MARS1

Summary

MARS1 (methionyl-tRNA synthetase 1, HGNC:6898) is a protein-coding gene on chromosome 12q13.3, encoding Methionine–tRNA ligase, cytoplasmic (P56192). Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA. It is a common-essential gene (DepMap: required in 99.3% of cancer cell lines).

This gene encodes a member of the class I family of aminoacyl-tRNA synthetases. These enzymes play a critical role in protein biosynthesis by charging tRNAs with their cognate amino acids. The encoded protein is a component of the multi-tRNA synthetase complex and catalyzes the ligation of methionine to tRNA molecules.

Source: NCBI Gene 4141 — RefSeq curated summary.

At a glance

• Gene–disease (curated): severe early-onset pulmonary alveolar proteinosis due to MARS deficiency (Strong, GenCC) — +6 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 919 total — 5 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 88
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.3% of screened cell lines (common-essential)
• MANE Select transcript: NM_004990

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6898
Approved symbol	MARS1
Name	methionyl-tRNA synthetase 1
Location	12q13.3
Locus type	gene with protein product
Status	Approved
Aliases	MetRS, SPG70, CMT2U
Ensembl gene	ENSG00000166986
Ensembl biotype	protein_coding
OMIM	156560
Entrez	4141

Gene structure

Transcript identifiers

Ensembl transcripts: 50 — 23 protein_coding, 14 retained_intron, 9 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined

ENST00000262027, ENST00000447721, ENST00000537638, ENST00000545888, ENST00000546481, ENST00000546971, ENST00000547062, ENST00000547501, ENST00000547665, ENST00000548146, ENST00000548202, ENST00000548630, ENST00000548674, ENST00000548714, ENST00000548944, ENST00000549048, ENST00000549074, ENST00000549133, ENST00000549603, ENST00000549827, ENST00000550449, ENST00000551172, ENST00000551431, ENST00000551805, ENST00000551842, ENST00000551892, ENST00000552007, ENST00000552371, ENST00000552499, ENST00000552914, ENST00000553123, ENST00000553162, ENST00000628866, ENST00000630571, ENST00000630803, ENST00000906525, ENST00000906526, ENST00000906527, ENST00000906528, ENST00000906529, ENST00000906530, ENST00000916094, ENST00000916095, ENST00000916096, ENST00000916097, ENST00000916098, ENST00000916099, ENST00000948582, ENST00000948583, ENST00000948584

RefSeq mRNA: 1 — MANE Select: NM_004990 NM_004990

CCDS: CCDS8942

Canonical transcript exons

ENST00000262027 — 21 exons

Exon	Start	End
ENSE00002353576	57516435	57516652
ENSE00003461370	57511698	57511868
ENSE00003497578	57515150	57515336
ENSE00003501560	57504225	57504299
ENSE00003503946	57512236	57512353
ENSE00003523871	57498420	57498623
ENSE00003532153	57489424	57489558
ENSE00003541791	57498157	57498273
ENSE00003546218	57514720	57514851
ENSE00003569699	57490207	57490379
ENSE00003605383	57512751	57512964
ENSE00003607148	57516245	57516337
ENSE00003624041	57512008	57512103
ENSE00003638435	57489267	57489345
ENSE00003669103	57489019	57489109
ENSE00003674894	57500321	57500522
ENSE00003678729	57488068	57488199
ENSE00003685228	57514954	57515058
ENSE00003685325	57489896	57489971
ENSE00003691729	57490538	57490644
ENSE00003694440	57515920	57515991

Expression profiles

Bgee: expression breadth ubiquitous, 301 present calls, max score 98.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 79.2989 / max 591.6933, expressed in 1824 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
126226	73.0242	1823
126227	5.8598	1679
126233	0.1662	41
126228	0.0788	19
126221	0.0691	32
126229	0.0607	16
126234	0.0402	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	98.82	gold quality
cerebellar hemisphere	UBERON:0002245	98.66	gold quality
cerebellar cortex	UBERON:0002129	98.61	gold quality
adenohypophysis	UBERON:0002196	98.57	gold quality
pituitary gland	UBERON:0000007	98.32	gold quality
right frontal lobe	UBERON:0002810	98.06	gold quality
tendon of biceps brachii	UBERON:0008188	98.06	gold quality
cerebellum	UBERON:0002037	98.01	gold quality
granulocyte	CL:0000094	98.00	gold quality
colonic epithelium	UBERON:0000397	97.96	gold quality
lower esophagus mucosa	UBERON:0035834	97.74	gold quality
left lobe of thyroid gland	UBERON:0001120	97.71	gold quality
right lobe of thyroid gland	UBERON:0001119	97.64	gold quality
upper lobe of left lung	UBERON:0008952	97.63	gold quality
body of pancreas	UBERON:0001150	97.59	gold quality
stromal cell of endometrium	CL:0002255	97.54	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.38	gold quality
tonsil	UBERON:0002372	97.37	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	97.36	gold quality
spleen	UBERON:0002106	97.36	gold quality
thyroid gland	UBERON:0002046	97.33	gold quality
lower esophagus	UBERON:0013473	97.32	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.32	gold quality
upper lobe of lung	UBERON:0008948	97.30	gold quality
body of stomach	UBERON:0001161	97.26	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.25	gold quality
pancreas	UBERON:0001264	97.24	gold quality
islet of Langerhans	UBERON:0000006	97.15	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.14	gold quality
left testis	UBERON:0004533	97.07	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.3% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 15)

