Details of Drug Off-Target (DOT)

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

• DOT Name: Aspartate--tRNA ligase, mitochondrial (DARS2)
• Synonyms: EC 6.1.1.12; Aspartyl-tRNA synthetase; AspRS
• Gene Name: DARS2
• Related Disease:
  Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome
  Mitochondrial disease
  Multiple sclerosis
  Cerebellar ataxia
  Leukodystrophy
  Non-insulin dependent diabetes
  Trichohepatoenteric syndrome
  Tuberculosis
  Hepatocellular carcinoma
  Mitochondrial DNA depletion syndrome 4a
  Pontocerebellar hypoplasia type 6
  Sensory ataxia
  Hereditary episodic ataxia
  Nervous system disease
  Neurodevelopmental disorder
• UniProt ID: SYDM_HUMAN
• PDB ID: 4AH6
• EC Number: 6.1.1.12
• Pfam ID: PF02938 ; PF00152 ; PF01336
• Sequence:
  MYFPSWLSQLYRGLSRPIRRTTQPIWGSLYRSLLQSSQRRIPEFSSFVVRTNTCGELRSS
  HLGQEVTLCGWIQYRRQNTFLVLRDFDGLVQVIIPQDESAASVKKILCEAPVESVVQVSG
  TVISRPAGQENPKMPTGEIEIKVKTAELLNACKKLPFEIKNFVKKTEALRLQYRYLDLRS
  FQMQYNLRLRSQMVMKMREYLCNLHGFVDIETPTLFKRTPGGAKEFLVPSREPGKFYSLP
  QSPQQFKQLLMVGGLDRYFQVARCYRDEGSRPDRQPEFTQIDIEMSFVDQTGIQSLIEGL
  LQYSWPNDKDPVVVPFPTMTFAEVLATYGTDKPDTRFGMKIIDISDVFRNTEIGFLQDAL
  SKPHGTVKAICIPEGAKYLKRKDIESIRNFAADHFNQEILPVFLNANRNWNSPVANFIME
  SQRLELIRLMETQEEDVVLLTAGEHNKACSLLGKLRLECADLLETRGVVLRDPTLFSFLW
  VVDFPLFLPKEENPRELESAHHPFTAPHPSDIHLLYTEPKKARSQHYDLVLNGNEIGGGS
  IRIHNAELQRYILATLLKEDVKMLSHLLQALDYGAPPHGGIALGLDRLICLVTGSPSIRD
  VIAFPKSFRGHDLMSNTPDSVPPEELKPYHIRVSKPTDSKAERAH
• Function: Catalyzes the attachment of aspartate to tRNA(Asp) in a two-step reaction: aspartate is first activated by ATP to form Asp-AMP and then transferred to the acceptor end of tRNA(Asp).
• KEGG Pathway: Aminoacyl-tR. biosynthesis (hsa00970)
• Reactome Pathway: Mitochondrial tRNA aminoacylation (R-HSA-379726)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	DISPBAUD	Definitive	Autosomal dominant	[1]
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[2]
Multiple sclerosis	DISB2WZI	Definitive	Genetic Variation	[3]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[4]
Leukodystrophy	DISVY1TT	Strong	Biomarker	[5]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[6]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[7]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[8]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[9]
Mitochondrial DNA depletion syndrome 4a	DISU4RVU	moderate	Biomarker	[10]
Pontocerebellar hypoplasia type 6	DIS9BKLQ	moderate	Altered Expression	[11]
Sensory ataxia	DISSMCYQ	moderate	Biomarker	[10]
Hereditary episodic ataxia	DISC4ZQW	Limited	Genetic Variation	[12]
Nervous system disease	DISJ7GGT	Limited	Genetic Variation	[13]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Aspartate--tRNA ligase, mitochondrial (DARS2).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Aspartate--tRNA ligase, mitochondrial (DARS2).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Aspartate--tRNA ligase, mitochondrial (DARS2).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Aspartate--tRNA ligase, mitochondrial (DARS2).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Aspartate--tRNA ligase, mitochondrial (DARS2).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Aspartate--tRNA ligase, mitochondrial (DARS2).	[19]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Aspartate--tRNA ligase, mitochondrial (DARS2).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Aspartate--tRNA ligase, mitochondrial (DARS2).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Aspartate--tRNA ligase, mitochondrial (DARS2).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Aspartate--tRNA ligase, mitochondrial (DARS2).	[23]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Aspartate--tRNA ligase, mitochondrial (DARS2).	[20]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] 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.
• [3] DARS2 mutations in mitochondrial leucoencephalopathy and multiple sclerosis.J Med Genet. 2010 Jan;47(1):66-70. doi: 10.1136/jmg.2009.068221. Epub 2009 Jul 9.
• [4] Next generation sequencing for molecular diagnosis of neurological disorders using ataxias as a model.Brain. 2013 Oct;136(Pt 10):3106-18. doi: 10.1093/brain/awt236. Epub 2013 Sep 11.
• [5] In vivocharacterization of the aspartyl-tRNA synthetase DARS: Homing in on the leukodystrophy HBSL.Neurobiol Dis. 2017 Jan;97(Pt A):24-35. doi: 10.1016/j.nbd.2016.10.008. Epub 2016 Nov 2.
• [6] Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.Science. 2007 Jun 1;316(5829):1331-6. doi: 10.1126/science.1142358. Epub 2007 Apr 26.
• [7] Spinal cord calcification in an early-onset progressive leukoencephalopathy.J Child Neurol. 2011 Jul;26(7):876-80. doi: 10.1177/0883073810390038. Epub 2011 Mar 22.
• [8] Identification and characterization of aspartyl-tRNA synthetase inhibitors against Mycobacterium tuberculosis by an integrated whole-cell target-based approach.Sci Rep. 2018 Aug 23;8(1):12664. doi: 10.1038/s41598-018-31157-3.
• [9] Upregulation of DARS2 by HBV promotes hepatocarcinogenesis through the miR-30e-5p/MAPK/NFAT5 pathway.J Exp Clin Cancer Res. 2017 Oct 19;36(1):148. doi: 10.1186/s13046-017-0618-x.
• [10] Epilepsy in mitochondrial disorders.Seizure. 2012 Jun;21(5):316-21. doi: 10.1016/j.seizure.2012.03.003. Epub 2012 Mar 27.
• [11] Three human aminoacyl-tRNA synthetases have distinct sub-mitochondrial localizations that are unaffected by disease-associated mutations.J Biol Chem. 2018 Aug 31;293(35):13604-13615. doi: 10.1074/jbc.RA118.003400. Epub 2018 Jul 13.
• [12] Acetazolamide-responsive exercise-induced episodic ataxia associated with a novel homozygous DARS2 mutation.J Med Genet. 2011 Oct;48(10):713-5. doi: 10.1136/jmg.2011.090282. Epub 2011 Jul 11.
• [13] Early-onset leukoencephalopathy due to a homozygous missense mutation in the DARS2 gene.Mol Cell Probes. 2015 Oct;29(5):319-22. doi: 10.1016/j.mcp.2015.06.005. Epub 2015 Aug 29.
• [14] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] 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.
• [17] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [18] 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.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [21] 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.
• [22] 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.
• [23] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.