Gene Ontology annotation through association of InterPro records with GO terms
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Gene Ontology annotation based on curation of immunofluorescence data
Electronic Gene Ontology annotations created by transferring manual GO annotations between related proteins based on shared sequence features
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Combined Automated Annotation using Multiple IEA Methods
UniProtKB record for human AARS1 (P49588)
Defining the membrane proteome of NK cells.
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The NK-cell membrane-fraction survey cautions that many detected proteins were nonintegral and potentially only transiently membrane associated.
"The remaining species were largely involved in cellular processes and molecular functions that could be predicted to be transiently associated with membranes."
MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.
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The source is a high-throughput proteomic survey of purified B-cell-derived exosomes that identified 539 proteins.
"we first analyzed the total proteome of highly purified B cell-derived exosomes using sensitive and accurate mass spectrometry (MS), and identified 539 proteins, including known and not previously identified constituents."
Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect.
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Biallelic AARS1 variants caused severe infantile encephalopathy and reduced enzyme function, linking defective alanyl-tRNA charging to recessive disease.
"The two identified mutations were found to result in a significant reduction in function."
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The authors explicitly concluded that impaired alanyl-tRNA charging can produce a broad spectrum of neurological disease.
"The autosomal-recessive AARS mutations identified in the individuals described here, however, cause a severe infantile epileptic encephalopathy with a central myelin defect and peripheral neuropathy, demonstrating that defects of alanyl-tRNA charging can result in a wide spectrum of disease manifestations."
Evolutionary Gain of Alanine Mischarging to Noncognate tRNAs with a G4:U69 Base Pair.
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Human AARS1 can mischarge alanine onto noncognate tRNAs, including tRNA(Cys), when their acceptor stems contain a G4:U69 identity element.
"Here we found human and not E. coli AlaRS has an intrinsic capacity for mispairing alanine onto nonalanyl-tRNAs including tRNACys."
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The G4:U69 acceptor-stem base pair is required for this expanded human AARS1 substrate specificity.
"All human AlaRS-mischarged tRNAs have a G4:U69 base pair in the acceptor stem. The base pair is required for the mischarging."
Two crystal structures reveal design for repurposing the C-Ala domain of human AlaRS.
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Human C-Ala adopts a divergent architecture that forms a dimer interface and DNA-binding groove rather than retaining the prokaryotic tRNA-docking role.
"This reshaping removes the role of C-Ala in prokaryotes for docking tRNA and instead repurposes it to form a dimer interface presenting a DNA-binding groove."
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Purified human C-Ala, but not the bacterial orthologous domain, bound DNA directly.
"Direct DNA binding by human C-Ala, but not by bacterial C-Ala, was demonstrated."
Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy.
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Two recessive human AARS1 variants reduced recombinant aminoacylation catalytic efficiency by 73% to 86%.
"The results showed that the p.Tyr690Leufs*3 mutation caused a 86% decrease in catalytic efficiency (kcat/Km) (Fig. 1D). The p.Gly913Asp mutation led to a 73% decrease in catalytic efficiency."
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Human AARS1 directly deacylates Ser-tRNA(Ala); the editing-domain truncation markedly impaired that activity while another disease variant retained wild-type-like deacylation.
"In the presence of AARS p.Tyr690Leufs*3, the deacylation of [3H] Ser-tRNAAla was diminished to a level comparable to the AARS p.Cys723Ala mutant (Fig. 1E). In contrast, the AARS p.Gly913Asp mutant maintained unaffected deacylation activity compared to the wild-type AARS."
Protein instability associated with AARS1 and MARS1 mutations causes trichothiodystrophy.
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Trichothiodystrophy-associated AARS1 variants destabilize the protein and reduce tRNA charging in patient fibroblasts.
"These variants result in the instability of the respective gene products alanyl- and methionyl-tRNA synthetase."
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Patient-fibroblast studies showed that the variants alter the rate of tRNA charging.
"Functional studies in skin fibroblasts from affected individuals demonstrate that these new variants also impact on the rate of tRNA charging, which is the first step in protein translation."
The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to promote YAP signaling in gastric cancer.
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AARS1 directly uses lactate and ATP to catalyze protein lysine lactylation.
"Here, we report that alanyl-tRNA synthetase 1 (AARS1) moonlights as a bona fide lactyltransferase that directly uses lactate and ATP to catalyze protein lactylation."
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Intracellular lactate drives AARS1 nuclear translocation, where AARS1 lactylates and activates the YAP-TEAD complex.
"Specifically, AARS1 was found to sense intracellular lactate and translocate into the nucleus to lactylate and activate the YAP-TEAD complex; and AARS1 itself was identified as a Hippo target gene that forms a positive-feedback loop with YAP-TEAD to promote gastric cancer (GC) cell proliferation."