• The last 15 residues of the previously defined N-terminal extension of hcMetRS are part of the catalytic domain, whereas the first 252 residues constitute the N-terminal extended domain. (PMID:19064003)
• Data show that aminoacyl-tRNA synthetase-interacting multifunctional protein-3 (AIMP3)/p18 is released from aminoacyl-tRNA synthetase-interacting multifunctional protein-3 (AIMP3) by UV irradiation-induced stress. (PMID:22106287)
• Here we present data suggesting that MARS is a very rare novel cause of late-onset CMT2. (PMID:23729695)
• The F370L and I523T mutations did not affect the association of MARS with the multisynthetase complex. (PMID:24103465)
• the association of rare MARS variant with late-onset autosomal dominant Charcot-Marie-Tooth neuropathy (PMID:24354524)
• identification of a founder mutation in MARS led to the molecular definition of a specific type of pulmonary alveolar proteinosis and will enable carrier screening in the affected community and possibly open new treatment opportunities. (PMID:25913036)
• analysis of the heterotetrameric complex structure of the glutathione transferase (GST) domains shared among the four MSC components, methionyl-tRNA synthetase (MRS), glutaminyl-prolyl-tRNA synthetase (EPRS), AIMP2 and AIMP3 (PMID:26472928)
• Genotype-phenotype correlation analysis suggests most of the interstitial lung and liver disease (ILLD), mutations locate in the catalytic domain of MARS. ILLD and Charcot-Marie-Tooth disease, axonal, type 2U might have different disease mechanism. (PMID:28148924)
• MRS is frequently overexpressed in NSCLC. Moreover, MRS is related to mTORC1 activity and its overexpression is associated with poor clinical outcomes, indicating that it has potential as a putative therapeutic target. (PMID:28679377)
• Compound Arg618Cys and Tyr307Cys variants were identified in an infant with syndromic interstitial lung and liver disease. Arg618Cys associated with Charcot-Marie-Tooth disease was inherited from an unaffected father. (PMID:29655802)
• The results establish that the pulmonary alveolar proteinosis-related substitutions in MARS impact the tRNAMet-aminoacylation reaction especially at the level of methionine recognition. (PMID:29775242)
• MRS/CD45 dual IF staining showed good diagnostic performance and may be a good tool complementing conventional cytology test for determining lymph node metastasis of non-small cell lung cancer. (PMID:31637881)
• Protein instability associated with AARS1 and MARS1 mutations causes trichothiodystrophy. (PMID:33909043)
• Structural basis for the dynamics of human methionyl-tRNA synthetase in multi-tRNA synthetase complexes. (PMID:34086935)
• Deep phenotyping of MARS1 (interstitial lung and liver disease) and LARS1 (infantile liver failure syndrome 1) recessive multisystemic disease using Human Phenotype Ontology annotation: Overlap and differences. Case report and review of literature. (PMID:34496286)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mars1	ENSDARG00000034396
mus_musculus	Mars1	ENSMUSG00000040354
rattus_norvegicus	Mars1	ENSRNOG00000025459
drosophila_melanogaster	MetRS	FBGN0034401
caenorhabditis_elegans		WBGENE00003415

Paralogs (7): LARS2 (ENSG00000011376), IARS2 (ENSG00000067704), LARS1 (ENSG00000133706), VARS2 (ENSG00000137411), IARS1 (ENSG00000196305), VARS1 (ENSG00000204394), MARS2 (ENSG00000247626)

Protein

Protein identifiers

Methionine–tRNA ligase, cytoplasmic — P56192 (reviewed: P56192)

Alternative names: Methionyl-tRNA synthetase

All UniProt accessions (13): P56192, F5H2V6, F8VPL7, F8VS26, F8VZZ9, F8W0M7, F8W0S4, H0YHL6, H0YHV5, H0YI27, H0YI94, H0YIC2, H0YIP0

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA. Plays a role in the synthesis of ribosomal RNA in the nucleolus.

Subunit / interactions. Monomer. Part of a multisubunit complex that groups 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 (PubMed:19131329, PubMed:19289464, PubMed:26472928, Ref.26). Forms a linear complex that contains MARS1, EEF1E1, EPRS1 and AIMP2 that is at the core of the multisubunit complex.

Subcellular location. Cytoplasm. Cytosol. Nucleus. Nucleolus.

Disease relevance. Interstitial lung and liver disease (ILLD) [MIM:615486] An autosomal recessive, life-threatening disorder characterized by respiratory insufficiency and progressive liver disease with onset in infancy or early childhood. Clinical features include failure to thrive, hypotonia, intermittent lactic acidosis, aminoaciduria, hypothyroidism, interstitial lung disease, pulmonary alveolar proteinosis, anemia, and liver canalicular cholestasis, steatosis, and iron deposition. The disease is caused by variants affecting the gene represented in this entry. Charcot-Marie-Tooth disease, axonal, type 2U (CMT2U) [MIM:616280] An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. CMT2U is a slowly progressive, autosomal dominant form characterized by late-adult onset. The disease is caused by variants affecting the gene represented in this entry. Trichothiodystrophy 9, non-photosensitive (TTD9) [MIM:619692] A form of trichothiodystrophy, a disease characterized by sulfur-deficient brittle hair and multisystem variable abnormalities. The spectrum of clinical features varies from mild disease with only hair involvement to severe disease with cutaneous, neurologic and profound developmental defects. Ichthyosis, intellectual and developmental disabilities, decreased fertility, abnormal characteristics at birth, ocular abnormalities, short stature, and infections are common manifestations. There are both photosensitive and non-photosensitive forms of the disorder. TTD9 is an autosomal recessive, non-photosensitive form characterized by brittle hair and nails, scaly skin, accompanied by failure to thrive, microcephaly, and neuromotor developmental delay. The disease may be caused by variants affecting the gene represented in this entry. Spastic paraplegia 70, autosomal recessive (SPG70) [MIM:620323] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG70 features may also include global developmental delay with variably impaired intellectual development, speech delay, feeding difficulties, and dysmorphic facial features. SPG70 is characterized by onset of symptoms in infancy. The disease may be caused by variants affecting the gene represented in this entry.

