LARS1

Summary

LARS1 (leucyl-tRNA synthetase 1, HGNC:6512) is a protein-coding gene on chromosome 5q32, encoding Leucine–tRNA ligase, cytoplasmic (Q9P2J5). Aminoacyl-tRNA synthetase that catalyzes the specific attachment of leucine to its cognate tRNA (tRNA(Leu)). It is a common-essential gene (DepMap: required in 99.5% of cancer cell lines).

This gene encodes a cytosolic leucine-tRNA synthetase, a member of the class I aminoacyl-tRNA synthetase family. The encoded enzyme catalyzes the ATP-dependent ligation of L-leucine to tRNA(Leu). It is found in the cytoplasm as part of a multisynthetase complex and interacts with the arginine tRNA synthetase through its C-terminal domain. A mutation in this gene was found in affected individuals with infantile liver failure syndrome 1. Alternatively spliced transcript variants of this gene have been observed.

Source: NCBI Gene 51520 — RefSeq curated summary.

At a glance

• Gene–disease (curated): infantile liver failure syndrome 1 (Strong, GenCC)
• Clinical variants (ClinVar): 606 total — 14 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 21
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.5% of screened cell lines (common-essential)
• MANE Select transcript: NM_020117

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6512
Approved symbol	LARS1
Name	leucyl-tRNA synthetase 1
Location	5q32
Locus type	gene with protein product
Status	Approved
Aliases	HSPC192, FLJ10595, FLJ21788, LEUS, RNTLS
Ensembl gene	ENSG00000133706
Ensembl biotype	protein_coding
OMIM	151350
Entrez	51520

Gene structure

Transcript identifiers

Ensembl transcripts: 48 — 27 protein_coding, 13 retained_intron, 5 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000394434, ENST00000504323, ENST00000505223, ENST00000506231, ENST00000507095, ENST00000508667, ENST00000508709, ENST00000510191, ENST00000511505, ENST00000512412, ENST00000618084, ENST00000674158, ENST00000674170, ENST00000674174, ENST00000674181, ENST00000674191, ENST00000674218, ENST00000674270, ENST00000674277, ENST00000674290, ENST00000674309, ENST00000674310, ENST00000674383, ENST00000674398, ENST00000674412, ENST00000674417, ENST00000674447, ENST00000674450, ENST00000674467, ENST00000674471, ENST00000674479, ENST00000907998, ENST00000907999, ENST00000908000, ENST00000908001, ENST00000908002, ENST00000908003, ENST00000908004, ENST00000923242, ENST00000923243, ENST00000923244, ENST00000923245, ENST00000923246, ENST00000923247, ENST00000923248, ENST00000923249, ENST00000970933, ENST00000970934

RefSeq mRNA: 4 — MANE Select: NM_020117 NM_001317964, NM_001317965, NM_016460, NM_020117

CCDS: CCDS34265, CCDS83029, CCDS93797, CCDS93798

Canonical transcript exons

ENST00000394434 — 32 exons

Exon	Start	End
ENSE00001026660	146153893	146153980
ENSE00001026662	146157403	146157628
ENSE00001026664	146131019	146131109
ENSE00001026669	146153174	146153227
ENSE00001026689	146151862	146152002
ENSE00001026692	146153734	146153810
ENSE00001156449	146132898	146133081
ENSE00001752781	146182488	146182650
ENSE00002465699	146130018	146130158
ENSE00002505955	146113034	146114311
ENSE00003471443	146128672	146128782
ENSE00003488127	146126435	146126545
ENSE00003492300	146123982	146124086
ENSE00003509120	146177547	146177665
ENSE00003509134	146120371	146120503
ENSE00003512870	146144624	146144709
ENSE00003536965	146157728	146157795
ENSE00003544811	146168128	146168265
ENSE00003548361	146135601	146135664
ENSE00003566597	146164310	146164471
ENSE00003567194	146159407	146159470
ENSE00003568827	146143412	146143550
ENSE00003569000	146144267	146144349
ENSE00003589329	146149622	146149699
ENSE00003609043	146171910	146171990
ENSE00003611362	146142872	146143084
ENSE00003618671	146128978	146129118
ENSE00003639628	146160374	146160486
ENSE00003643699	146144472	146144537
ENSE00003643724	146140204	146140261
ENSE00003656293	146172687	146172774
ENSE00003666274	146122492	146122587

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 97.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 82.7100 / max 2081.2741, expressed in 1819 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63988	77.6466	1819
63986	2.9721	1141
63987	1.2529	632
63985	0.8383	311

Top tissues by expression

296 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	97.76	gold quality
endothelial cell	CL:0000115	97.43	silver quality
ventricular zone	UBERON:0003053	97.33	gold quality
adrenal tissue	UBERON:0018303	96.92	gold quality
middle temporal gyrus	UBERON:0002771	96.86	gold quality
body of pancreas	UBERON:0001150	96.76	gold quality
right uterine tube	UBERON:0001302	96.52	gold quality
ganglionic eminence	UBERON:0004023	96.49	gold quality
primary visual cortex	UBERON:0002436	96.21	gold quality
cartilage tissue	UBERON:0002418	96.14	gold quality
pancreas	UBERON:0001264	96.03	gold quality
islet of Langerhans	UBERON:0000006	95.85	gold quality
colonic epithelium	UBERON:0000397	95.85	gold quality
tonsil	UBERON:0002372	95.80	gold quality
mucosa of paranasal sinus	UBERON:0005030	95.68	gold quality
gastrocnemius	UBERON:0001388	95.65	gold quality
cortical plate	UBERON:0005343	95.65	gold quality
stromal cell of endometrium	CL:0002255	95.51	gold quality
muscle of leg	UBERON:0001383	95.46	gold quality
corpus callosum	UBERON:0002336	95.39	gold quality
germinal epithelium of ovary	UBERON:0001304	95.36	gold quality
medial globus pallidus	UBERON:0002477	95.36	gold quality
endometrium	UBERON:0001295	95.30	gold quality
cerebellar cortex	UBERON:0002129	95.24	gold quality
cerebellar hemisphere	UBERON:0002245	95.23	gold quality
tendon of biceps brachii	UBERON:0008188	95.20	gold quality
right lobe of thyroid gland	UBERON:0001119	95.08	gold quality
superficial temporal artery	UBERON:0001614	95.08	gold quality
cerebellum	UBERON:0002037	94.98	gold quality
heart right ventricle	UBERON:0002080	94.97	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.62
E-GEOD-124858	no	676.35
E-MTAB-9689	no	389.19