Alanyl-tRNA synthetase, AARS1, is a lactate sensor and lactyltransferase that lactylates p53 and contributes to tumorigenesis.
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AARS1 binds lactate, forms lactate-AMP, and transfers the lactyl group to protein lysine residues.
"AARS1 binds to lactate and catalyzes the formation of lactate-AMP, followed by transfer of lactate to the lysince acceptor residue."
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AARS1 lactylates TP53 at Lys-120 and Lys-139, impairing TP53 phase separation, DNA binding, and transcriptional activation.
"AARS1 lactylation of p53 hinders its liquid-liquid phase separation, DNA binding, and transcriptional activation."
AARS1 and AARS2 sense L-lactate to regulate cGAS as global lysine lactyltransferases.
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AARS1 and AARS2 bind L-lactate and directly catalyze ATP-dependent lysine lactylation.
"AARS1/2 and the evolutionarily conserved Escherichia coli orthologue AlaRS bind to L-lactate with micromolar affinity and they directly catalyse L-lactate for ATP-dependent lactylation on the lysine acceptor end."
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The cGAS association, lactylation, and inactivation experiments in this paper identify AARS2, not AARS1, as the responsible paralog.
"In response to L-lactate, AARS2 associates with cyclic GMP-AMP synthase (cGAS) and mediates its lactylation and inactivation in cells and in mice."
The C-Ala domain brings together editing and aminoacylation functions on one tRNA.
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AlaRS editing recognizes tRNA(Ala) mischarged with either glycine or serine.
"In this way, the editing domain checks for mischarging by picking out tRNAs that have Gly or Ser and a G3•U70 pair."
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Human C-Ala and its linker restored nearly full Ser-tRNA(Ala) clearance when grafted onto the E. coli AlaRS editing domain.
"Grafting C-Ala and its linker from human AlaRS to ED of E. coli AlaRS gave nearly full activity for clearance of Ser-tRNAAla (Fig. 3)."
Double mimicry evades tRNA synthetase editing by toxic vegetable-sourced non-proteinogenic amino acid.
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Human AARS1 activates the alanine mimic azetidine-2-carboxylic acid but its editing system rejects more than 99% of the activated nonproteinogenic substrate.
"Here we show that although Aze is activated by both human (Hs) AlaRS and Hs ProRS, it is rejected (>99%) by the AlaRS but not the ProRS editing system and therefore almost exclusively misincorporates into Pro positions of proteins."
Hypermorphic and hypomorphic AARS alleles in patients with CMT2N expand clinical and molecular heterogeneities.
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Dominant CMT2N AARS1 alleles can be hypomorphic or hypermorphic rather than sharing one uniform loss-of-function mechanism.
"Yeast complementation assays demonstrated that two mutations (p.Ser627Leu and p.Arg326Trp) represent loss-of-function alleles, while the third (p.Glu337Lys) represents a hypermorphic allele."
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The hypermorphic p.Glu337Lys allele increases tRNA charging velocity.
"Further, aminoacylation assays confirmed that the third mutation (p.Glu337Lys) increases tRNA charging velocity."
Class I histone deacetylases catalyze lysine lactylation.
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AARS1 or AARS2 depletion did not reduce basal global lysine lactylation in untreated proliferating HEK293T cells.
"However, the knockdown of either enzyme did not alter Kla levels (Fig. S6, B–E), suggesting the AARS pathway is also not required for global lysine lactylation."
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The reported AARS1 lactyl-AMP reaction has a millimolar Km, making substantial activity unlikely at healthy lactate concentrations.
"Likewise, the reported Km for AARS1 to generate lactyl-AMP to transfer lactate to lysine has Km = 36 ± 7.09 mM, again making this pathway unlikely to occur at healthy lactate levels (20)."
Human alanyl-tRNA synthetase: conservation in evolution of catalytic core and microhelix recognition.
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Active human AARS1 recognizes the conserved tRNA(Ala) acceptor-stem G3:U70 base pair and aminoacylates acceptor-stem RNA duplexes.
"In particular, we show that both the E. coli enzyme and the human enzyme purified from Pichia aminoacylate 9-base pair RNA duplexes whose sequences are based on the acceptor stems of either E. coli or human alanine tRNAs."
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The expressed human enzyme behaves as a monomer.
"This divergence correlates with the expressed human enzyme behaving as a monomer."
Wide cross-species aminoacyl-tRNA synthetase replacement in vivo: yeast cytoplasmic alanine enzyme replaced by human polymyositis serum antigen.
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Human AARS1 restored growth of yeast lacking its essential cytoplasmic AlaRS, demonstrating accurate in-vivo aminoacylation across species.
"Growth of cells harboring the ala1 disrupted allele was restored by a cDNA clone encoding human alanyl-tRNA synthetase, which is a serum antigen for many polymyositis-afflicted individuals."