Activity regulation. Enzyme activity is increased by spermidine, EEF1A1, and when the Mg(2+) concentration is increased from 5 mM to 13 mM (in vitro), possibly by promoting the dissociation of the complex between the enzyme and its product.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P56192-1	1	yes
P56192-2	2

RefSeq proteins (1): NP_004981* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000738	WHEP-TRS_dom	Domain
IPR001412	aa-tRNA-synth_I_CS	Conserved_site
IPR004046	GST_C	Domain
IPR009068	uS15_NS1_RNA-bd_sf	Homologous_superfamily
IPR009080	tRNAsynth_Ia_anticodon-bd	Homologous_superfamily
IPR010987	Glutathione-S-Trfase_C-like	Domain
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR014758	Met-tRNA_synth	Family
IPR015413	Methionyl/Leucyl_tRNA_Synth	Domain
IPR023458	Met-tRNA_ligase_1	Family
IPR029038	MetRS_Zn	Homologous_superfamily
IPR033911	MetRS_core	Domain
IPR036282	Glutathione-S-Trfase_C_sf	Homologous_superfamily
IPR041598	MARS_N	Domain
IPR041872	Anticodon_Met	Domain

Pfam: PF00043, PF00458, PF09334, PF18485, PF19303

Enzyme classification (BRENDA):

• EC 6.1.1.10 — methionine-tRNA ligase (BRENDA: 44 organisms, 96 substrates, 374 inhibitors, 197 Km, 123 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
TRNAMET	0.0001–1	62
ATP	0.029–58	52
L-METHIONINE	0.0003–58	47
MET	0.005–0.078	7
L-MET	0.027–0.26	4
L-METHIONYL-TRNAMET	0.003–0.0418	3
BETA3-METHIONINE	0.56–1.2	2
COA	1.2–6.3	2
L-HOMOCYSTEINE	1.8–3.1	2
NORLEUCINE	0.383–28.6	2
SELENOMETHIONINE	0.038–0.31	2
TRNA FRACTION FROM SACCHAROMYCES CEREVISIAE	0.0007–0.0008	2
(S)-2-AMINOHEX-5-ENOIC ACID	15.68	1
(S)-2-AMINOHEX-5-YNOIC ACID	2.42	1
L-NORLEUCINE	4.12	1

Catalyzed reactions (Rhea), 1 shown:

• tRNA(Met) + L-methionine + ATP = L-methionyl-tRNA(Met) + AMP + diphosphate (RHEA:13481)

UniProt features (119 total): helix 44, strand 22, sequence variant 16, turn 14, mutagenesis site 7, sequence conflict 6, domain 2, short sequence motif 2, modified residue 2, splice variant 2, chain 1, binding site 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
4BVX	X-RAY DIFFRACTION	1.6
4BL7	X-RAY DIFFRACTION	1.89
4BVY	X-RAY DIFFRACTION	1.99
5GL7	X-RAY DIFFRACTION	2.01
5GOY	X-RAY DIFFRACTION	2.28
5Y6L	X-RAY DIFFRACTION	2.9
2DJV	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P56192-F1	90.61	0.75

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 (1): 596

Post-translational modifications (2): 825, 835

Mutagenesis-validated functional residues (7):

Position	Phenotype
64	loss of interaction with eef1e1.
86	loss of interaction with eef1e1.
857	no effect on enzyme activity.
860	strongly decreased affinity for trna.
863	slightly decreased enzyme activity.
866	slightly decreased enzyme activity.
880	strongly decreased affinity for trna.

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: 396 (showing top): GOBP_AMINO_ACID_ACTIVATION, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GOBP_TRNA_METABOLIC_PROCESS, SHAFFER_IRF4_TARGETS_IN_ACTIVATED_B_LYMPHOCYTE, AACYNNNNTTCCS_UNKNOWN, MORF_HDAC2, GOBP_RESPONSE_TO_EPIDERMAL_GROWTH_FACTOR, GOBP_RRNA_TRANSCRIPTION, GOBP_TRANSLATION, KOKKINAKIS_METHIONINE_DEPRIVATION_96HR_UP, LI_WILMS_TUMOR_VS_FETAL_KIDNEY_1_DN, GOBP_RESPONSE_TO_PLATELET_DERIVED_GROWTH_FACTOR, KOKKINAKIS_METHIONINE_DEPRIVATION_48HR_UP, MORF_RFC4, MORF_PRKDC

GO Biological Process (7): tRNA aminoacylation for protein translation (GO:0006418), methionyl-tRNA aminoacylation (GO:0006431), rRNA transcription (GO:0009303), cellular response to platelet-derived growth factor stimulus (GO:0036120), cellular response to epidermal growth factor stimulus (GO:0071364), positive regulation of transcription of nucleolar large rRNA by RNA polymerase I (GO:1901838), translation (GO:0006412)

GO Molecular Function (7): tRNA binding (GO:0000049), methionine-tRNA ligase activity (GO:0004825), ATP binding (GO:0005524), nucleotide binding (GO:0000166), RNA binding (GO:0003723), aminoacyl-tRNA ligase activity (GO:0004812), ligase activity (GO:0016874)

GO Cellular Component (10): nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), aminoacyl-tRNA synthetase multienzyme complex (GO:0017101), extracellular exosome (GO:0070062), sperm midpiece (GO:0097225), sperm principal piece (GO:0097228), sperm end piece (GO:0097229), nucleus (GO:0005634)

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	6
sperm flagellum	3
cellular response to growth factor stimulus	2
translation	1
tRNA aminoacylation	1
tRNA aminoacylation for protein translation	1
DNA-templated transcription	1
rRNA metabolic process	1
response to platelet-derived growth factor	1
response to epidermal growth factor	1
nucleolar large rRNA transcription by RNA polymerase I	1
positive regulation of transcription by RNA polymerase I	1
regulation of transcription of nucleolar large rRNA by RNA polymerase I	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
RNA binding	1
aminoacyl-tRNA ligase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
nucleic acid binding	1
ligase activity, forming carbon-oxygen bonds	1
catalytic activity, acting on a tRNA	1
catalytic activity	1
nuclear lumen	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
cytoplasm	1
intracellular protein-containing complex	1
catalytic complex	1
extracellular vesicle	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

5114 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MARS1	IARS1	P41252	996
MARS1	IARS2	Q9NSE4	994
MARS1	LARS1	Q9P2J5	993
MARS1	KARS1	Q15046	991
MARS1	EPRS1	P07814	990
MARS1	LARS2	Q15031	988
MARS1	QARS1	P47897	987
MARS1	EEF1E1	O43324	981
MARS1	RARS2	Q5T160	955
MARS1	EARS2	Q5JPH6	953
MARS1	RARS1	P54136	942
MARS1	YARS1	P54577	908
MARS1	YARS2	Q9Y2Z4	904
MARS1	AIMP2	Q13155	891
MARS1	PARS2	Q7L3T8	880