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF4

miRNA regulators (miRDB)

63 targeting LARS1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-3646	100.00	73.56	5283
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-10395-5P	99.86	67.35	676
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.5% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 22)

• leucyl-tRNA synthetase requires its C-terminal domain for its interaction with arginyl-tRNA synthetase in the multi-tRNA synthetase complex (PMID:16055448)
• We identified a novel G3283A transition in the mitochondrial DNA tRNA(Leu (UUR)) gene in a patient with ptosis, ophthalmoparesis and hyporeflexia. (PMID:17363246)
• Results show that K600 in human leucyl-tRNA synthetase affects amino acid specificity and tRNA aminoacylation. (PMID:17378584)
• findings suggest that LARS1 may play roles in migration and growth of lung cancer cells, which suggest its potential implication in lung tumorigenesis (PMID:18446061)
• Study of crystal structures of the editing domain from 2 eukaryotic cytosolic LeuRS; shows a conserved structural core containing the active site for hydrolysis, with distinct bacterial, archeal, or eukaryotic peripheral insertions. (PMID:19426743)
• the introduction of bulky residues into the amino acid binding pocket failed to block deacylation of tRNA, indicating that the architecture of the amino acid binding pocket is different compared to that of other characterized LeuRSs (PMID:19702327)
• hcLeuRS can charge RNALeu with non-cognate amino acids and exclude the incorrect products by multiple editing pathways. (PMID:20805241)
• This work demonstrates that LRS is a key mediator for amino acid signaling to mTORC1. (PMID:22424946)
• Identification of a mutation in LARS as a novel cause of infantile hepatopathy (PMID:22607940)
• the carboxy-terminal domain of human mitochondrial (mt) leucyl-tRNA synthetase can be used to correct mt dysfunctions caused by mt-tRNA mutations. (PMID:24413190)
• Lack of a CP1 hairpin in LeuRS led to complete loss of aminoacylation, amino acid activation, and tRNA binding; however, the mutants retained post-transfer editing. (PMID:25051973)
• the KMSKS catalytic loop affects the aminoacylation and editing capacities of leucyl-tRNA synthetase (PMID:25817995)
• The results showed a decrease in autophagy on addition of leucine, demonstrating crosstalk between leucine sensing, LRS translocation, RagD interaction, and mTORC1 activation. (PMID:28882589)
• Leucyl-tRNA synthetase (LRS) is a leucine sensor of the mTORC1 pathway. (PMID:28963468)
• this study provides evidence for a role of leucyl-tRNA synthetase 1 (LARS1) in glucose-dependent control of leucine usage. (PMID:31780625)
• Molecular basis of the multifaceted functions of human leucyl-tRNA synthetase in protein synthesis and beyond. (PMID:32232361)
• Genotypic diversity and phenotypic spectrum of infantile liver failure syndrome type 1 due to variants in LARS1. (PMID:32699352)
• Severe course with lethal hepatocellular injury and skeletal muscular dysgenesis in a neonate with infantile liver failure syndrome type 1 caused by novel LARS1 mutations. (PMID:33300650)
• Infantile Liver Failure Syndrome 1 associated with a novel variant of the LARS1 gene: Clinical, genetic, and functional characterization. (PMID:33314043)
• Leucyl-tRNA synthetase 1 is required for proliferation of TSC-null cells. (PMID:34325132)
• O-GlcNAc modification of leucyl-tRNA synthetase 1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine. (PMID:35614056)
• Identification of LARS as an essential gene for osteosarcoma proliferation through large-Scale CRISPR-Cas9 screening database and experimental verification. (PMID:35962451)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	lars1b	ENSDARG00000019280
danio_rerio	lars1a	ENSDARG00000090988
mus_musculus	Lars1	ENSMUSG00000024493
rattus_norvegicus	Lars1	ENSRNOG00000018304
drosophila_melanogaster	LeuRS	FBGN0284253
caenorhabditis_elegans		WBGENE00003073

Paralogs (7): LARS2 (ENSG00000011376), IARS2 (ENSG00000067704), VARS2 (ENSG00000137411), MARS1 (ENSG00000166986), IARS1 (ENSG00000196305), VARS1 (ENSG00000204394), MARS2 (ENSG00000247626)

Protein

Protein identifiers

Leucine–tRNA ligase, cytoplasmic — Q9P2J5 (reviewed: Q9P2J5)

Alternative names: Leucyl-tRNA synthetase

All UniProt accessions (13): A0A6I8PIP7, A0A6I8PIT3, A0A6I8PIV1, A0A6I8PL42, A0A6I8PLB3, A0A6I8PLB8, A0A6I8PRP1, A0A6I8PRS0, A0A6I8PRU9, A0A6I8PS05, A0A6I8PTV8, B4DER1, Q9P2J5

UniProt curated annotations — full annotation on UniProt →

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).

Subunit / interactions. Part of the aminoacyl-tRNA synthetase multienzyme complex, also known as multisynthetase complex (MSC), that is composed of the aminoacyl-tRNA ligases for Arg (RARS1), Asp (DARS1), Gln (QARS1), Ile (IARS1), Leu (LARS1), Lys (KARS1), Met (MARS1) the bifunctional ligase for Glu and Pro (EPRS1) and the auxiliary subunits AIMP1/p43, AIMP2/p38 and EEF1E1/p18.

