Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOB0KSG)

• DOT Name: Alanine--tRNA ligase, mitochondrial (AARS2)
• Synonyms: EC 6.1.1.7; Alanyl-tRNA synthetase; AlaRS
• Gene Name: AARS2
• Related Disease:
  Cardiomyopathy
  Dementia
  Leukoencephalopathy, progressive, with ovarian failure
  Mitochondrial disease
  Cerebellar ataxia
  Combined oxidative phosphorylation defect type 8
  Combined oxidative phosphorylation deficiency
  Galactosialidosis
  Isolated congenital microcephaly
  Leukodystrophy
  Leukoencephalopathy, hereditary diffuse, with spheroids
  Mitochondrial encephalomyopathy
  Myopathy
  Myositis disease
  Non-immune hydrops fetalis
  Female hypogonadism
  Frontotemporal dementia
  Obsolete hereditary diffuse leukoencephalopathy with axonal spheroids and pigmented glia
  Obsolete ovarioleukodystrophy
  Retinopathy
• UniProt ID: SYAM_HUMAN
• PDB ID: 6NLQ; 6NLY; 6NOW
• EC Number: 6.1.1.7
• Pfam ID: PF01411 ; PF07973
• Sequence:
  MAASVAAAARRLRRAIRRSPAWRGLSHRPLSSEPPAAKASAVRAAFLNFFRDRHGHRLVP
  SASVRPRGDPSLLFVNAGMNQFKPIFLGTVDPRSEMAGFRRVANSQKCVRAGGHHNDLED
  VGRDLSHHTFFEMLGNWAFGGEYFKEEACNMAWELLTQVYGIPEERLWISYFDGDPKAGL
  DPDLETRDIWLSLGVPASRVLSFGPQENFWEMGDTGPCGPCTEIHYDLAGGVGAPQLVEL
  WNLVFMQHNREADGSLQPLPQRHVDTGMGLERLVAVLQGKHSTYDTDLFSPLLNAIQQGC
  RAPPYLGRVGVADEGRTDTAYRVVADHIRTLSVCISDGIFPGMSGPPLVLRRILRRAVRF
  SMEILKAPPGFLGSLVPVVVETLGDAYPELQRNSAQIANLVSEDEAAFLASLERGRRIID
  RTLRTLGPSDMFPAEVAWSLSLCGDLGLPLDMVELMLEEKGVQLDSAGLERLAQEEAQHR
  ARQAEPVQKQGLWLDVHALGELQRQGVPPTDDSPKYNYSLRPSGSYEFGTCEAQVLQLYT
  EDGTAVASVGKGQRCGLLLDRTNFYAEQGGQASDRGYLVRAGQEDVLFPVARAQVCGGFI
  LHEAVAPECLRLGDQVQLHVDEAWRLGCMAKHTATHLLNWALRQTLGPGTEQQGSHLNPE
  QLRLDVTTQTPLTPEQLRAVENTVQEAVGQDEAVYMEEVPLALTAQVPGLRSLDEVYPDP
  VRVVSVGVPVAHALDPASQAALQTSVELCCGTHLLRTGAVGDLVIIGDRQLSKGTTRLLA
  VTGEQAQQARELGQSLAQEVKAATERLSLGSRDVAEALRLSKDIGRLIEAVETAVMPQWQ
  RRELLATVKMLQRRANTAIRKLQMGQAAKKTQELLERHSKGPLIVDTVSAESLSVLVKVV
  RQLCEQAPSTSVLLLSPQPMGKVLCACQVAQGAMPTFTAEAWALAVCSHMGGKAWGSRVV
  AQGTGSTTDLEAALSIAQTYALSQL
• Function: Catalyzes the attachment of alanine to tRNA(Ala) in a two-step reaction: alanine is first activated by ATP to form Ala-AMP and then transferred to the acceptor end of tRNA(Ala). Also edits incorrectly charged tRNA(Ala) via its editing domain.
• KEGG Pathway: Aminoacyl-tR. biosynthesis (hsa00970)
• Reactome Pathway: Mitochondrial tRNA aminoacylation (R-HSA-379726)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiomyopathy	DISUPZRG	Definitive	Biomarker	[1]
Dementia	DISXL1WY	Definitive	Biomarker	[2]
Leukoencephalopathy, progressive, with ovarian failure	DISGHL9L	Definitive	Autosomal recessive	[3]
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[4]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[5]
Combined oxidative phosphorylation defect type 8	DIS8YAVJ	Strong	Autosomal recessive	[6]
Combined oxidative phosphorylation deficiency	DISG5MW9	Strong	Biomarker	[6]
Galactosialidosis	DIS0XSEE	Strong	Genetic Variation	[7]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[8]
Leukodystrophy	DISVY1TT	Strong	Biomarker	[9]
Leukoencephalopathy, hereditary diffuse, with spheroids	DIS4DF8A	Strong	Biomarker	[10]
Mitochondrial encephalomyopathy	DISA6PTN	Strong	Genetic Variation	[11]
Myopathy	DISOWG27	Strong	Biomarker	[11]
Myositis disease	DISCIXF0	Strong	Biomarker	[12]
Non-immune hydrops fetalis	DISPUY8C	Strong	Genetic Variation	[7]
Female hypogonadism	DISWASB4	moderate	Genetic Variation	[13]
Frontotemporal dementia	DISKYHXL	moderate	Biomarker	[2]
Obsolete hereditary diffuse leukoencephalopathy with axonal spheroids and pigmented glia	DISKMF1F	Supportive	Autosomal dominant	[14]
Obsolete ovarioleukodystrophy	DIS0K85C	Supportive	Autosomal recessive	[15]
Retinopathy	DISB4B0F	Limited	Genetic Variation	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Alanine--tRNA ligase, mitochondrial (AARS2).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Alanine--tRNA ligase, mitochondrial (AARS2).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Alanine--tRNA ligase, mitochondrial (AARS2).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Alanine--tRNA ligase, mitochondrial (AARS2).	[19]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Alanine--tRNA ligase, mitochondrial (AARS2).	[21]