IntAct

174 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
QARS1	EEF1E1	psi-mi:“MI:0914”(association)	0.530
GATA2	BANF1	psi-mi:“MI:0914”(association)	0.530
SDCBP	TARS3	psi-mi:“MI:0914”(association)	0.530
rep	MARS1	psi-mi:“MI:0915”(physical association)	0.490
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
CFTR	CNOT1	psi-mi:“MI:0914”(association)	0.480
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
gag	SDCBP	psi-mi:“MI:0914”(association)	0.460
OXER1	MARS1	psi-mi:“MI:0915”(physical association)	0.400
USH1C	MARS1	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
Hacd3	MARS1	psi-mi:“MI:0915”(physical association)	0.400
MARS1	PPP5C	psi-mi:“MI:0915”(physical association)	0.400
MARS1	EEF1E1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (439): MARS (Affinity Capture-MS), MARS (Affinity Capture-MS), MARS (Affinity Capture-MS), MARS (Affinity Capture-MS), MARS (Reconstituted Complex), MARS (Affinity Capture-MS), AIMP2 (Co-fractionation), EEA1 (Co-fractionation), EEF1E1 (Co-fractionation), EPRS (Co-fractionation), GARS (Co-fractionation), GFPT1 (Co-fractionation), HARS (Co-fractionation), IARS (Co-fractionation), KARS (Co-fractionation)

ESM2 similar proteins: A0JML8, A0JP70, A2BID5, A2CEI4, A6NNW6, A9JTS5, E7FAW3, F1QNV4, O75153, O75800, O95248, P0CI65, P56192, P97874, Q08CY4, Q0VC30, Q14689, Q17QN2, Q1LWH4, Q1LXZ7, Q29S07, Q2T9L8, Q32PH0, Q3B7U4, Q3U308, Q3UAW9, Q3UH60, Q3UY23, Q4R4F1, Q641Y9, Q68FL6, Q6DG91, Q6GPP1, Q6PJN8, Q6TEN6, Q6ZNJ1, Q6ZPE2, Q6ZQA0, Q7T006, Q8BWT5

Diamond homologs: A0M5Z9, A1B3P3, A1R019, A1RRE2, A1RXT9, A2BLU2, A3MVB7, A3PLG8, A4SE77, A4WKG3, A4WV24, A4YI01, A5FLM7, A5UUW9, A6GVQ2, A6KYR3, A6LFP0, A7NND5, A8ABN0, A8LIJ9, A8MA54, A8ZQ66, A9WKM1, B0B9D9, B0BB18, B0T3J0, B1L7J9, B1VFI1, B1YAZ7, B2RHF5, B2S0T6, B3ECI3, B3QT85, B4SGQ6, B5RME0, B5RPT6, B6YUN0, B7J2F0, B8G6F7, B8H5U4

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
EIF2AK4	down-regulates	MARS1	phosphorylation
MARS1	“form complex”	“Multiaminoacyl-tRNA synthetase”	binding
ERK1/2	“up-regulates activity”	MARS1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 159 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
Cytosolic tRNA aminoacylation	7	28.2×	1e-06
TRAF6 mediated NF-kB activation	5	20.9×	5e-04
tRNA Aminoacylation	7	18.3×	2e-05
Selenoamino acid metabolism	10	18.1×	1e-07
Transcriptional and post-translational regulation of MITF-M expression and activity	9	14.7×	2e-06
MyD88 cascade initiated on plasma membrane	5	9.3×	8e-03
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	5	8.7×	1e-02
MyD88 dependent cascade initiated on endosome	5	8.7×	1e-02

GO biological processes:

GO term	Partners	Fold	FDR
cytoplasmic translation	8	10.7×	9e-04
ribosomal small subunit biogenesis	6	9.9×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	3
Uncertain significance	519
Likely benign	306
Benign	15

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
1799839	NM_004990.4(MARS1):c.224G>A (p.Trp75Ter)	Pathogenic
1800104	NM_004990.4(MARS1):c.561_562del (p.Glu187fs)	Pathogenic
189365	NM_004990.4(MARS1):c.1814A>T (p.Asp605Val)	Pathogenic
2499490	NM_004990.4(MARS1):c.1166G>A (p.Cys389Tyr)	Pathogenic
989147	NM_004990.4(MARS1):c.2426del (p.Gln809fs)	Pathogenic
1172762	NM_004990.4(MARS1):c.1547A>G (p.Tyr516Cys)	Likely pathogenic
4845906	NM_004990.4(MARS1):c.1133_1134del (p.Phe378fs)	Likely pathogenic
496635	NM_004990.4(MARS1):c.920A>G (p.Tyr307Cys)	Likely pathogenic

SpliceAI

5236 predictions. Top by Δscore:

Variant	Effect	Δscore
12:57475481:A:AC	donor_gain	1.0000
12:57475482:C:CC	donor_gain	1.0000
12:57475633:C:CT	acceptor_gain	1.0000
12:57475639:G:T	acceptor_gain	1.0000
12:57475775:CCCCA:C	donor_gain	1.0000
12:57475782:C:CA	donor_gain	1.0000
12:57475808:C:A	donor_gain	1.0000
12:57475932:C:CC	acceptor_gain	1.0000
12:57475940:C:CT	acceptor_gain	1.0000
12:57476069:A:AC	donor_gain	1.0000
12:57476070:C:CC	donor_gain	1.0000
12:57476070:CGTG:C	donor_gain	1.0000
12:57476357:CA:C	donor_gain	1.0000
12:57476361:CA:C	donor_loss	1.0000
12:57476362:A:AC	donor_gain	1.0000
12:57476362:AC:A	donor_gain	1.0000
12:57476363:C:CC	donor_gain	1.0000
12:57476363:C:CG	donor_loss	1.0000
12:57476363:CC:C	donor_gain	1.0000
12:57476363:CCCAG:C	donor_gain	1.0000
12:57476366:AG:A	donor_gain	1.0000
12:57476451:CTTC:C	acceptor_gain	1.0000
12:57476453:TCC:T	acceptor_loss	1.0000
12:57476455:C:CC	acceptor_gain	1.0000
12:57476455:CTG:C	acceptor_loss	1.0000
12:57476456:T:A	acceptor_loss	1.0000
12:57477268:TTCTG:T	acceptor_loss	1.0000
12:57477270:C:CC	acceptor_gain	1.0000
12:57477275:T:C	acceptor_gain	1.0000
12:57477275:T:TC	acceptor_gain	1.0000