Subcellular location. Cytoplasm.

Disease relevance. Infantile liver failure syndrome 1 (ILFS1) [MIM:615438] A life-threatening disorder of hepatic function that manifests with acute liver failure in the first few months of life. Clinical features include anemia, renal tubulopathy, developmental delay, seizures, failure to thrive, and liver steatosis and fibrosis. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. 5-fluoro-1,3-dihydro-1-hydroxy-1,2-benzoxaborole inhibits LARS1 by forming a covalent adduct with the 3’ adenosine of tRNA(Leu) at the editing site, thus locking the enzyme in an inactive conformation.

Domain organisation. The structure of cytoplasmic leucine-tRNA ligase includes four main functional domains: the Rossmann-fold aminoacylation domain, the editing domain known as connective peptide 1 (CP1), the anticodon binding domain for tRNA recognition, and the vertebrate C-terminal (VC) domain for tRNA binding.

Similarity. Belongs to the class-I aminoacyl-tRNA synthetase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9P2J5-1	1	yes
Q9P2J5-2	2
Q9P2J5-3	3

RefSeq proteins (4): NP_001304893, NP_001304894, NP_057544, NP_064502* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001412	aa-tRNA-synth_I_CS	Conserved_site
IPR002300	aa-tRNA-synth_Ia	Domain
IPR004493	Leu-tRNA-synth_Ia_arc/euk	Family
IPR009008	Val/Leu/Ile-tRNA-synth_edit	Homologous_superfamily
IPR009080	tRNAsynth_Ia_anticodon-bd	Homologous_superfamily
IPR013155	M/V/L/I-tRNA-synth_anticd-bd	Domain
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR054509	LARS1_ULD	Domain
IPR055416	RBD_LARS1	Domain

Pfam: PF00133, PF08264, PF22947, PF24810

Enzyme classification (BRENDA):

• EC 6.1.1.4 — leucine-tRNA ligase (BRENDA: 40 organisms, 173 substrates, 199 inhibitors, 375 Km, 348 kcat entries)

Substrate kinetics (BRENDA)

40 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-LEUCINE	0.0011–0.9	91
TRNALEU	0.0001–0.0273	81
ATP	0.08–5.8	68
TRNAGAGLEU	0.0001–0.0058	21
TRNALEU(UAA)	0.0013–0.0044	10
L-ISOLEUCINE	0.25–14	8
TRNALEUCUN	0.0002–0.025	7
TRNALEUUUR	—	7
TRNAUAALEU	0.0015–0.0025	6
L-LEU	0.008–0.05	5
ILE-TRNALEU	0.002–0.0025	4
L-ISOLEUCYL-TRNALEU	0.0092–0.0173	4
L-METHIONINE	0.983–7.5	3
TRNALEU FROM AQUIFEX AEOLICUS	0.0003–0.0014	3
TRNALEU FROM ESCHERICHIA COLI	0.0008–0.0015	3

Catalyzed reactions (Rhea), 2 shown:

• tRNA(Leu) + L-leucine + ATP = L-leucyl-tRNA(Leu) + AMP + diphosphate (RHEA:11688)
• L-methionyl-tRNA(Leu) + H2O = tRNA(Leu) + L-methionine + H(+) (RHEA:77535)

UniProt features (142 total): helix 50, strand 44, mutagenesis site 15, turn 12, binding site 5, modified residue 4, sequence variant 3, sequence conflict 3, splice variant 2, short sequence motif 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
6LPF	X-RAY DIFFRACTION	2.49
6LR6	X-RAY DIFFRACTION	3.01
6KID	X-RAY DIFFRACTION	3.15
6KIE	X-RAY DIFFRACTION	3.15
2WFD	X-RAY DIFFRACTION	3.25
6KQY	X-RAY DIFFRACTION	3.3
6KR7	X-RAY DIFFRACTION	4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P2J5-F1	90.78	0.74

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (5): 52; 54; 594; 597; 719

Post-translational modifications (4): 720, 970, 1047, 167

Mutagenesis-validated functional residues (15):

Position	Phenotype
236–256	loss of leucyl-trna ligase activity. decreased activity in post-transfer editing of trna(leu) mischarged with methionine
242	reduced leucyl-trna ligase activity.
245	no effect on leucyl-trna ligase activity.
245	reduced leucyl-trna ligase activity.
245	loss of leucyl-trna ligase activity.
247	reduced leucyl-trna ligase activity.
250	reduced leucyl-trna ligase activity. decreased activity in pre-transfer editing and no effect on post-transfer editing o
250	no effect on leucyl-trna ligase activity.
250	reduced leucyl-trna ligase activity.
250	loss of leucyl-trna ligase activity.
514–534	loss of leucyl-trna ligase activity. decreased activity in post-transfer editing of trna(leu) mischarged with methionine
519	reduced leucyl-trna ligase activity.
523	reduced leucyl-trna ligase activity.
525	reduced leucyl-trna ligase activity.
527	reduced leucyl-trna ligase activity.

