Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC8X3H9)

• DOT Name: Histidine--tRNA ligase, mitochondrial (HARS2)
• Synonyms: EC 6.1.1.21; Histidine--tRNA ligase-like; Histidyl-tRNA synthetase; HisRS
• Gene Name: HARS2
• Related Disease:
  Autoimmune disease
  Idiopathic inflammatory myopathy
  Myopathy
  Myositis disease
  Osteoarthritis
  Peripheral neuropathy
  Perrault syndrome 2
  Polymyositis
  Rheumatic fever
  Rheumatoid arthritis
  Sensorineural hearing loss disorder
  Glioblastoma multiforme
  Perrault syndrome
  Usher syndrome type 3B
  Axonal neuropathy
  Female hypogonadism
• UniProt ID: SYHM_HUMAN
• EC Number: 6.1.1.21
• Pfam ID: PF03129 ; PF13393
• Sequence:
  MPLLGLLPRRAWASLLSQLLRPPCASCTGAVRCQSQVAEAVLTSQLKAHQEKPNFIIKTP
  KGTRDLSPQHMVVREKILDLVISCFKRHGAKGMDTPAFELKETLTEKYGEDSGLMYDLKD
  QGGELLSLRYDLTVPFARYLAMNKVKKMKRYHVGKVWRRESPTIVQGRYREFCQCDFDIA
  GQFDPMIPDAECLKIMCEILSGLQLGDFLIKVNDRRIVDGMFAVCGVPESKFRAICSSID
  KLDKMAWKDVRHEMVVKKGLAPEVADRIGDYVQCHGGVSLVEQMFQDPRLSQNKQALEGL
  GDLKLLFEYLTLFGIADKISFDLSLARGLDYYTGVIYEAVLLQTPTQAGEEPLNVGSVAA
  GGRYDGLVGMFDPKGHKVPCVGLSIGVERIFYIVEQRMKTKGEKVRTTETQVFVATPQKN
  FLQERLKLIAELWDSGIKAEMLYKNNPKLLTQLHYCESTGIPLVVIIGEQELKEGVIKIR
  SVASREEVAIKRENFVAEIQKRLSES
• Function: Mitochondrial aminoacyl-tRNA synthetase that catalyzes the ATP-dependent ligation of histidine to the 3'-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (His-AMP).
• Tissue Specificity: A high level expression is seen in the heart, kidney and skeletal muscle while a lower level expression is seen in the brain and liver.
• KEGG Pathway: Aminoacyl-tR. biosynthesis (hsa00970)
• Reactome Pathway: Mitochondrial tRNA aminoacylation (R-HSA-379726)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoimmune disease	DISORMTM	Strong	Biomarker	[1]
Idiopathic inflammatory myopathy	DISGB1BZ	Strong	Biomarker	[2]
Myopathy	DISOWG27	Strong	Biomarker	[3]
Myositis disease	DISCIXF0	Strong	Biomarker	[4]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[5]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[6]
Perrault syndrome 2	DIS5PQ0K	Strong	Autosomal recessive	[7]
Polymyositis	DIS5DHFP	Strong	Biomarker	[8]
Rheumatic fever	DISLUF66	Strong	Biomarker	[9]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[5]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Genetic Variation	[10]
Glioblastoma multiforme	DISK8246	moderate	Genetic Variation	[11]
Perrault syndrome	DISG2YOV	Supportive	Autosomal recessive	[7]
Usher syndrome type 3B	DISPLHUS	Disputed	Genetic Variation	[12]
Axonal neuropathy	DIS5S2BC	Limited	Genetic Variation	[13]
Female hypogonadism	DISWASB4	Limited	Genetic Variation	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Histidine--tRNA ligase, mitochondrial (HARS2).	[15]

5 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 Histidine--tRNA ligase, mitochondrial (HARS2).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Histidine--tRNA ligase, mitochondrial (HARS2).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Histidine--tRNA ligase, mitochondrial (HARS2).	[18]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Histidine--tRNA ligase, mitochondrial (HARS2).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Histidine--tRNA ligase, mitochondrial (HARS2).	[20]

References

• [1] Hodgkin's lymphoma in a patient with Jo-1 syndrome.Virchows Arch. 2007 Jul;451(1):101-4. doi: 10.1007/s00428-007-0429-0. Epub 2007 May 24.
• [2] Proinflammatory Histidyl-Transfer RNA Synthetase-Specific CD4+ T Cells in the Blood and Lungs of Patients With Idiopathic Inflammatory Myopathies.Arthritis Rheumatol. 2020 Jan;72(1):179-191. doi: 10.1002/art.41075. Epub 2019 Nov 26.
• [3] Entering a new phase of immunogenetics in the idiopathic inflammatory myopathies.Curr Opin Rheumatol. 2013 Nov;25(6):735-41. doi: 10.1097/01.bor.0000434676.70268.66.
• [4] Secreted histidyl-tRNA synthetase splice variants elaborate major epitopes for autoantibodies in inflammatory myositis.J Biol Chem. 2014 Jul 11;289(28):19269-75. doi: 10.1074/jbc.C114.571026. Epub 2014 Jun 4.
• [5] The potential role of human endogenous retrovirus K10 in the pathogenesis of rheumatoid arthritis: a preliminary study.Ann Rheum Dis. 2006 May;65(5):612-6. doi: 10.1136/ard.2004.031146. Epub 2005 Sep 28.
• [6] A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo.Hum Mutat. 2013 Jan;34(1):191-9. doi: 10.1002/humu.22210. Epub 2012 Oct 11.
• [7] Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6543-8. doi: 10.1073/pnas.1103471108. Epub 2011 Apr 4.
• [8] Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes.Genes Immun. 2015 Oct;16(7):470-80. doi: 10.1038/gene.2015.28. Epub 2015 Aug 20.
• [9] Histidyl-tRNA synthetase.Biol Chem. 1999 Jun;380(6):623-46. doi: 10.1515/BC.1999.079.
• [10] Novel HARS2 missense variants identified in individuals with sensorineural hearing impairment and Perrault syndrome.Eur J Med Genet. 2020 Mar;63(3):103733. doi: 10.1016/j.ejmg.2019.103733. Epub 2019 Aug 23.
• [11] Search for new loci and low-frequency variants influencing glioma risk by exome-array analysis.Eur J Hum Genet. 2016 May;24(5):717-24. doi: 10.1038/ejhg.2015.170. Epub 2015 Aug 12.
• [12] The Usher Syndrome Type IIIB Histidyl-tRNA Synthetase Mutation Confers Temperature Sensitivity.Biochemistry. 2017 Jul 18;56(28):3619-3631. doi: 10.1021/acs.biochem.7b00114. Epub 2017 Jul 7.
• [13] Substrate interaction defects in histidyl-tRNA synthetase linked to dominant axonal peripheral neuropathy.Hum Mutat. 2018 Mar;39(3):415-432. doi: 10.1002/humu.23380. Epub 2017 Dec 26.
• [14] A recurrent missense variant in HARS2 results in variable sensorineural hearing loss in three unrelated families.J Hum Genet. 2020 Mar;65(3):305-311. doi: 10.1038/s10038-019-0706-1. Epub 2019 Dec 12.
• [15] 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.
• [16] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] 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.
• [20] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.