AlphaMissense

5854 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:57498224:C:G	H280D	1.000
12:57512261:A:T	K554I	1.000
12:57512262:A:C	K554N	1.000
12:57512262:A:T	K554N	1.000
12:57512263:G:C	D555H	1.000
12:57512264:A:C	D555A	1.000
12:57512264:A:T	D555V	1.000
12:57512783:A:G	K596E	1.000
12:57512785:G:C	K596N	1.000
12:57512785:G:T	K596N	1.000
12:57512799:G:A	G601E	1.000
12:57512804:T:C	F603L	1.000
12:57512806:T:A	F603L	1.000
12:57512806:T:G	F603L	1.000
12:57512900:T:A	W635R	1.000
12:57512900:T:C	W635R	1.000
12:57512951:A:G	N652D	1.000
12:57512953:C:A	N652K	1.000
12:57512953:C:G	N652K	1.000
12:57498194:A:C	S270R	0.999
12:57498196:T:A	S270R	0.999
12:57498196:T:G	S270R	0.999
12:57498214:C:A	N276K	0.999
12:57498214:C:G	N276K	0.999
12:57498224:C:A	H280N	0.999
12:57498226:C:A	H280Q	0.999
12:57498226:C:G	H280Q	0.999
12:57498228:T:A	L281H	0.999
12:57498231:G:A	G282E	0.999
12:57498231:G:T	G282V	0.999

dbSNP variants (sampled 300 via entrez): RS1000034386 (12:57486118 G>T), RS1000218817 (12:57515790 G>C), RS1000295897 (12:57486439 T>A), RS1000489410 (12:57486354 C>G), RS1000652256 (12:57505531 G>A,T), RS1000825893 (12:57514113 G>A,T), RS1000879140 (12:57492799 A>C), RS1000890264 (12:57512454 G>A), RS1000897394 (12:57508444 C>A,T), RS1000928325 (12:57508058 C>T), RS1000934741 (12:57505849 C>G), RS1001110998 (12:57514492 G>A,C), RS1001229351 (12:57506899 A>G), RS1001349667 (12:57503267 C>T), RS1001413696 (12:57492325 C>G,T)

Disease associations

OMIM: gene MIM:156560 | disease phenotypes: MIM:615486, MIM:616280, MIM:620323, MIM:619692, MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
severe early-onset pulmonary alveolar proteinosis due to MARS deficiency	Strong	Autosomal recessive
Charcot-Marie-Tooth disease axonal type 2U	Strong	Autosomal dominant
trichothiodystrophy	Strong	Autosomal recessive
autosomal recessive spastic paraplegia type 70	Supportive	Autosomal recessive
Charcot-Marie-Tooth disease	Limited	Autosomal dominant
trichothiodystrophy 9, nonphotosensitive	Limited	Autosomal recessive
spastic paraplegia 70, autosomal recessive	Limited	Unknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease	Limited	AD

Mondo (9): severe early-onset pulmonary alveolar proteinosis due to MARS deficiency (MONDO:0014206), Charcot-Marie-Tooth disease axonal type 2U (MONDO:0014566), autosomal recessive spastic paraplegia type 70 (MONDO:0018422), trichothiodystrophy 9, nonphotosensitive (MONDO:0030518), Charcot-Marie-Tooth disease (MONDO:0015626), pulmonary alveolar proteinosis (MONDO:0001437), distal hereditary motor neuropathy (MONDO:0018894), (MONDO:0957221), trichothiodystrophy (MONDO:0018053)

Orphanet (5): Autosomal dominant Charcot-Marie-Tooth disease type 2U (Orphanet:397735), Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency (Orphanet:440427), Autosomal recessive spastic paraplegia type 70 (Orphanet:401835), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Distal hereditary motor neuropathy (Orphanet:53739)

HPO phenotypes

88 total (30 of 88 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000100	Nephrotic syndrome
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000407	Sensorineural hearing impairment
HP:0000689	Dental malocclusion
HP:0000750	Delayed speech and language development
HP:0000821	Hypothyroidism
HP:0001156	Brachydactyly
HP:0001217	Clubbing
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001315	Reduced tendon reflexes
HP:0001347	Hyperreflexia
HP:0001382	Joint hypermobility
HP:0001394	Cirrhosis
HP:0001395	Hepatic fibrosis

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010703_209	Brain morphology (MOSTest)	2.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D011649	Pulmonary Alveolar Proteinosis	C08.381.719

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2870 (SINGLE PROTEIN)

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

ChEMBL bioactivities

76 potent at pChembl≥5 of 131 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL304237
8.15	IC50	7	nM	CHEMBL1163059
7.92	IC50	12	nM	CHEMBL58615
7.75	IC50	18	nM	CHEMBL55652
7.40	IC50	40	nM	CHEMBL56582
7.16	IC50	70	nM	CHEMBL57382
7.09	Kd	80.64	nM	CHEMBL3752910
7.09	ED50	80.64	nM	CHEMBL3752910
7.06	IC50	87	nM	CHEMBL59204
6.89	IC50	130	nM	CHEMBL72005
6.89	IC50	130	nM	CHEMBL307342
6.82	IC50	150	nM	CHEMBL308349
6.77	IC50	170	nM	CHEMBL59259
6.77	IC50	170	nM	CHEMBL431521
6.75	IC50	180	nM	CHEMBL57816
6.52	IC50	300	nM	CHEMBL74224
6.52	IC50	300	nM	CHEMBL307660
6.47	IC50	340	nM	CHEMBL293288
6.37	IC50	430	nM	CHEMBL410312
6.30	IC50	500	nM	CHEMBL308309
6.30	IC50	500	nM	CHEMBL60402
6.29	IC50	510	nM	CHEMBL292003
6.28	IC50	530	nM	CHEMBL304562
6.20	IC50	630	nM	CHEMBL302471
6.18	IC50	660	nM	CHEMBL304618
6.17	IC50	680	nM	CHEMBL56024
6.14	IC50	730	nM	CHEMBL57382
6.12	IC50	760	nM	CHEMBL292230
6.09	IC50	810	nM	CHEMBL56185
6.07	IC50	850	nM	CHEMBL55894
6.04	IC50	910	nM	CHEMBL73305
5.99	IC50	1020	nM	CHEMBL69993
5.96	IC50	1090	nM	CHEMBL71729
5.96	IC50	1100	nM	CHEMBL299272
5.96	IC50	1100	nM	CHEMBL605595
5.92	IC50	1190	nM	CHEMBL73462
5.92	IC50	1200	nM	CHEMBL605589
5.89	IC50	1280	nM	CHEMBL57816
5.87	IC50	1340	nM	CHEMBL70475
5.85	IC50	1400	nM	CHEMBL292003
5.82	IC50	1510	nM	CHEMBL307466
5.78	IC50	1670	nM	CHEMBL56463
5.75	IC50	1790	nM	CHEMBL308349
5.72	IC50	1900	nM	CHEMBL605806
5.71	IC50	1930	nM	CHEMBL302471
5.57	IC50	2680	nM	CHEMBL72038
5.53	IC50	2950	nM	CHEMBL72460
5.51	IC50	3056	nM	CHEMBL2159537
5.51	IC50	3110	nM	CHEMBL292230
5.48	IC50	3280	nM	CHEMBL442177