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-2408522	Selenoamino acid metabolism
R-HSA-379716	Cytosolic tRNA aminoacylation
R-HSA-9856649	Transcriptional and post-translational regulation of MITF-M expression and activity
R-HSA-1266738	Developmental Biology
R-HSA-1430728	Metabolism
R-HSA-379724	tRNA Aminoacylation
R-HSA-392499	Metabolism of proteins
R-HSA-71291	Metabolism of amino acids and derivatives
R-HSA-72766	Translation
R-HSA-9730414	MITF-M-regulated melanocyte development

MSigDB gene sets: 268 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_AMINO_ACID_ACTIVATION, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_TRNA_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_TOR_SIGNALING, MEF2_02, GOBP_CELLULAR_RESPONSE_TO_ACID_CHEMICAL, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, AACWWCAANK_UNKNOWN, GOBP_TRANSLATION, WANG_LMO4_TARGETS_DN, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELLULAR_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION

GO Biological Process (13): tRNA aminoacylation for protein translation (GO:0006418), glutaminyl-tRNA aminoacylation (GO:0006425), leucyl-tRNA aminoacylation (GO:0006429), cellular response to amino acid starvation (GO:0034198), cellular response to amino acid stimulus (GO:0071230), cellular response to L-leucine (GO:0071233), positive regulation of TORC1 signaling (GO:1904263), cellular response to leucine starvation (GO:1990253), translation (GO:0006412), regulation of cell size (GO:0008361), positive regulation of TOR signaling (GO:0032008), positive regulation of GTPase activity (GO:0043547), aminoacyl-tRNA metabolism involved in translational fidelity (GO:0106074)

GO Molecular Function (9): aminoacyl-tRNA deacylase activity (GO:0002161), glutamine-tRNA ligase activity (GO:0004819), leucine-tRNA ligase activity (GO:0004823), GTPase activator activity (GO:0005096), ATP binding (GO:0005524), nucleotide binding (GO:0000166), aminoacyl-tRNA ligase activity (GO:0004812), protein binding (GO:0005515), ligase activity (GO:0016874)

GO Cellular Component (7): cytoplasm (GO:0005737), lysosome (GO:0005764), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), endomembrane system (GO:0012505), nuclear body (GO:0016604), aminoacyl-tRNA synthetase multienzyme complex (GO:0017101)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1
tRNA Aminoacylation	1
MITF-M-regulated melanocyte development	1
Translation	1
Metabolism	1
Metabolism of proteins	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
tRNA aminoacylation for protein translation	2
GTPase activity	2
catalytic activity, acting on a tRNA	2
aminoacyl-tRNA ligase activity	2
cytoplasm	2
translation	1
tRNA aminoacylation	1
cellular response to starvation	1
response to amino acid starvation	1
response to amino acid	1
cellular response to acid chemical	1
response to L-leucine	1
cellular response to amino acid stimulus	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
positive regulation of TOR signaling	1
TORC1 signaling	1
regulation of TORC1 signaling	1
cellular response to amino acid starvation	1
peptidyltransferase activity	1
translational initiation	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
regulation of cellular component size	1
TOR signaling	1
regulation of TOR signaling	1
positive regulation of intracellular signal transduction	1
regulation of GTPase activity	1
positive regulation of hydrolase activity	1
tRNA metabolic process	1
regulation of translational fidelity	1
carboxylic ester hydrolase activity	1
aminoacyl-tRNA metabolism involved in translational fidelity	1
deacylase activity	1
enzyme activator activity	1
GTPase regulator activity	1

Protein interactions and networks

STRING

2883 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LARS1	IARS1	P41252	998
LARS1	KARS1	Q15046	995
LARS1	MARS1	P56192	993
LARS1	IARS2	Q9NSE4	993
LARS1	QARS1	P47897	992
LARS1	MARS2	Q96GW9	988
LARS1	RARS2	Q5T160	986
LARS1	EPRS1	P07814	984
LARS1	RARS1	P54136	982
LARS1	TARS3	A2RTX5	972
LARS1	TARS2	Q9BW92	971
LARS1	TARS1	P26639	970
LARS1	RRAGD	Q9NQL2	961
LARS1	PARS2	Q7L3T8	961
LARS1	RPS14	P06366	927

IntAct

157 interactions, top by confidence:

A	B	Type	Score
MTOR	RPTOR	psi-mi:“MI:0914”(association)	0.980
RRAGD	RRAGA	psi-mi:“MI:0914”(association)	0.830
LARS1	RARS1	psi-mi:“MI:0915”(physical association)	0.760
LARS1	RARS1	psi-mi:“MI:0914”(association)	0.760
RARS1	LARS1	psi-mi:“MI:0407”(direct interaction)	0.760
RRAGD	RRAGB	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
LARS1	RRAGD	psi-mi:“MI:0915”(physical association)	0.600
RRAGD	LARS1	psi-mi:“MI:0915”(physical association)	0.600
RRAGD	LARS1	psi-mi:“MI:0403”(colocalization)	0.600
gag	EEF1E1	psi-mi:“MI:0914”(association)	0.560
NEURL4	APBB1	psi-mi:“MI:0914”(association)	0.530
QARS1	EEF1E1	psi-mi:“MI:0914”(association)	0.530
SDCBP	TARS3	psi-mi:“MI:0914”(association)	0.530
RPTOR	LARS1	psi-mi:“MI:0914”(association)	0.510
FOXM1	PES1	psi-mi:“MI:0914”(association)	0.500
CUL3	ACOT7	psi-mi:“MI:0914”(association)	0.500
CFTR	CNOT1	psi-mi:“MI:0914”(association)	0.480

BioGRID (474): LARS (Affinity Capture-MS), LARS (Affinity Capture-MS), LARS (Reconstituted Complex), LARS (Affinity Capture-MS), AIMP1 (Co-fractionation), ARHGAP1 (Co-fractionation), EPRS (Co-fractionation), ETF1 (Co-fractionation), KARS (Co-fractionation), LARS (Co-fractionation), LARS (Co-fractionation), LARS (Co-fractionation), LARS (Co-fractionation), LARS (Co-fractionation), LARS (Co-fractionation)

ESM2 similar proteins: A1A8U7, A4W846, A9BDK6, B0JSP4, B1LLC4, B1WVA3, B2IZP5, B2VBN3, B5YQM4, B7K5H5, B7KFT1, B7LKT3, B7MPI5, B7N9S6, B7NMN1, C5BGA4, F4I116, P0C123, P0C124, P36428, P47897, P52780, Q05506, Q09996, Q10490, Q1REN7, Q32IQ0, Q3KRD0, Q3MHH4, Q5R614, Q66H61, Q6DIJ1, Q6LTD1, Q6PF21, Q6PI48, Q7MUD3, Q7ZX51, Q8BIP0, Q8BMJ2, Q8BML9

