Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0EU4SV)

DOT Name	Lysine--tRNA ligase (KARS1)
Synonyms	EC 2.7.7.-; EC 6.1.1.6; Lysyl-tRNA synthetase; LysRS
Gene Name	KARS1
Related Disease	Cryptosporidium infection ( ) Advanced cancer ( ) Autoimmune disease ( ) Autosomal recessive nonsyndromic hearing loss 89 ( ) Charcot marie tooth disease ( ) Colon cancer ( ) Colon carcinoma ( ) Dermatomyositis ( ) Hypertrophic cardiomyopathy ( ) Intellectual disability ( ) Isolated congenital microcephaly ( ) Kufor-Rakeb syndrome ( ) Lactic acidosis ( ) Leukodystrophy ( ) Leukoencephalopathy, progressive, infantile-onset, with or without deafness ( ) Lung cancer ( ) Lung carcinoma ( ) Lyme disease ( ) Malaria ( ) Mitochondrial disease ( ) Neoplasm ( ) Non-small-cell lung cancer ( ) Peripheral neuropathy ( ) Polymyositis ( ) Polyneuropathy ( ) Prion disease ( ) Sciatic neuropathy ( ) Cardiomyopathy ( ) Charcot-Marie-Tooth disease recessive intermediate B ( ) Hearing loss, autosomal recessive ( ) Melanoma ( ) Nonsyndromic genetic hearing loss ( ) Optic nerve disorder ( ) Sensorineural hearing loss disorder ( )
UniProt ID	SYK_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	3BJU; 4DPG; 4YCU; 4YCW; 6CHD; 6ILD; 6ILH; 7EA9
EC Number	2.7.7.-; 6.1.1.6
Pfam ID	PF00152 ; PF01336
Sequence	MAAVQAAEVKVDGSEPKLSKNELKRRLKAEKKVAEKEAKQKELSEKQLSQATAAATNHTT DNGVGPEEESVDPNQYYKIRSQAIHQLKVNGEDPYPHKFHVDISLTDFIQKYSHLQPGDH LTDITLKVAGRIHAKRASGGKLIFYDLRGEGVKLQVMANSRNYKSEEEFIHINNKLRRGD IIGVQGNPGKTKKGELSIIPYEITLLSPCLHMLPHLHFGLKDKETRYRQRYLDLILNDFV RQKFIIRSKIITYIRSFLDELGFLEIETPMMNIIPGGAVAKPFITYHNELDMNLYMRIAP ELYHKMLVVGGIDRVYEIGRQFRNEGIDLTHNPEFTTCEFYMAYADYHDLMEITEKMVSG MVKHITGSYKVTYHPDGPEGQAYDVDFTPPFRRINMVEELEKALGMKLPETNLFETEETR KILDDICVAKAVECPPPRTTARLLDKLVGEFLEVTCINPTFICDHPQIMSPLAKWHRSKE GLTERFELFVMKKEICNAYTELNDPMRQRQLFEEQAKAKAAGDDEAMFIDENFCTALEYG LPPTAGWGMGIDRVAMFLTDSNNIKEVLLFPAMKPEDKKENVATTDTLESTTVGTSV
Function	Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA. When secreted, acts as a signaling molecule that induces immune response through the activation of monocyte/macrophages. Catalyzes the synthesis of the signaling molecule diadenosine tetraphosphate (Ap4A), and thereby mediates disruption of the complex between HINT1 and MITF and the concomitant activation of MITF transcriptional activity ; (Microbial infection) Interacts with HIV-1 virus GAG protein, facilitating the selective packaging of tRNA(3)(Lys), the primer for reverse transcription initiation.
KEGG Pathway	Aminoacyl-tR. biosynthesis (hsa00970 )
Reactome Pathway	Cytosolic tRNA aminoacylation (R-HSA-379716 ) Mitochondrial tRNA aminoacylation (R-HSA-379726 ) Selenoamino acid metabolism (R-HSA-2408522 )