PubChem BioAssay actives

74 with measured affinity, of 188 total; 50 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
2-[3-[(6,8-dibromo-1,2,3,4-tetrahydroquinolin-4-yl)amino]propylamino]-1H-quinolin-4-one	108062: In vitro inhibitory concentration against Methionyl-tRNA synthetase in a pyrophosphate exchange assay	ic50	0.0010	uM
[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl N-[(2S)-2-amino-4-methylsulfanylbutanoyl]sulfamate	108061: Inhibitory activity against Escherichia coli Methionyl-tRNA synthetase was determined	ic50	0.0070	uM
2-[3-[(6-ethyl-8-iodo-1,2,3,4-tetrahydroquinolin-4-yl)amino]propylamino]-1H-quinolin-4-one	108063: In vitro inhibitory concentration against Staphylococcus aureus Methionyl-tRNA synthetase	ic50	0.0120	uM
(2S)-N-[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-1-[(1Z)-1-[2-(2,4-dichlorophenyl)-5-oxo-1,3-oxazol-4-ylidene]propyl]azetidine-2-carboxamide	108064: Inhibition of Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	0.0180	uM
(2S)-N-[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-1-[(1Z)-1-[2-(2,4-dichlorophenyl)-5-oxo-1,3-oxazol-4-ylidene]butyl]azetidine-2-carboxamide	108064: Inhibition of Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	0.0400	uM
(2S)-N-[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-1-[(Z)-[2-(2,4-dichlorophenyl)-5-oxo-1,3-oxazol-4-ylidene]methyl]azetidine-2-carboxamide	108064: Inhibition of Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	0.0700	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148721: Binding affinity to human MARS incubated for 45 mins by Kinobead based pull down assay	kd	0.0806	uM
(2S)-N-[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-1-[(1Z)-1-[2-(4-bromophenyl)-5-oxo-1,3-oxazol-4-ylidene]butyl]azetidine-2-carboxamide	108064: Inhibition of Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	0.0870	uM
5-[4-(2,4-dichlorophenyl)phenyl]-1-pyridin-3-yl-N-(2H-tetrazol-5-ylmethyl)pyrazole-3-carboxamide	206240: Inhibitory activity against Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	0.1300	uM
3-[5-[4-(2,4-dichlorophenyl)phenyl]-3-(tetrazol-1-yl)pyrazol-1-yl]pyridine	108065: Inhibitory activity against Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	0.1300	uM
2-[5-[4-(2,4-dichlorophenyl)phenyl]-3-(tetrazol-1-yl)pyrazol-1-yl]pyridine	108065: Inhibitory activity against Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	0.1500	uM
(2S)-N-[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-1-[(1Z)-1-[2-(2,4-dichlorophenyl)-5-oxo-1,3-oxazol-4-ylidene]butyl]pyrrolidine-2-carboxamide	108064: Inhibition of Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	0.1700	uM
(2S)-N-[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-1-[(1Z)-1-[2-(4-bromophenyl)-5-oxo-1,3-oxazol-4-ylidene]propyl]azetidine-2-carboxamide	108064: Inhibition of Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	0.1700	uM
(2S)-N-[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-1-[(1Z)-1-[2-(2,4-dichlorophenyl)-5-oxo-1,3-oxazol-4-ylidene]propyl]pyrrolidine-2-carboxamide	108064: Inhibition of Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	0.1800	uM
2-[[5-[4-(2,4-dichlorophenyl)phenyl]-1-pyridin-3-ylpyrazole-3-carbonyl]amino]acetic acid	206240: Inhibitory activity against Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	0.3000	uM
5-[4-(2,4-dichlorophenyl)phenyl]-1-pyridin-3-ylpyrazole-3-carboxylic acid	206240: Inhibitory activity against Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	0.3000	uM
(2S)-N-[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-1-[(1Z)-1-[2-(2,4-dichlorophenyl)-5-oxo-1,3-oxazol-4-ylidene]ethyl]pyrrolidine-2-carboxamide	108064: Inhibition of Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	0.3400	uM
(2S)-N-[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-1-[(Z)-[2-(2,4-dichlorophenyl)-5-oxo-1,3-oxazol-4-ylidene]-phenylmethyl]pyrrolidine-2-carboxamide	108064: Inhibition of Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	0.4300	uM
5-[4-(2,4-dichlorophenyl)phenyl]-1-(pyridin-4-ylmethyl)pyrazole-3-carboxylic acid	108065: Inhibitory activity against Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	0.5000	uM
2-[3-[(3,4-dichlorophenyl)methylamino]propylamino]-1H-quinolin-4-one	108062: In vitro inhibitory concentration against Methionyl-tRNA synthetase in a pyrophosphate exchange assay	ic50	0.5000	uM
(2S)-N-[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-1-[(Z)-[2-(4-bromophenyl)-5-oxo-1,3-oxazol-4-ylidene]methyl]azetidine-2-carboxamide	108064: Inhibition of Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	0.5100	uM
1-[5-[4-(2,4-dichlorophenyl)phenyl]-1-(2-methoxyphenyl)pyrazol-3-yl]tetrazole	206240: Inhibitory activity against Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	0.5300	uM
5-[4-(2,4-dichlorophenyl)phenyl]-1-pyridin-2-ylpyrazole-3-carboxylic acid	206240: Inhibitory activity against Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	0.6300	uM
5-[4-(2,4-dichlorophenyl)phenyl]-1-(pyridin-3-ylmethyl)pyrazole-3-carboxylic acid	108065: Inhibitory activity against Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	0.6600	uM
(2S)-N-[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-1-[(Z)-[2-(2,4-dichlorophenyl)-5-oxo-1,3-oxazol-4-ylidene]methyl]pyrrolidine-2-carboxamide	108064: Inhibition of Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	0.6800	uM
(2S)-N-[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-1-[(1Z)-1-[2-(4-bromophenyl)-5-oxo-1,3-oxazol-4-ylidene]butyl]pyrrolidine-2-carboxamide	108064: Inhibition of Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	0.7600	uM
(2S)-N-[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-1-[(Z)-[2-(4-bromophenyl)-5-oxo-1,3-oxazol-4-ylidene]-phenylmethyl]pyrrolidine-2-carboxamide	108064: Inhibition of Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	0.8100	uM
(2S)-N-[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-1-[(1Z)-1-[2-(4-bromophenyl)-5-oxo-1,3-oxazol-4-ylidene]propyl]pyrrolidine-2-carboxamide	108064: Inhibition of Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	0.8500	uM