Diamond homologs: A0B7B7, A1RTX9, A3DKS1, A3MU00, A4FYA3, A4WHK6, A4YE96, A4YI28, A6USJ5, A6UTK3, A6VK04, A8A8T2, B1YAS9, B6YST9, F4I116, O27552, O30250, O33768, O58698, O67411, P26637, P58176, P61760, Q09996, Q12WA2, Q46AW0, Q47IN0, Q4J8J7, Q4JBP0, Q58050, Q5R614, Q6LZD2, Q8BMJ2, Q8NKR7, Q8Q054, Q8TQD3, Q8TVM4, Q8U2E6, Q8ZXT6, Q970Z6

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
ATF4	“up-regulates quantity by expression”	LARS1	“transcriptional regulation”
LARS1	“form complex”	“Multiaminoacyl-tRNA synthetase”	binding
LRRK2	“down-regulates activity”	LARS1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 154 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
mTORC1-mediated signalling	5	22.4×	2e-04
Energy dependent regulation of mTOR by LKB1-AMPK	6	22.3×	3e-05
Cytosolic tRNA aminoacylation	5	20.7×	2e-04
PTEN Regulation	7	15.1×	4e-05
MTOR signalling	6	15.0×	2e-04
tRNA Aminoacylation	5	13.5×	1e-03
Selenoamino acid metabolism	7	13.0×	9e-05
Autophagy	9	12.6×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to amino acid stimulus	6	14.1×	2e-03
lipid transport	6	12.2×	2e-03
negative regulation of autophagy	6	12.0×	2e-03
cellular response to starvation	6	8.9×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

606 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	14
Uncertain significance	210
Likely benign	176
Benign	126

Top pathogenic / likely-pathogenic (28)

Variant ID	HGVS	Classification
1048520	NM_020117.11(LARS1):c.2504A>G (p.Tyr835Cys)	Pathogenic
1939971	NM_020117.11(LARS1):c.727A>T (p.Lys243Ter)	Pathogenic
214578	NM_020117.11(LARS1):c.137_141del (p.Tyr46fs)	Pathogenic
214579	NM_020117.11(LARS1):c.84_85del (p.Arg28fs)	Pathogenic
2533694	NM_020117.11(LARS1):c.1237C>T (p.Arg413Ter)	Pathogenic
2803844	NM_020117.11(LARS1):c.11_12del (p.Arg4fs)	Pathogenic
3117894	NM_020117.11(LARS1):c.2500A>T (p.Lys834Ter)	Pathogenic
3699253	NM_020117.11(LARS1):c.2383dup (p.Arg795fs)	Pathogenic
4688932	NM_020117.11(LARS1):c.1812del (p.Phe603_Tyr604insTer)	Pathogenic
4712611	NM_020117.11(LARS1):c.900del (p.Phe300fs)	Pathogenic
4734755	NM_020117.11(LARS1):c.904C>T (p.Gln302Ter)	Pathogenic
4736046	NM_020117.11(LARS1):c.2342G>A (p.Trp781Ter)	Pathogenic
4738075	NM_020117.11(LARS1):c.1621A>T (p.Lys541Ter)	Pathogenic
65476	NM_020117.11(LARS1):c.1118A>G (p.Tyr373Cys)	Pathogenic
1702695	NM_020117.11(LARS1):c.2889del (p.Asn963fs)	Likely pathogenic
1722447	NM_020117.11(LARS1):c.661C>T (p.Gln221Ter)	Likely pathogenic
1723363	NM_020117.11(LARS1):c.1755G>A (p.Trp585Ter)	Likely pathogenic
1912446	NM_020117.11(LARS1):c.771+2T>G	Likely pathogenic
2505884	NM_020117.11(LARS1):c.2391dup (p.Ala798fs)	Likely pathogenic
2690634	NM_020117.11(LARS1):c.2781del (p.Lys927fs)	Likely pathogenic
2824624	NM_020117.11(LARS1):c.1738+1G>A	Likely pathogenic
3362591	NM_020117.11(LARS1):c.3325+1del	Likely pathogenic
3385080	NM_020117.11(LARS1):c.743G>T (p.Cys248Phe)	Likely pathogenic
388496	NM_020117.11(LARS1):c.1306G>A (p.Gly436Ser)	Likely pathogenic
388497	NM_020117.11(LARS1):c.3064G>C (p.Glu1022Gln)	Likely pathogenic
3896649	NM_020117.11(LARS1):c.1351A>T (p.Ile451Phe)	Likely pathogenic
418282	NM_020117.11(LARS1):c.2816A>G (p.Tyr939Cys)	Likely pathogenic
432995	NM_020117.11(LARS1):c.725C>T (p.Pro242Leu)	Likely pathogenic

SpliceAI

4194 predictions. Top by Δscore:

Variant	Effect	Δscore
5:146114311:TCT:T	acceptor_loss	1.0000
5:146114312:C:CC	acceptor_gain	1.0000
5:146114312:CTA:C	acceptor_loss	1.0000
5:146114313:T:C	acceptor_loss	1.0000
5:146120366:CTTA:C	donor_loss	1.0000
5:146120367:TTAC:T	donor_loss	1.0000
5:146120368:TACCT:T	donor_loss	1.0000
5:146120369:A:C	donor_loss	1.0000
5:146120370:C:CG	donor_loss	1.0000
5:146120499:CCAGG:C	acceptor_gain	1.0000
5:146120500:CAGG:C	acceptor_gain	1.0000
5:146120500:CAGGC:C	acceptor_gain	1.0000
5:146120501:AGG:A	acceptor_gain	1.0000
5:146120501:AGGCT:A	acceptor_loss	1.0000
5:146120502:GG:G	acceptor_gain	1.0000
5:146120504:C:CC	acceptor_gain	1.0000
5:146120504:CTAGG:C	acceptor_loss	1.0000
5:146122490:A:AC	donor_gain	1.0000
5:146122491:C:CC	donor_gain	1.0000
5:146122491:CTT:C	donor_gain	1.0000
5:146122491:CTTCT:C	donor_gain	1.0000
5:146122536:C:A	donor_gain	1.0000
5:146122584:CTAG:C	acceptor_gain	1.0000
5:146122585:TAG:T	acceptor_gain	1.0000
5:146122588:C:CC	acceptor_gain	1.0000
5:146123976:TCTTA:T	donor_loss	1.0000
5:146123977:CTTAC:C	donor_loss	1.0000
5:146123978:TTAC:T	donor_loss	1.0000
5:146123979:TACCT:T	donor_loss	1.0000
5:146123980:A:AG	donor_loss	1.0000