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Conservation of the G3:U70 recognition system is sufficient for accurate cross-species aminoacylation in vivo.
"We conclude that, in spite of substantial differences between human and yeast tRNA sequences in evolution, strong conservation of the G3.U70 system of recognition is sufficient to yield accurate aminoacylation in vivo across wide species distances."
Cytosolic tRNA aminoacylation
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Reactome places cytosolic AARS1 in the pathway that charges nuclear-encoded tRNAs with their cognate amino acids using ATP.
"Cytosolic tRNA synthetases catalyze the reactions of tRNAs encoded in the nuclear genome, their cognate amino acids, and ATP to form aminoacyl-tRNAs, AMP, and pyrophosphate."
alanine + tRNA(Ala) + ATP => Ala-tRNA(Ala) + AMP + pyrophosphate
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Reactome assigns monomeric cytosolic AARS1 the alanine-tRNA(Ala) ligation reaction.
"AARS (cytosolic alanyl tRNA synthetase) catalyzes the reaction of alanine, tRNA(ala), and ATP to form Ala tRNA(Ala), AMP, and pyrophosphate. The enzyme, a class II tRNA synthetase, is a monomer (Shiba et al. 1995)."
A humanized yeast model reveals dominant-negative properties of neuropathy-associated alanyl-tRNA synthetase mutations.
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Multiple neuropathy-associated AARS1 variants interfere with wild-type AARS1 in a humanized yeast model; reducing their interaction rescues growth.
"We show that multiple loss-of-function AARS1 mutations impair yeast growth through an interaction with wild-type AARS1, but that reducing this interaction rescues yeast growth."
Recessive, pathogenic AARS1 variants display variable loss-of-function and dominant-negative effects.
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K81T and E99G AARS1 combine loss-of-function and dominant-negative behavior in yeast, illustrating overlap between recessive-allele biochemistry and dominant neuropathy mechanisms.
"Interestingly, K81T and E99G AARS1 demonstrated both loss-of-function and dominant-negative effects, indicating that certain AARS1 variants can cause both dominant and recessive disease phenotypes."
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Humanized-yeast co-expression of K81T or E99G with wild-type AARS1 reduces growth; the authors interpret this as dominant-negative interference in a homodimer context, rather than measuring endogenous human-cell oligomeric state.
"In contrast, when K81T or E99G human AARS1 were co-expressed with wild-type human AARS1, there was significantly reduced yeast cell growth compared to that with wild-type AARS1 (Fig. 5C,D and Fig. 6; Figs S8 and S9)."
Covalent allosteric inhibition of AARS1 lactyltransferase.
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Structural, biochemical and cellular inhibitor studies corroborate AARS1 lactate recognition and lactate-dependent YAP lactylation.
"we show that XY353 and its derivative XY353-1 inhibit AARS1 by competing with lactate via the C184-F175-W176 relay"
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XY353-1 preserves the measured alanine-substrate activity at 5–20 micromolar but partly inhibits it at 40 micromolar.
"Notably, XY353-1 did not significantly affect AARS1 activity when alanine was used as the substrate at concentrations of 5–20 μM, while partial inhibition (33.5%) was observed at 40 μM (Supplementary Fig. 23a)."
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In U2OS cells, XY353-1 inhibits global lactylation at a lower concentration than protein synthesis, defining a bounded pharmacological selectivity window.
"Importantly, XY353-1 reduced global lactylation with an IC50 of 12.9 μM, whereas inhibition of protein synthesis occurred at a higher IC50 of 34.7 μM in U2OS cells (Supplementary Fig. 24), further demonstrating its functional selectivity."
Excess intracellular lactate represses mRNA translation and tumor progression through lactate-tRNA charging.
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A 2026 primary report describes lactate charging onto tRNAs by AARS1 under excess intracellular lactate, a chemically distinct outcome from protein lysine lactylation.
"alanyl-tRNA synthetase 1 (AARS1) charges tRNAs with lactate instead of amino acids."
Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration.
Deficiencies in tRNA synthetase editing activity cause cardioproteinopathy.
ANKRD16 prevents neuron loss caused by an editing-defective tRNA synthetase.
Falcon/Edison deep research report for human AARS1 (2026-09-25)
Expanded phenotype of AARS1-related white matter disease.
Yeast models for Charcot-Marie-Tooth disease-causing aminoacyl-tRNA synthetase alleles reveal the cellular basis of disease.
AARS1 and AARS2: From Protein Synthesis to Lactylation-Driven Oncogenesis.
The role of Alanyl-tRNA synthetase 1 lactylation in tumors and other diseases.
Comprehensive pan-cancer analysis of AARS1, a newly identified lactyltransferase in human cancers.
Alanyl-tRNA synthetase from Escherichia coli, Bombyx mori and Ratus ratus. Existence of common structural features.