Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJS37LE)

• DOT Name: Leucine--tRNA ligase, mitochondrial (LARS2)
• Synonyms: EC 6.1.1.4; Leucyl-tRNA synthetase; LeuRS
• Gene Name: LARS2
• Related Disease:
  Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome
  Perrault syndrome
  Perrault syndrome 4
• UniProt ID: SYLM_HUMAN
• EC Number: 6.1.1.4
• Pfam ID: PF08264 ; PF00133 ; PF13603
• Sequence:
  MASVWQRLGFYASLLKRQLNGGPDVIKWERRVIPGCTRSIYSATGKWTKEYTLQTRKDVE
  KWWHQRIKEQASKISEADKSKPKFYVLSMFPYPSGKLHMGHVRVYTISDTIARFQKMRGM
  QVINPMGWDAFGLPAENAAVERNLHPQSWTQSNIKHMRKQLDRLGLCFSWDREITTCLPD
  YYKWTQYLFIKLYEAGLAYQKEALVNWDPVDQTVLANEQVDEHGCSWRSGAKVEQKYLRQ
  WFIKTTAYAKAMQDALADLPEWYGIKGMQAHWIGDCVGCHLDFTLKVHGQATGEKLTAYT
  ATPEAIYGTSHVAISPSHRLLHGHSSLKEALRMALVPGKDCLTPVMAVNMLTQQEVPVVI
  LAKADLEGSLDSKIGIPSTSSEDTILAQTLGLAYSEVIETLPDGTERLSSSAEFTGMTRQ
  DAFLALTQKARGKRVGGDVTSDKLKDWLISRQRYWGTPIPIVHCPVCGPTPVPLEDLPVT
  LPNIASFTGKGGPPLAMASEWVNCSCPRCKGAAKRETDTMDTFVDSAWYYFRYTDPHNPH
  SPFNTAVADYWMPVDLYIGGKEHAVMHLFYARFFSHFCHDQKMVKHREPFHKLLAQGLIK
  GQTFRLPSGQYLQREEVDLTGSVPVHAKTKEKLEVTWEKMSKSKHNGVDPEEVVEQYGID
  TIRLYILFAAPPEKDILWDVKTDALPGVLRWQQRLWTLTTRFIEARASGKSPQPQLLSNK
  EKAEARKLWEYKNSVISQVTTHFTEDFSLNSAISQLMGLSNALSQASQSVILHSPEFEDA
  LCALMVMAAPLAPHVTSEIWAGLALVPRKLCAHYTWDASVLLQAWPAVDPEFLQQPEVVQ
  MAVLINNKACGKIPVPQQVARDQDKVHEFVLQSELGVRLLQGRSIKKSFLSPRTALINFL
  VQD
• Function: Catalyzes the attachment of leucine to its cognate tRNA.
• Tissue Specificity: Ubiquitously expressed, but highest expression in tissues with high metabolic rates, such as skeletal muscle, heart, and kidney.
• KEGG Pathway: Aminoacyl-tR. biosynthesis (hsa00970)
• Reactome Pathway: Mitochondrial tRNA aminoacylation (R-HSA-379726)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome	DISD1JXS	Strong	Autosomal recessive	[1]
Perrault syndrome	DISG2YOV	Strong	Autosomal recessive	[2]
Perrault syndrome 4	DISCAHXP	Strong	Autosomal recessive	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Leucine--tRNA ligase, mitochondrial (LARS2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Leucine--tRNA ligase, mitochondrial (LARS2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Leucine--tRNA ligase, mitochondrial (LARS2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Leucine--tRNA ligase, mitochondrial (LARS2).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Leucine--tRNA ligase, mitochondrial (LARS2).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Leucine--tRNA ligase, mitochondrial (LARS2).	[9]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Leucine--tRNA ligase, mitochondrial (LARS2).	[10]

References

• [1] LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure. JIMD Rep. 2016;28:49-57. doi: 10.1007/8904_2015_515. Epub 2015 Nov 5.
• [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] PanelApp crowdsources expert knowledge to establish consensus diagnostic gene panels. Nat Genet. 2019 Nov;51(11):1560-1565. doi: 10.1038/s41588-019-0528-2.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [10] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.