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Cryptosporidium infection	DISLBTU2	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Autoimmune disease	DISORMTM	Strong	Biomarker	[3]
Autosomal recessive nonsyndromic hearing loss 89	DIS61QAO	Strong	Autosomal recessive	[4]
Charcot marie tooth disease	DIS3BT2L	Strong	Biomarker	[5]
Colon cancer	DISVC52G	Strong	Biomarker	[2]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[2]
Dermatomyositis	DIS50C5O	Strong	Biomarker	[3]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Genetic Variation	[6]
Intellectual disability	DISMBNXP	Strong	Biomarker	[7]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[6]
Kufor-Rakeb syndrome	DIS09C7Z	Strong	Genetic Variation	[8]
Lactic acidosis	DISZI1ZK	Strong	Biomarker	[9]
Leukodystrophy	DISVY1TT	Strong	Genetic Variation	[10]
Leukoencephalopathy, progressive, infantile-onset, with or without deafness	DISHT2FX	Strong	Autosomal recessive	[11]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[12]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[12]
Lyme disease	DISO70G5	Strong	Biomarker	[13]
Malaria	DISQ9Y50	Strong	Biomarker	[14]
Mitochondrial disease	DISKAHA3	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[15]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[5]
Polymyositis	DIS5DHFP	Strong	Biomarker	[3]
Polyneuropathy	DISB9G3W	Strong	Genetic Variation	[6]
Prion disease	DISOUMB0	Strong	Genetic Variation	[16]
Sciatic neuropathy	DISMGDKX	Strong	Biomarker	[17]
Cardiomyopathy	DISUPZRG	moderate	Biomarker	[9]
Charcot-Marie-Tooth disease recessive intermediate B	DIS9ODHZ	Supportive	Autosomal recessive	[5]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[4]
Melanoma	DIS1RRCY	Limited	Biomarker	[18]
Nonsyndromic genetic hearing loss	DISZX61P	Limited	Autosomal recessive	[19]
Optic nerve disorder	DISSOQM8	Limited	Genetic Variation	[20]
Sensorineural hearing loss disorder	DISJV45Z	Limited	Genetic Variation	[9]
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⏷ Show the Full List of 34 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

10 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 Lysine--tRNA ligase (KARS1).	[21]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Lysine--tRNA ligase (KARS1).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Lysine--tRNA ligase (KARS1).	[23]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Lysine--tRNA ligase (KARS1).	[24]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Lysine--tRNA ligase (KARS1).	[25]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Lysine--tRNA ligase (KARS1).	[26]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Lysine--tRNA ligase (KARS1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Lysine--tRNA ligase (KARS1).	[29]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Lysine--tRNA ligase (KARS1).	[30]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Lysine--tRNA ligase (KARS1).	[31]
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⏷ Show the Full List of 10 Drug(s)

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Lysine--tRNA ligase (KARS1).	[28]
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References

