Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMBBH7K)

• DOT Name: Probable proline--tRNA ligase, mitochondrial (PARS2)
• Synonyms: EC 6.1.1.15; Prolyl-tRNA synthetase; ProRS; Prolyl-tRNA synthetase 2, mitochondrial
• Gene Name: PARS2
• Related Disease:
  Malaria
  Chikungunya virus infection
  Coccidiosis
  Craniosynostosis
  Developmental and epileptic encephalopathy, 75
  Epilepsy
  Mitochondrial DNA depletion syndrome 4a
  West syndrome
  Mitochondrial disease
  Undetermined early-onset epileptic encephalopathy
• UniProt ID: SYPM_HUMAN
• EC Number: 6.1.1.15
• Pfam ID: PF03129 ; PF00587
• Sequence:
  MEGLLTRCRALPALATCSRQLSGYVPCRFHHCAPRRGRRLLLSRVFQPQNLREDRVLSLQ
  DKSDDLTCKSQRLMLQVGLIYPASPGCYHLLPYTVRAMEKLVRVIDQEMQAIGGQKVNMP
  SLSPAELWQATNRWDLMGKELLRLRDRHGKEYCLGPTHEEAITALIASQKKLSYKQLPFL
  LYQVTRKFRDEPRPRFGLLRGREFYMKDMYTFDSSPEAAQQTYSLVCDAYCSLFNKLGLP
  FVKVQADVGTIGGTVSHEFQLPVDIGEDRLAICPRCSFSANMETLDLSQMNCPACQGPLT
  KTKGIEVGHTFYLGTKYSSIFNAQFTNVCGKPTLAEMGCYGLGVTRILAAAIEVLSTEDC
  VRWPSLLAPYQACLIPPKKGSKEQAASELIGQLYDHITEAVPQLHGEVLLDDRTHLTIGN
  RLKDANKFGYPFVIIAGKRALEDPAHFEVWCQNTGEVAFLTKDGVMDLLTPVQTV
• Function: Mitochondrial aminoacyl-tRNA synthetase that catalyzes the specific attachment of the proline amino acid (aa) to the homologous transfer RNA (tRNA), further participating in protein synthesis. The reaction occurs in a two steps: proline is first activated by ATP to form Pro-AMP and then transferred to the acceptor end of tRNA(Pro).
• KEGG Pathway: Aminoacyl-tR. biosynthesis (hsa00970)
• Reactome Pathway: Mitochondrial tRNA aminoacylation (R-HSA-379726)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Malaria	DISQ9Y50	Definitive	Biomarker	[1]
Chikungunya virus infection	DISDXEHY	Strong	Biomarker	[2]
Coccidiosis	DISVU41B	Strong	Biomarker	[3]
Craniosynostosis	DIS6J405	Strong	Genetic Variation	[4]
Developmental and epileptic encephalopathy, 75	DISSOK3E	Strong	Autosomal recessive	[5]
Epilepsy	DISBB28L	Strong	Genetic Variation	[6]
Mitochondrial DNA depletion syndrome 4a	DISU4RVU	Strong	Genetic Variation	[7]
West syndrome	DISLIAU9	Strong	Genetic Variation	[8]
Mitochondrial disease	DISKAHA3	Moderate	Autosomal recessive	[9]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Supportive	Autosomal dominant	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Probable proline--tRNA ligase, mitochondrial (PARS2).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Probable proline--tRNA ligase, mitochondrial (PARS2).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Probable proline--tRNA ligase, mitochondrial (PARS2).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Probable proline--tRNA ligase, mitochondrial (PARS2).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Probable proline--tRNA ligase, mitochondrial (PARS2).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Probable proline--tRNA ligase, mitochondrial (PARS2).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Probable proline--tRNA ligase, mitochondrial (PARS2).	[16]

References

• [1] Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase.ACS Infect Dis. 2017 Jan 13;3(1):34-44. doi: 10.1021/acsinfecdis.6b00078. Epub 2016 Nov 16.
• [2] A potent prolyl tRNA synthetase inhibitor antagonizes Chikungunya and Dengue viruses.Antiviral Res. 2019 Jan;161:163-168. doi: 10.1016/j.antiviral.2018.11.017. Epub 2018 Dec 3.
• [3] Targeting Prolyl-tRNA Synthetase to Accelerate Drug Discovery against Malaria, Leishmaniasis, Toxoplasmosis, Cryptosporidiosis, and Coccidiosis.Structure. 2017 Oct 3;25(10):1495-1505.e6. doi: 10.1016/j.str.2017.07.015. Epub 2017 Aug 31.
• [4] Chronic Rhinosinusitis Patients Show Accumulation of Genetic Variants in PARS2.PLoS One. 2016 Jun 27;11(6):e0158202. doi: 10.1371/journal.pone.0158202. eCollection 2016.
• [5] Whole exome sequencing reveals mutations in NARS2 and PARS2, encoding the mitochondrial asparaginyl-tRNA synthetase and prolyl-tRNA synthetase, in patients with Alpers syndrome. Mol Genet Genomic Med. 2015 Jan;3(1):59-68. doi: 10.1002/mgg3.115. Epub 2014 Oct 23.
• [6] PARS2 and NARS2 mutations in infantile-onset neurodegenerative disorder.J Hum Genet. 2017 Apr;62(5):525-529. doi: 10.1038/jhg.2016.163. Epub 2017 Jan 12.
• [7] The genotypic and phenotypic spectrum of PARS2-related infantile-onset encephalopathy. J Hum Genet. 2018 Sep;63(9):971-980. doi: 10.1038/s10038-018-0478-z. Epub 2018 Jun 18.
• [8] Clinical and molecular characteristics of newly reported mitochondrial disease entity caused by biallelic PARS2 mutations.J Hum Genet. 2018 Apr;63(4):473-485. doi: 10.1038/s10038-017-0401-z. Epub 2018 Feb 6.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Comparison of quantitation methods in proteomics to define relevant toxicological information on AhR activation of HepG2 cells by BaP. Toxicology. 2021 Jan 30;448:152652. doi: 10.1016/j.tox.2020.152652. Epub 2020 Dec 2.
• [15] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.