3-[4-(2,4-dichlorophenyl)phenyl]-1-(pyridin-4-ylmethyl)pyrazole-5-carboxylic acid	108065: Inhibitory activity against Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	0.9100	uM
5-[4-(2,4-dichlorophenyl)phenyl]-1-ethylpyrazole-3-carboxylic acid	206240: Inhibitory activity against Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	1.0200	uM
3-[4-(2,4-dichlorophenyl)phenyl]-1-(pyridin-3-ylmethyl)pyrazole-5-carboxylic acid	108065: Inhibitory activity against Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	1.0900	uM
(2S)-N-[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-1-[(Z)-[2-(4-bromophenyl)-5-oxo-1,3-oxazol-4-ylidene]methyl]pyrrolidine-2-carboxamide	108064: Inhibition of Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	1.1000	uM
[(2R,3S,4R)-5-(6-amino-2-ethynylpurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl N-[(2S)-2-amino-4-methylsulfanylbutanoyl]sulfamate	108061: Inhibitory activity against Escherichia coli Methionyl-tRNA synthetase was determined	ic50	1.1000	uM
1-(3-carboxyphenyl)-5-[4-(2,4-dichlorophenyl)phenyl]pyrazole-3-carboxylic acid	206240: Inhibitory activity against Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	1.1900	uM
[(2R,3S,4R)-5-(6-amino-2-iodopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl N-[(2S)-2-amino-4-methylsulfanylbutanoyl]sulfamate	108061: Inhibitory activity against Escherichia coli Methionyl-tRNA synthetase was determined	ic50	1.2000	uM
5-[4-(2,4-dichlorophenyl)phenyl]-1-(pyridin-2-ylmethyl)pyrazole-3-carboxylic acid	108065: Inhibitory activity against Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	1.3400	uM
5-[4-(2,4-dichlorophenyl)phenyl]-1-(2-methoxyphenyl)pyrazole-3-carboxylic acid	206240: Inhibitory activity against Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	1.5100	uM
(2S)-N-[(2S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-1-[(1Z)-1-[2-(4-bromophenyl)-5-oxo-1,3-oxazol-4-ylidene]ethyl]pyrrolidine-2-carboxamide	108064: Inhibition of Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	1.6700	uM
[(2R,3S,4R)-5-(6-amino-2-hex-1-ynylpurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl N-[(2S)-2-amino-4-methylsulfanylbutanoyl]sulfamate	108061: Inhibitory activity against Escherichia coli Methionyl-tRNA synthetase was determined	ic50	1.9000	uM
3-[4-(2,4-dichlorophenyl)phenyl]-1-(pyridin-2-ylmethyl)pyrazole-5-carboxylic acid	108065: Inhibitory activity against Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	2.6800	uM
5-[4-(2,4-dichlorophenyl)phenyl]-1-pyridin-2-ylpyrazole-3-carboxamide	206240: Inhibitory activity against Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	2.9500	uM
1-[3-[(3,5-dichlorophenyl)methylamino]propyl]-3-thiophen-2-ylurea	694011: Inhibition of human mitochondrial MetRS aminoacylation activity assessed as reduction in [3H]methionine incorporation into Escherichia coli tRNA pre-incubated for 15 mins before tRNA addition and measured after 120 mins by scintillation counting	ic50	3.0560	uM
3-[4-(2,4-dichlorophenyl)phenyl]-1H-pyrazole-5-carboxylic acid	108065: Inhibitory activity against Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	3.2800	uM
1-(carboxymethyl)-5-[4-(2,4-dichlorophenyl)phenyl]pyrazole-3-carboxylic acid	206240: Inhibitory activity against Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	3.4200	uM
[(2R,3S,4R,5S)-5-[(6-aminopurin-9-yl)methyl]-3,4-dihydroxyoxolan-2-yl]methyl (2S)-2-amino-4-methylsulfanylbutanoate	222180: Inhibition of [35S]methionyl incorporation by Escherichia coli methionyl-tRNA synthetase (MetRS)	ic50	3.6000	uM
1-[3-[(3,5-dichlorophenyl)methylamino]propyl]-3-(2-hydroxyphenyl)urea	694011: Inhibition of human mitochondrial MetRS aminoacylation activity assessed as reduction in [3H]methionine incorporation into Escherichia coli tRNA pre-incubated for 15 mins before tRNA addition and measured after 120 mins by scintillation counting	ic50	3.7200	uM
1-benzyl-5-[4-(2,4-dichlorophenyl)phenyl]pyrazole-3-carboxylic acid	206240: Inhibitory activity against Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	3.9400	uM
1-[3-[(3,5-dichlorophenyl)methylamino]propyl]-3-(3-fluorophenyl)urea	694011: Inhibition of human mitochondrial MetRS aminoacylation activity assessed as reduction in [3H]methionine incorporation into Escherichia coli tRNA pre-incubated for 15 mins before tRNA addition and measured after 120 mins by scintillation counting	ic50	4.2460	uM
1-[3-[(3,5-dichlorophenyl)methylamino]propyl]-3-thiophen-3-ylurea	694011: Inhibition of human mitochondrial MetRS aminoacylation activity assessed as reduction in [3H]methionine incorporation into Escherichia coli tRNA pre-incubated for 15 mins before tRNA addition and measured after 120 mins by scintillation counting	ic50	4.3490	uM
5-[4-(2,4-dichlorophenyl)phenyl]-1-(2-hydroxyethyl)pyrazole-3-carboxylic acid	206240: Inhibitory activity against Staphylococcus aureus methionyl-tRNA synthetase (SaMetRS)	ic50	4.4600	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, increases expression	4
Cyclosporine	increases expression	4
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, increases expression, affects cotreatment	2
2,2’,4,4’-tetrabromodiphenyl ether	increases expression, decreases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Tunicamycin	increases expression	2
Particulate Matter	increases abundance, increases expression, affects cotreatment	2
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
methylmercuric chloride	increases expression	1
pyrogallol 1,3-dimethyl ether	decreases expression, affects localization, increases expression, affects cotreatment	1
salinomycin	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
sodium arsenite	increases expression	1
nickel chloride	increases expression	1
ochratoxin A	decreases expression	1
aflatoxin B2	increases methylation	1
1-nitropyrene	increases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
pentabromodiphenyl ether	increases expression	1
chloropicrin	decreases expression	1
K 7174	increases expression	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	increases expression, affects cotreatment	1

