Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4557NF)

• DOT Name: Leucine--tRNA ligase, cytoplasmic (LARS1)
• Synonyms: EC 6.1.1.4; Leucyl-tRNA synthetase; LeuRS; cLRS
• Gene Name: LARS1
• Related Disease:
  Aicardi-Goutieres syndrome
  Alzheimer disease
  Infantile liver failure syndrome 1
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Neoplasm
  Non-small-cell lung cancer
  Tuberculosis
  Ulcerative colitis
  Urinary tract infection
  Acute myelogenous leukaemia
  Non-insulin dependent diabetes
  Rectal carcinoma
  Type-1 diabetes
• UniProt ID: SYLC_HUMAN
• PDB ID: 2WFD; 6KID; 6KIE; 6KQY; 6KR7; 6LPF; 6LR6
• EC Number: 6.1.1.4
• Pfam ID: PF08264 ; PF00133
• Sequence:
  MAERKGTAKVDFLKKIEKEIQQKWDTERVFEVNASNLEKQTSKGKYFVTFPYPYMNGRLH
  LGHTFSLSKCEFAVGYQRLKGKCCLFPFGLHCTGMPIKACADKLKREIELYGCPPDFPDE
  EEEEEETSVKTEDIIIKDKAKGKKSKAAAKAGSSKYQWGIMKSLGLSDEEIVKFSEAEHW
  LDYFPPLAIQDLKRMGLKVDWRRSFITTDVNPYYDSFVRWQFLTLRERNKIKFGKRYTIY
  SPKDGQPCMDHDRQTGEGVGPQEYTLLKLKVLEPYPSKLSGLKGKNIFLVAATLRPETMF
  GQTNCWVRPDMKYIGFETVNGDIFICTQKAARNMSYQGFTKDNGVVPVVKELMGEEILGA
  SLSAPLTSYKVIYVLPMLTIKEDKGTGVVTSVPSDSPDDIAALRDLKKKQALRAKYGIRD
  DMVLPFEPVPVIEIPGFGNLSAVTICDELKIQSQNDREKLAEAKEKIYLKGFYEGIMLVD
  GFKGQKVQDVKKTIQKKMIDAGDALIYMEPEKQVMSRSSDECVVALCDQWYLDYGEENWK
  KQTSQCLKNLETFCEETRRNFEATLGWLQEHACSRTYGLGTHLPWDEQWLIESLSDSTIY
  MAFYTVAHLLQGGNLHGQAESPLGIRPQQMTKEVWDYVFFKEAPFPKTQIAKEKLDQLKQ
  EFEFWYPVDLRVSGKDLVPNHLSYYLYNHVAMWPEQSDKWPTAVRANGHLLLNSEKMSKS
  TGNFLTLTQAIDKFSADGMRLALADAGDTVEDANFVEAMADAGILRLYTWVEWVKEMVAN
  WDSLRSGPASTFNDRVFASELNAGIIKTDQNYEKMMFKEALKTGFFEFQAAKDKYRELAV
  EGMHRELVFRFIEVQTLLLAPFCPHLCEHIWTLLGKPDSIMNASWPVAGPVNEVLIHSSQ
  YLMEVTHDLRLRLKNYMMPAKGKKTDKQPLQKPSHCTIYVAKNYPPWQHTTLSVLRKHFE
  ANNGKLPDNKVIASELGSMPELKKYMKKVMPFVAMIKENLEKMGPRILDLQLEFDEKAVL
  MENIVYLTNSLELEHIEVKFASEAEDKIREDCCPGKPLNVFRIEPGVSVSLVNPQPSNGH
  FSTKIEIRQGDNCDSIIRRLMKMNRGIKDLSKVKLMRFDDPLLGPRRVPVLGKEYTEKTP
  ISEHAVFNVDLMSKKIHLTENGIRVDIGDTIIYLVH
• Function: Aminoacyl-tRNA synthetase that catalyzes the specific attachment of leucine to its cognate tRNA (tRNA(Leu)). It performs tRNA aminoacylation in a two-step reaction: Leu is initially activated by ATP to form a leucyl-adenylate (Leu-AMP) intermediate; then the leucyl moiety is transferred to the acceptor 3' end of the tRNA to yield leucyl-tRNA. To improve the fidelity of catalytic reactions, it is also able to hydrolyze misactivated aminoacyl-adenylate intermediates (pre-transfer editing) and mischarged aminoacyl-tRNAs (post-transfer editing).
• KEGG Pathway: Aminoacyl-tR. biosynthesis (hsa00970)
• Reactome Pathway:
  Cytosolic tRNA aminoacylation (R-HSA-379716)
  Selenoamino acid metabolism (R-HSA-2408522)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aicardi-Goutieres syndrome	DIS1NH4X	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Infantile liver failure syndrome 1	DISFONJI	Strong	Autosomal recessive	[3]
Lung cancer	DISCM4YA	Strong	Altered Expression	[4]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[4]
Lung neoplasm	DISVARNB	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[5]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[6]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[7]
Urinary tract infection	DISMT6UV	Strong	Biomarker	[8]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[9]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[10]
Rectal carcinoma	DIS8FRR7	Limited	Biomarker	[11]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[12]

18 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 Leucine--tRNA ligase, cytoplasmic (LARS1).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Leucine--tRNA ligase, cytoplasmic (LARS1).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Leucine--tRNA ligase, cytoplasmic (LARS1).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Leucine--tRNA ligase, cytoplasmic (LARS1).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Leucine--tRNA ligase, cytoplasmic (LARS1).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Leucine--tRNA ligase, cytoplasmic (LARS1).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Leucine--tRNA ligase, cytoplasmic (LARS1).	[19]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Leucine--tRNA ligase, cytoplasmic (LARS1).	[20]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Leucine--tRNA ligase, cytoplasmic (LARS1).	[21]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of Leucine--tRNA ligase, cytoplasmic (LARS1).	[16]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Leucine--tRNA ligase, cytoplasmic (LARS1).	[16]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of Leucine--tRNA ligase, cytoplasmic (LARS1).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Leucine--tRNA ligase, cytoplasmic (LARS1).	[23]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Leucine--tRNA ligase, cytoplasmic (LARS1).	[25]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Leucine--tRNA ligase, cytoplasmic (LARS1).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Leucine--tRNA ligase, cytoplasmic (LARS1).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Leucine--tRNA ligase, cytoplasmic (LARS1).	[28]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Leucine--tRNA ligase, cytoplasmic (LARS1).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Leucine--tRNA ligase, cytoplasmic (LARS1).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Leucine--tRNA ligase, cytoplasmic (LARS1).	[24]

References

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