Details of Drug Off-Target (DOT)

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

• DOT Name: Probable cysteine--tRNA ligase, mitochondrial (CARS2)
• Synonyms: EC 6.1.1.16; Cysteinyl-tRNA synthetase; CysRS
• Gene Name: CARS2
• Related Disease:
  Anaplastic large cell lymphoma
  Autism
  Autism spectrum disorder
  Combined oxidative phosphorylation defect type 27
  Movement disorder
  Progressive myoclonus epilepsy
  Unverricht-Lundborg syndrome
  Mitochondrial disease
• UniProt ID: SYCM_HUMAN
• EC Number: 6.1.1.16
• Pfam ID: PF01406
• Sequence:
  MLRTTRGPGLGPPLLQAALGLGRAGWHWPAGRAASGGRGRAWLQPTGRETGVQVYNSLTG
  RKEPLIVAHAEAASWYSCGPTVYDHAHLGHACSYVRFDIIRRILTKVFGCSIVMVMGITD
  VDDKIIKRANEMNISPASLASLYEEDFKQDMAALKVLPPTVYLRVTENIPQIISFIEGII
  ARGNAYSTAKGNVYFDLKSRGDKYGKLVGVVPGPVGEPADSDKRHASDFALWKAAKPQEV
  FWASPWGPGRPGWHIECSAIASMVFGSQLDIHSGGIDLAFPHHENEIAQCEVFHQCEQWG
  NYFLHSGHLHAKGKEEKMSKSLKNYITIKDFLKTFSPDVFRFFCLRSSYRSAIDYSDSAM
  LQAQQLLLGLGSFLEDARAYMKGQLACGSVREAMLWERLSSTKRAVKAALADDFDTPRVV
  DAILGLAHHGNGQLRASLKEPEGPRSPAVFGAIISYFEQFFETVGISLANQQYVSGDGSE
  ATLHGVVDELVRFRQKVRQFALAMPEATGDARRQQLLERQPLLEACDTLRRGLTAHGINI
  KDRSSTTSTWELLDQRTKDQKSAG
• Function: Mitochondrial cysteine-specific aminoacyl-tRNA synthetase that catalyzes the ATP-dependent ligation of cysteine to tRNA(Cys); In addition to its role as an aminoacyl-tRNA synthetase, has also cysteine persulfide synthase activity. Produces reactive persulfide species such as cysteine persulfide (CysSSH) from substrate cysteine and mediate direct incorporation of CysSSH into proteins during translations, resulting in protein persulfides and polysulfides. CysSSHs behave as potent antioxidants and cellular protectants.
• KEGG Pathway: Aminoacyl-tR. biosynthesis (hsa00970)
• Reactome Pathway: Mitochondrial tRNA aminoacylation (R-HSA-379726)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anaplastic large cell lymphoma	DISP4D1R	Strong	Genetic Variation	[1]
Autism	DISV4V1Z	Strong	Biomarker	[2]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[2]
Combined oxidative phosphorylation defect type 27	DISXLOZD	Strong	Autosomal recessive	[3]
Movement disorder	DISOJJ2D	Strong	Genetic Variation	[4]
Progressive myoclonus epilepsy	DISAMCNS	Strong	Biomarker	[3]
Unverricht-Lundborg syndrome	DISG4WLX	Strong	Biomarker	[3]
Mitochondrial disease	DISKAHA3	Moderate	Autosomal recessive	[5]

11 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 Probable cysteine--tRNA ligase, mitochondrial (CARS2).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Probable cysteine--tRNA ligase, mitochondrial (CARS2).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Probable cysteine--tRNA ligase, mitochondrial (CARS2).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Probable cysteine--tRNA ligase, mitochondrial (CARS2).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Probable cysteine--tRNA ligase, mitochondrial (CARS2).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Probable cysteine--tRNA ligase, mitochondrial (CARS2).	[12]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Probable cysteine--tRNA ligase, mitochondrial (CARS2).	[13]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Probable cysteine--tRNA ligase, mitochondrial (CARS2).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Probable cysteine--tRNA ligase, mitochondrial (CARS2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Probable cysteine--tRNA ligase, mitochondrial (CARS2).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Probable cysteine--tRNA ligase, mitochondrial (CARS2).	[18]

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 cysteine--tRNA ligase, mitochondrial (CARS2).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Probable cysteine--tRNA ligase, mitochondrial (CARS2).	[15]

References

• [1] Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor.Genes Chromosomes Cancer. 2002 Aug;34(4):354-62. doi: 10.1002/gcc.10033.
• [2] Diagnostic Accuracy of Indian Scale for Assessment of Autism in Indian Children Aged 2-5 Years.Indian Pediatr. 2019 Oct 15;56(10):831-836.
• [3] A homozygous splice-site mutation in CARS2 is associated with progressive myoclonic epilepsy. Neurology. 2014 Dec 2;83(23):2183-7. doi: 10.1212/WNL.0000000000001055. Epub 2014 Oct 31.
• [4] Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder. J Med Genet. 2015 Aug;52(8):532-40. doi: 10.1136/jmedgenet-2015-103049. Epub 2015 Mar 18.
• [5] 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.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [14] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [15] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [16] 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.
• [17] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.