AlphaMissense

7803 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:146133040:C:G	D752H	0.999
5:146135656:T:A	K719N	0.999
5:146135656:T:G	K719N	0.999
5:146135658:T:C	K719E	0.999
5:146135663:A:G	M717T	0.999
5:146140229:C:T	G708E	0.999
5:146142932:A:G	L677P	0.999
5:146142936:C:G	D676H	0.999
5:146144272:C:T	G578D	0.999
5:146144640:C:G	A525P	0.999
5:146144647:A:C	C522W	0.999
5:146144662:C:A	R517S	0.999
5:146144662:C:G	R517S	0.999
5:146144663:C:A	R517M	0.999
5:146144663:C:G	R517T	0.999
5:146153791:A:C	S391R	0.999
5:146153791:A:T	S391R	0.999
5:146153793:T:G	S391R	0.999
5:146159419:T:A	R253S	0.999
5:146159419:T:G	R253S	0.999
5:146159425:A:C	H251Q	0.999
5:146159425:A:T	H251Q	0.999
5:146159427:G:C	H251D	0.999
5:146159434:G:C	C248W	0.999
5:146172715:C:T	G62E	0.999
5:146172722:G:C	H60D	0.999
5:146172732:A:C	N56K	0.999
5:146172732:A:T	N56K	0.999
5:146128713:A:G	W947R	0.998
5:146128713:A:T	W947R	0.998

dbSNP variants (sampled 300 via entrez): RS1000036306 (5:146146812 C>A,G), RS1000098401 (5:146153725 G>A,C,T), RS1000156708 (5:146180216 T>C), RS1000242695 (5:146126913 T>C,G), RS1000248293 (5:146160116 GTATT>G), RS1000288827 (5:146147596 A>G), RS1000314081 (5:146176364 A>G), RS1000346860 (5:146176971 A>C,T), RS1000378021 (5:146132320 G>A), RS1000380555 (5:146134435 T>C), RS1000385765 (5:146181858 T>C), RS1000459013 (5:146183206 T>A), RS1000486485 (5:146140862 C>T), RS1000487441 (5:146128389 A>G,T), RS1000549273 (5:146146255 C>A,T)

Disease associations

OMIM: gene MIM:151350 | disease phenotypes: MIM:615438, MIM:613070

GenCC curated gene-disease

Disease	Classification	Inheritance
infantile liver failure syndrome 1	Strong	Autosomal recessive

Mondo (4): infantile liver failure syndrome 1 (MONDO:0024568), acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins (MONDO:0013111), microcephaly (MONDO:0001149), sensorineural hearing loss disorder (MONDO:0020678)

Orphanet (2): Acute infantile liver failure-multisystemic involvement syndrome (Orphanet:370088), Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins (Orphanet:217371)

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000293	Full cheeks
HP:0000407	Sensorineural hearing impairment
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001397	Hepatic steatosis
HP:0001508	Failure to thrive
HP:0001903	Anemia
HP:0001972	Macrocytic anemia
HP:0002007	Frontal bossing
HP:0002194	Delayed gross motor development
HP:0002240	Hepatomegaly
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003128	Lactic acidosis
HP:0003256	Abnormality of the coagulation cascade
HP:0006554	Acute hepatic failure
HP:0010511	Long toe
HP:0100807	Long fingers

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3258 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

28 potent at pChembl≥5 of 42 total, top 28 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.80	IC50	1.6	nM	CHEMBL340082
8.22	IC50	6	nM	CHEMBL341331
7.80	IC50	16	nM	CHEMBL421500
7.65	IC50	22.34	nM	LEUSA
7.48	IC50	33	nM	CHEMBL4174152
7.16	IC50	70.04	nM	CHEMBL4558130
6.80	IC50	160	nM	CHEMBL4163450
6.66	IC50	220	nM	CHEMBL4171458
6.58	Kd	264.8	nM	CHEMBL5653589
6.58	ED50	264.8	nM	CHEMBL5653589
6.47	IC50	337.1	nM	CHEMBL4104169
6.31	IC50	490	nM	CHEMBL4172643
6.22	IC50	600	nM	CHEMBL340082
6.14	IC50	730	nM	CHEMBL332104
6.07	IC50	850	nM	CHEMBL4159778
6.00	IC50	1000	nM	CHEMBL264002
5.96	IC50	1100	nM	CHEMBL4160841
5.94	IC50	1150	nM	CHEMBL341331
5.92	IC50	1200	nM	CHEMBL4163140
5.88	IC50	1310	nM	CHEMBL45426
5.81	IC50	1550	nM	CHEMBL74395
5.70	IC50	2000	nM	CHEMBL4167692
5.64	IC50	2300	nM	CHEMBL74755
5.47	IC50	3400	nM	CHEMBL4171058
5.41	IC50	3900	nM	CHEMBL4161986
5.35	IC50	4500	nM	CHEMBL4174897
5.33	Kd	4627	nM	CHEMBL3752910
5.33	ED50	4627	nM	CHEMBL3752910

