homozygous [Cys25]PTH(1-84) Mutation That Impairs PTH/PTHrP Receptor Activation Defines a Novel Form of Hypoparathyroidism.J Bone Miner Res. 2015 Oct;30(10):1803-13. doi: 10.1002/jbmr.2532. Epub 2015 Jun 8.
• [14] Calciotrophic hormones and hyperglycemia modulate vitamin D receptor and 25 hydroxyy vitamin D 1- hydroxylase mRNA expression in human vascular smooth muscle cells.J Steroid Biochem Mol Biol. 2015 Apr;148:210-3. doi: 10.1016/j.jsbmb.2014.11.007. Epub 2014 Nov 13.
• [15] Sub-picomolar quantification of PTH 1-34 in plasma by UHPLC-MS/MS after subcutaneous injection of teriparatide and identification of PTH 1-33, its degradation product.J Pharm Biomed Anal. 2019 Mar 20;166:205-212. doi: 10.1016/j.jpba.2019.01.011. Epub 2019 Jan 9.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [23] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.