ChEMBL screening assays

26 unique, capped per target: 26 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2161886	Binding	Inhibition of human mitochondrial MetRS aminoacylation activity assessed as reduction in [3H]methionine incorporation into Escherichia coli tRNA pre-incubated for 15 mins before tRNA addition and measured after 120 mins by scintillation cou	Urea-based inhibitors of Trypanosoma brucei methionyl-tRNA synthetase: selectivity and in vivo characterization. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT00030056	PHASE2	TERMINATED	GM-CSF in Patients With Pulmonary Alveolar Proteinosis
NCT00552461	PHASE2	COMPLETED	Prospective Trial of Rituximab for Primary Pulmonary Alveolar Proteinosis
NCT01983657	PHASE2	UNKNOWN	Study of Subcutaneous Injection of Low-dose rhGM-CSF +/- WLL in PAP.
NCT03316651	PHASE2	UNKNOWN	Sequential Therapy With WLL/Inhaling GM-CSF for Autoimmune Pulmonary Alveolar Proteinosis
NCT06989333	PHASE2	NOT_YET_RECRUITING	Local Spraying of GM-CSF Via Bronchoscopy in the Treatment of Autoimmune Pulmonary Alveolar Proteinosis
NCT01842386	PHASE1	COMPLETED	Rituximab for Anti-cytokine Autoantibody-Associated Diseases
NCT02468908	PHASE1	COMPLETED	Inhaled Molgramostim (rhGM-CSF) in Healthy Adult Subjects
NCT01289704	PHASE2/PHASE3	UNKNOWN	Treadmill, Stretching and Proprioceptive Exercise (TreSPE) Rehabilitation Program for Charcot-Marie-Tooth Neuropathy Type 1A (CMT1A)
NCT00541164	PHASE1/PHASE2	COMPLETED	Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease
NCT05361031	PHASE1/PHASE2	COMPLETED	The Safety and Tolerability of Engensis (VM202) in Patients With Charcot-Marie-Tooth Disease Subtype 1A (CMT1A)
NCT07223632	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Treatment of Charcot-Marie-Tooth Disease, Axonal, Type 2S (CMT2S) in an Individual Patient
NCT00149045	Not specified	COMPLETED	Follow up and Observation of Charcot Marie Tooth Disease in Families
NCT01193075	Not specified	RECRUITING	Natural History Evaluation of Charcot Marie Tooth Disease (CMT) Types CMT1B, CMT2A, CMT4A, CMT4C, and Others
NCT01203085	Not specified	COMPLETED	Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale for Children With CMT
NCT01455623	Not specified	COMPLETED	Development and Validation of a Disability Severity Index for CMT
NCT01918826	Not specified	UNKNOWN	Evaluation of the Analgesic Efficiency of the Transcutaneous Neurostimulation in the Charcot Syndrome Marie Tooth on the Pains of Lower Limbs
NCT02001038	Not specified	COMPLETED	Survey of Current Management of Orthopaedic Complications in CMT Patients
NCT02011204	Not specified	COMPLETED	Study of Electrical Impedance Myography (EIM) in ALS
NCT02194010	Not specified	COMPLETED	Disability Severity Scale (DSI) and Hereditary Motor and Sensory Neuropathy Overall Disability Scale (HMSN-R-ODS)
NCT02429947	Not specified	COMPLETED	An Analysis of the Symptomatic Domains Most Relevant to Charcot Marie Tooth Neuropathy (CMT) Patients
NCT02532244	Not specified	COMPLETED	Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT02788734	Not specified	COMPLETED	Patient Reported Outcomes Measures (PROM) in Carpal Tunnel Therapies in Patients With Inherited Neuropathies
NCT02979145	Not specified	UNKNOWN	Charcot-Marie-Tooth Disease (CMT) Infant Scale (INC-6611)
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03460951	Not specified	COMPLETED	Diffusion Tensor Imaging in Chronic Inflammatory Demyelinating Polyneuropathy (PIDC)
NCT03715283	Not specified	COMPLETED	Change in MUNIX in Patients With CMT1A Undergoing a Home Ankle Strengthening Program Versus Standard of Care
NCT03782883	Not specified	COMPLETED	The Impact of Charcot-Marie-Tooth Disease in the Real World
NCT03810508	Not specified	TERMINATED	A Natural History Study of Charcot-Marie-Tooth 4J (CMT4J)
NCT03966287	Not specified	COMPLETED	Analysis of Pain and Quality of Life in Patients With Charcot-Marie-Tooth Neuropathy (CMT)