PubChem BioAssay actives

27 with measured affinity, of 177 total; 24 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
[(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(4-phenoxyphenyl)-1,3-thiazol-2-yl]oxolan-2-yl]methyl N-[(2S)-2-amino-4-methylpentanoyl]sulfamate	101350: Compound tested for the inhibition of Escherichia coli Leucyl-tRNA synthetase	ic50	0.0016	uM
[(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(2-phenylethyl)-1,3-thiazol-2-yl]oxolan-2-yl]methyl N-[(2S)-2-amino-4-methylpentanoyl]sulfamate	101350: Compound tested for the inhibition of Escherichia coli Leucyl-tRNA synthetase	ic50	0.0020	uM
[(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-[2-(4-phenoxyphenyl)ethyl]-1,3-thiazol-2-yl]oxolan-2-yl]methyl N-[(2S)-2-amino-4-methylpentanoyl]sulfamate	101350: Compound tested for the inhibition of Escherichia coli Leucyl-tRNA synthetase	ic50	0.0060	uM
(4aR,6S,7R,7aS)-7-[[2-[[(2S)-2-amino-4-methylpentanoyl]sulfamoyl]acetyl]amino]-4-carbamoyl-6-hydroxy-2-methyl-4a,5,6,7a-tetrahydro-1H-cyclopenta[c]pyridine-7-carboxylic acid	101353: Compound was evaluated for its inhibitory activity against Leucyl-tRNA synthetase from staphylococcus aureus WCUH29	ic50	0.0160	uM
[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl N-[(2S)-2-amino-4-methylpentanoyl]sulfamate	1686658: Inhibition of catalytic activity of LRS (unknown origin) by aminoleucylation assay	ic50	0.0223	uM
(2S)-2-amino-N-[3-(2-amino-6-phenylpyrimidin-4-yl)phenyl]sulfonyl-4-methylpentanamide	1350198: Inhibition of human LeuRS assessed as reduction in ATP consumption	ic50	0.0330	uM
[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl N-[(2S,3R)-2,3-dihydroxy-4-methylpentanoyl]sulfamate	1686658: Inhibition of catalytic activity of LRS (unknown origin) by aminoleucylation assay	ic50	0.0700	uM
(2S)-2-amino-N-[3-(2-amino-6-methylpyrimidin-4-yl)phenyl]sulfonyl-4-methylpentanamide	1350198: Inhibition of human LeuRS assessed as reduction in ATP consumption	ic50	0.1600	uM
(2S)-2-amino-4-methyl-N-naphthalen-2-ylsulfonylpentanamide	1350198: Inhibition of human LeuRS assessed as reduction in ATP consumption	ic50	0.2200	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148639: Binding affinity to human LARS incubated for 45 mins by Kinobead based pull down assay	kd	0.2648	uM
[(2R,3S,4R,5R)-5-(6-amino-2-iodopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl N-[(2S)-2-hydroxy-4-methylpentanoyl]sulfamate	1686658: Inhibition of catalytic activity of LRS (unknown origin) by aminoleucylation assay	ic50	0.3371	uM
(2S)-2-amino-N-[3-(2-amino-4-pyridinyl)phenyl]sulfonyl-4-methylpentanamide	1350198: Inhibition of human LeuRS assessed as reduction in ATP consumption	ic50	0.4900	uM
(2S)-2-amino-N-[3-(6-amino-2-pyridinyl)phenyl]sulfonyl-4-methylpentanamide	1350198: Inhibition of human LeuRS assessed as reduction in ATP consumption	ic50	0.8500	uM
[(2R,3S,4R,5R)-3,4-dihydroxy-5-(4-phenyl-1,3-thiazol-2-yl)oxolan-2-yl]methyl N-[(2S,3S)-2-amino-3-methylpentanoyl]sulfamate	101350: Compound tested for the inhibition of Escherichia coli Leucyl-tRNA synthetase	ic50	1.0000	uM
(2S)-2-amino-N-(benzenesulfonyl)-4-methylpentanamide	1350198: Inhibition of human LeuRS assessed as reduction in ATP consumption	ic50	1.1000	uM
(2S)-2-amino-4-methyl-N-(3-pyridin-4-ylphenyl)sulfonylpentanamide	1350198: Inhibition of human LeuRS assessed as reduction in ATP consumption	ic50	1.2000	uM
1-[5-[4-(4-chlorophenyl)phenoxy]pentyl]-3-pyridin-4-ylimidazolidin-2-one	255776: Inhibitory activity against Echovirus 9 using plaque reduction assay	ic50	1.3100	uM
(4aR,6S,7R,7aS)-7-[[2-[[(2S,3S)-2-amino-3-methylpentanoyl]sulfamoyl]acetyl]amino]-4-carbamoyl-6-hydroxy-2-methyl-4a,5,6,7a-tetrahydro-1H-cyclopenta[c]pyridine-7-carboxylic acid	101353: Compound was evaluated for its inhibitory activity against Leucyl-tRNA synthetase from staphylococcus aureus WCUH29	ic50	1.5500	uM
(2S)-2-amino-4-methyl-N-[3-(6-methylpyrimidin-4-yl)phenyl]sulfonylpentanamide	1350198: Inhibition of human LeuRS assessed as reduction in ATP consumption	ic50	2.0000	uM
(4aR,6S,7R,7aS)-7-[[2-[[(2S)-2-amino-3-methylbutanoyl]sulfamoyl]acetyl]amino]-4-carbamoyl-6-hydroxy-2-methyl-4a,5,6,7a-tetrahydro-1H-cyclopenta[c]pyridine-7-carboxylic acid	101353: Compound was evaluated for its inhibitory activity against Leucyl-tRNA synthetase from staphylococcus aureus WCUH29	ic50	2.3000	uM
(2S)-2-amino-4-methyl-N-(3-phenylphenyl)sulfonylpentanamide	1350198: Inhibition of human LeuRS assessed as reduction in ATP consumption	ic50	3.4000	uM
(2S)-2-amino-N-[3-(2-aminopyrimidin-4-yl)phenyl]sulfonyl-4-methylpentanamide	1350198: Inhibition of human LeuRS assessed as reduction in ATP consumption	ic50	3.9000	uM
(2S)-2-amino-N-[3-[[2-(4-bromo-2-chlorophenoxy)acetyl]carbamothioylamino]phenyl]sulfonyl-4-methylpentanamide	1350210: Inhibition of human cytoplasmic LeuRS assessed as reduction in protein synthesis measured after 10 mins in presence of [3H]Leu by scintillation counting method	ic50	4.5000	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148639: Binding affinity to human LARS incubated for 45 mins by Kinobead based pull down assay	kd	4.6274	uM