1	Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis.Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):7015-7020. doi: 10.1073/pnas.1814685116. Epub 2019 Mar 20.
2	Lysyl-tRNA synthetase-expressing colon spheroids induce M2 macrophage polarization to promote metastasis.J Clin Invest. 2018 Nov 1;128(11):5034-5055. doi: 10.1172/JCI99806. Epub 2018 Oct 8.
3	Lysyl-Transfer RNA Synthetase Induces the Maturation of Dendritic Cells through MAPK and NF-B Pathways, Strongly Contributing to Enhanced Th1 Cell Responses.J Immunol. 2018 Nov 1;201(9):2832-2841. doi: 10.4049/jimmunol.1800386. Epub 2018 Oct 1.
4	Mutations in KARS, encoding lysyl-tRNA synthetase, cause autosomal-recessive nonsyndromic hearing impairment DFNB89. Am J Hum Genet. 2013 Jul 11;93(1):132-40. doi: 10.1016/j.ajhg.2013.05.018. Epub 2013 Jun 13.
5	Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy. Am J Hum Genet. 2010 Oct 8;87(4):560-6. doi: 10.1016/j.ajhg.2010.09.008.
6	Novel mutations in KARS cause hypertrophic cardiomyopathy and combined mitochondrial respiratory chain defect.Clin Genet. 2017 Jun;91(6):918-923. doi: 10.1111/cge.12931. Epub 2017 Mar 17.
7	Novel Causative Variants in DYRK1A, KARS, and KAT6A Associated with Intellectual Disability and Additional Phenotypic Features.J Pediatr Genet. 2017 Jun;6(2):77-83. doi: 10.1055/s-0037-1598639. Epub 2017 Feb 14.
8	ATP13A2 mutations impair mitochondrial function in fibroblasts from patients with Kufor-Rakeb syndrome.Neurobiol Aging. 2012 Aug;33(8):1843.e1-7. doi: 10.1016/j.neurobiolaging.2011.12.035. Epub 2012 Jan 31.
9	Inhibition of mitochondrial translation in fibroblasts from a patient expressing the KARS p.(Pro228Leu) variant and presenting with sensorineural deafness, developmental delay, and lactic acidosis.Hum Mutat. 2018 Dec;39(12):2047-2059. doi: 10.1002/humu.23657. Epub 2018 Oct 3.
10	Biallelic KARS pathogenic variants cause an early-onset progressive leukodystrophy.Brain. 2019 Mar 1;142(3):560-573. doi: 10.1093/brain/awz001.
11	Targeted exome sequencing of suspected mitochondrial disorders. Neurology. 2013 May 7;80(19):1762-70. doi: 10.1212/WNL.0b013e3182918c40. Epub 2013 Apr 17.
12	Ultrasensitive Detection of Circulating Tumor DNA of Lung Cancer via an Enzymatically Amplified SERS-Based Frequency Shift Assay.ACS Appl Mater Interfaces. 2019 May 22;11(20):18145-18152. doi: 10.1021/acsami.9b02953. Epub 2019 May 10.
13	Differentiation of Borrelia burgdorferi sensu lato strains using class I lysyl-tRNA synthetase-encoding genes.Med Microbiol Immunol. 2003 May;192(2):79-83. doi: 10.1007/s00430-002-0149-7. Epub 2002 Sep 25.
14	Side chain rotameric changes and backbone dynamics enable specific cladosporin binding in Plasmodium falciparum lysyl-tRNA synthetase.Proteins. 2019 Sep;87(9):730-737. doi: 10.1002/prot.25699. Epub 2019 May 9.
15	Serine 207 phosphorylated lysyl-tRNA synthetase predicts disease-free survival of non-small-cell lung carcinoma.Oncotarget. 2017 May 22;8(39):65186-65198. doi: 10.18632/oncotarget.18053. eCollection 2017 Sep 12.
16	Biological network inferences for a protection mechanism against familial Creutzfeldt-Jakob disease with E200K pathogenic mutation.BMC Med Genomics. 2014 Aug 22;7:52. doi: 10.1186/1755-8794-7-52.
17	Expression profile of aminoacyl-tRNA synthetases in dorsal root ganglion neurons after peripheral nerve injury.J Mol Histol. 2015 Feb;46(1):115-22. doi: 10.1007/s10735-014-9601-4. Epub 2014 Dec 3.
18	Post-translational modification of HINT1 mediates activation of MITF transcriptional activity in human melanoma cells.Oncogene. 2017 Aug 17;36(33):4732-4738. doi: 10.1038/onc.2017.81. Epub 2017 Apr 10.
19	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.
20	Mutations in KARS cause a severe neurological and neurosensory disease with optic neuropathy.Hum Mutat. 2019 Oct;40(10):1826-1840. doi: 10.1002/humu.23799. Epub 2019 Jun 18.
21	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.
22	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.
23	Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
24	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.
25	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
26	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.
27	Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
28	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.
29	Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
30	Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
31	ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.