References

• [1] Instability of the mitochondrial alanyl-tRNA synthetase underlies fatal infantile-onset cardiomyopathy.Hum Mol Genet. 2019 Jan 15;28(2):258-268. doi: 10.1093/hmg/ddy294.
• [2] Analysis of frontotemporal dementia, amyotrophic lateral sclerosis, and other dementia-related genes in 107 Korean patients with frontotemporal dementia.Neurobiol Aging. 2018 Dec;72:186.e1-186.e7. doi: 10.1016/j.neurobiolaging.2018.06.031. Epub 2018 Jun 30.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] 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.
• [5] Alanyl-tRNA Synthetase 2 (AARS2)-Related Ataxia Without Leukoencephalopathy.Cerebellum. 2020 Feb;19(1):154-160. doi: 10.1007/s12311-019-01080-y.
• [6] Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy. Am J Hum Genet. 2011 May 13;88(5):635-42. doi: 10.1016/j.ajhg.2011.04.006. Epub 2011 May 5.
• [7] Inborn errors of metabolism in a cohort of pregnancies with non-immune hydrops fetalis: a single center experience.J Perinat Med. 2018 Nov 27;46(9):968-974. doi: 10.1515/jpm-2017-0124.
• [8] Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy. Hum Mutat. 2017 Oct;38(10):1348-1354. doi: 10.1002/humu.23250. Epub 2017 Jun 23.
• [9] Mitochondrial aminoacyl-tRNA synthetase disorders: an emerging group of developmental disorders of myelination.J Neurodev Disord. 2019 Dec 16;11(1):29. doi: 10.1186/s11689-019-9292-y.
• [10] AARS2 Compound Heterozygous Variants in a Case of Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia.J Neuropathol Exp Neurol. 2018 Nov 1;77(11):997-1000. doi: 10.1093/jnen/nly087.
• [11] AARS2 leukoencephalopathy: A new variant of mitochondrial encephalomyopathy.Mol Genet Genomic Med. 2019 Apr;7(4):e00582. doi: 10.1002/mgg3.582. Epub 2019 Jan 31.
• [12] Pulmonary Pathologic Manifestations of Anti-Alanyl-tRNA Synthetase (Anti-PL-12)-Related Inflammatory Myopathy.Arch Pathol Lab Med. 2018 Feb;142(2):191-197. doi: 10.5858/arpa.2017-0010-OA. Epub 2017 Oct 2.
• [13] Novel alanyl-tRNA synthetase 2 (AARS2) homozygous mutation in a consanguineous Chinese family with premature ovarian insufficiency.Fertil Steril. 2019 Sep;112(3):569-576.e2. doi: 10.1016/j.fertnstert.2019.05.005. Epub 2019 Jul 4.
• [14] Analysis of Mutations in AARS2 in a Series of CSF1R-Negative Patients With Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia. JAMA Neurol. 2016 Dec 1;73(12):1433-1439. doi: 10.1001/jamaneurol.2016.2229.
• [15] Novel (ovario) leukodystrophy related to AARS2 mutations. Neurology. 2014 Jun 10;82(23):2063-71. doi: 10.1212/WNL.0000000000000497. Epub 2014 May 7.
• [16] Retinopathy and optic atrophy: Expanding the phenotypic spectrum of pathogenic variants in the AARS2 gene.Ophthalmic Genet. 2018 Jan-Feb;39(1):99-102. doi: 10.1080/13816810.2017.1350723. Epub 2017 Aug 18.
• [17] 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.
• [18] Human 3D multicellular microtissues: an upgraded model for the in vitro mechanistic investigation of inflammation-associated drug toxicity. Toxicol Lett. 2019 Sep 15;312:34-44.
• [19] 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.
• [20] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [21] Comparison of the global gene expression profiles produced by methylparaben, n-butylparaben and 17beta-oestradiol in MCF7 human breast cancer cells. J Appl Toxicol. 2007 Jan-Feb;27(1):67-77. doi: 10.1002/jat.1200.