CTD chemical–gene interactions

55 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	4
Cyclosporine	increases expression	4
bisphenol A	decreases expression, affects expression	3
trichostatin A	affects cotreatment, decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	2
Tetrachlorodibenzodioxin	decreases expression	2
Tretinoin	decreases expression	2
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
geldanamycin	increases expression	1
chloroacetaldehyde	decreases expression	1
methylmercuric chloride	decreases expression	1
pyrogallol 1,3-dimethyl ether	decreases expression, increases expression, affects cotreatment, affects localization	1
arsenite	affects binding, decreases reaction	1
2-bromopalmitate	increases abundance, increases palmitoylation, decreases reaction	1
ochratoxin A	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
nutlin 3	affects cotreatment, increases secretion	1
torcetrapib	increases expression	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	increases expression	1

ChEMBL screening assays

35 unique, capped per target: 32 binding, 2 admet, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3769291	Binding	Inhibition of human leucyl-tRNA synthetase assessed as reduction of [14C]-L-leucine ligation to tRNA incubated for 5 mins by scintillation counting method in presence of ATP	Discovery of potent anti-tuberculosis agents targeting leucyl-tRNA synthetase. — Bioorg Med Chem
CHEMBL4020313	ADMET	Inhibition of human N-terminal 6His-tagged cytoplasmic LeuRS expressed in Escherichia coli BL21(DE3) assessed as L-[14C]leucine incorporation in to Escherichia coli tRNA after 20 mins by liquid scintillation counting analysis	Discovery of a Potent and Specific M. tuberculosis Leucyl-tRNA Synthetase Inhibitor: (S)-3-(Aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol (GSK656). — J Med Chem
CHEMBL885012	Functional	Inhibitory activity against Echovirus 9 using plaque reduction assay	Synthesis and antipicornavirus activity of (R)- and (S)-1-[5-(4’-chlorobiphenyl-4-yloxy)-3-methylpentyl]-3-pyridin-4-yl-imidazolidin-2-one. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

107 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01655212	PHASE3	TERMINATED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment in a Randomized Controlled Trial
NCT02005822	PHASE3	COMPLETED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment
NCT03374514	PHASE3	UNKNOWN	Cochlear Electrical Impedance and the Effect of Topical Dexamethasone on Cochlear Implant Surgery
NCT02497690	PHASE2	COMPLETED	Effectiveness of Therapy Via Telemedicine Following Cochlear Implants
NCT03107871	PHASE2	ACTIVE_NOT_RECRUITING	Randomized Controlled Trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants
NCT04120116	PHASE2	COMPLETED	FX-322 in Adults With Stable Sensorineural Hearing Loss
NCT05061758	PHASE2	WITHDRAWN	A Trial of LY3056480 in Patients With SNLH
NCT07364747	PHASE2	RECRUITING	Protective Effect of Acetylcysteine Against Cisplatinum-Induced Ototoxicity: A Randomized Controlled Trial
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT05514470	Not specified	WITHDRAWN	Impact of Mutations in Aminoacyl tRNA Synthetases on Protein Translation and Cellular Stress
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.
NCT02693704	PHASE2/PHASE3	COMPLETED	Evaluation of a Binaural Spatialization Method for Hearing Aids
NCT02882477	PHASE2/PHASE3	UNKNOWN	Treatment of Wolfram Syndrome Type 2 With the Chelator Deferiprone and Incretin Based Therapy
NCT01267994	PHASE1/PHASE2	COMPLETED	A Clinical Trial of Anakinra for Steroid-Resistant Autoimmune Inner Ear Disease
NCT01902914	PHASE1/PHASE2	UNKNOWN	Effectiveness of P02 Digital Hearing Aids
NCT02038972	PHASE1/PHASE2	COMPLETED	Safety of Autologous Stem Cell Infusion for Children With Acquired Hearing Loss
NCT02616172	PHASE1/PHASE2	SUSPENDED	Autologous Bone Marrow Harvest and Transplant for Sensorineural Hearing Loss
NCT03616223	PHASE1/PHASE2	COMPLETED	FX-322 in Sensorineural Hearing Loss
NCT04129775	PHASE1/PHASE2	COMPLETED	OTO-413 in Subjects With Speech-in-Noise Hearing Impairment
NCT04462198	PHASE1/PHASE2	COMPLETED	Phase I/IIa Study Evaluating Safety and Efficacy of an Intratympanic Dose of PIPE-505 in Subjects With Hearing Loss
NCT07032038	PHASE1/PHASE2	NOT_YET_RECRUITING	First In Human Randomised Trial of Rincell-1 in Adults With a Cochlear Implant
NCT06025097	EARLY_PHASE1	COMPLETED	Intra-Tympanic Steroid With PRP Combination in Sensorineural Hearing Loss and Tinnitus.
NCT06707389	EARLY_PHASE1	NOT_YET_RECRUITING	Autologous Blood Monocyte Vesicles for the Treatment of Sudden Deafness
NCT07472023	EARLY_PHASE1	ENROLLING_BY_INVITATION	Regenerative Medicine and Stem Cell-Based Interventions for Inner Ear Trauma, Tinnitus, and Sensorineural Hearing Loss