Proposed New Ontology Terms

peptidyl-lysine lactylation

Definition: A peptidyl-lysine modification process in which a lactyl group is covalently added to the epsilon-amino group of a lysine residue within a protein.

Justification: GO:0141207 captures the ATP-dependent molecular activity but no current biological process term captures its immediate protein-modification outcome. The proposed term should be placed under GO:0018205 peptidyl-lysine modification and related to the broader GO:0043543 protein acylation branch; it would support curation of AARS1 and other experimentally established lysine lactylation mechanisms without conflating them with downstream signaling phenotypes.

Parent term: peptidyl-lysine modification

Supporting Evidence:

PMID:38512451 : AARS1 translocated into the nucleus, where it directly catalyzed lactylation of YAP at K90 and TEAD1 at K108, thereby activating downstream target gene expression to promote tumor cell proliferation.
PMID:38653238 : AARS1 binds to lactate and catalyzes the formation of lactate-AMP, followed by transfer of lactate to the lysince acceptor residue.

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: IBA cytosol assignment, consistent with AARS1's identity as the cytoplasmic AlaRS and with independent HPA and experimental cytoplasmic localization. Reason: The cytosol is the primary compartment for the core tRNA-charging and editing functions. Propagation Review Root cause: NO FAILURE CORE
GO:0004813 alanine-tRNA ligase activity	IBA GO_REF:0000033	ACCEPT	Summary: IBA assignment of substrate-specific alanine-tRNA ligase activity, corroborated by multiple human biochemical studies. Reason: This is AARS1's principal conserved molecular function. Propagation Review Root cause: NO FAILURE CORE Supporting Evidence: PMID:28493438 The aminoacylation activities of both variants were then tested using 14C-labeled alanine with various concentrations of tRNA.
GO:0002161 aminoacyl-tRNA deacylase activity	IBA GO_REF:0000033	ACCEPT	Summary: IBA assignment of the editing-domain deacylase activity; human AARS1 editing was directly measured with Ser-tRNA(Ala). Reason: Post-transfer editing is a conserved core function and is directly verified in the human target. Propagation Review Root cause: NO FAILURE CORE Supporting Evidence: PMID:28493438 AARS possesses an editing domain that is capable of hydrolyzing the mischarged tRNAAla
GO:0006419 alanyl-tRNA aminoacylation	IBA GO_REF:0000033	ACCEPT	Summary: IBA assignment of the process producing Ala-tRNA(Ala), supported by human enzymology and cross-species complementation. Reason: Alanyl-tRNA aminoacylation is the central conserved process executed by AARS1. Propagation Review Root cause: NO FAILURE CORE
GO:0000166 nucleotide binding	IEA GO_REF:0000002	MODIFY	Summary: InterPro inference of generic nucleotide binding from AlaRS catalytic/editing domains; the relevant nucleotide substrate is ATP. Reason: The parent binding term is true but too broad; ATP binding is the mechanistically relevant specificity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: ATP binding
GO:0003676 nucleic acid binding	IEA GO_REF:0000002	MODIFY	Summary: InterPro inference of generic nucleic-acid binding; the core physiological nucleic-acid ligand is tRNA. Reason: Use informative tRNA binding. Isolated C-Ala can bind DNA in vitro, but that does not justify generic nucleic-acid binding as the core annotation. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: tRNA binding
GO:0004812 aminoacyl-tRNA ligase activity	IEA GO_REF:0000002	MODIFY	Summary: InterPro inference of broad aminoacyl-tRNA ligase activity from the class-II synthetase fold. Reason: The activity is correct but too general for a protein with established alanine specificity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: alanine-tRNA ligase activity
GO:0004813 alanine-tRNA ligase activity	IEA GO_REF:0000120	ACCEPT	Summary: Convergent ARBA, UniRule, InterPro, EC 6.1.1.7 and RHEA:12540 assignment of alanine-tRNA ligase activity. Reason: The electronic mapping exactly matches the directly characterized core reaction. Propagation Review Root cause: NO FAILURE CORE
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: Electronic ATP-binding assignment from conserved AlaRS catalytic domains and UniRule. Reason: ATP binding is obligatory for adenylate-intermediate formation in AARS1 catalysis. Propagation Review Root cause: NO FAILURE CORE
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: Electronic nuclear localization mapped from reviewed UniProt localization and corroborated by lactate-induced, KPNA4-dependent nuclear entry in human cells. Reason: The nucleus is a bona fide elevated-lactate conditional execution site for AARS1 protein lactyltransferase activity. Acceptance does not imply that AARS1 is constitutively nuclear or that the nucleus replaces its primary cytoplasmic localization. Propagation Review Root cause: NO FAILURE CORE
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: Electronic cytoplasmic localization inferred from AlaRS domains and reviewed UniProt localization. Reason: The cytoplasm is the primary setting for AARS1 tRNA charging/editing and is independently observed in human cells. Propagation Review Root cause: NO FAILURE CORE
GO:0006419 alanyl-tRNA aminoacylation	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assignment of alanyl-tRNA aminoacylation from convergent family, orthology and domain evidence. Reason: This is AARS1's core process and is directly established by human enzymology and loss-of-function studies. Propagation Review Root cause: NO FAILURE CORE
GO:0008270 zinc ion binding	IEA GO_REF:0000104	ACCEPT	Summary: UniRule transfer of zinc-ion binding; the reviewed AARS1 record specifies one zinc ion per subunit. Reason: Zinc binding is a conserved component of AlaRS architecture with no evidence of target-specific loss. Propagation Review Root cause: NO FAILURE CORE
GO:0043039 tRNA aminoacylation	IEA GO_REF:0000002	MODIFY	Summary: InterPro inference of broad tRNA aminoacylation from the tRNA-synthetase additional domain. Reason: Use the alanine-specific child process established for AARS1. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: alanyl-tRNA aminoacylation
GO:0106074 aminoacyl-tRNA metabolism involved in translational fidelity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic inference of aminoacyl-tRNA quality-control metabolism from AARS1's deacylase activities. Reason: The term accurately captures editing that removes incorrect amino acids from charged tRNA. Propagation Review Root cause: NO FAILURE CORE
GO:0141207 peptide lactyltransferase (ATP-dependent) activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assignment of ATP-dependent peptide lactyltransferase activity from the exact Rhea reactions, corroborated by three independent 2024 studies. Reason: This is a real intrinsic AARS1 activity under elevated-lactate and substrate-specific conditions; PMID:40835008 shows it is not required for basal global Kla in HEK293T cells. Propagation Review Root cause: NO FAILURE CORE Supporting Evidence: PMID:38512451 AARS1 was able to directly lactylate histone H3 and H4 in a manner dependent on both lactate and ATP PMID:40835008 However, the knockdown of either enzyme did not alter Kla levels
GO:0000049 tRNA binding	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl orthology transfer of tRNA binding from rat AARS1, concordant with human tRNA/microhelix recognition experiments. Reason: tRNA binding is essential to aminoacylation/editing and is conserved in cytoplasmic AlaRS. Propagation Review Root cause: NO FAILURE CORE
GO:0002161 aminoacyl-tRNA deacylase activity	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl transfer of aminoacyl-tRNA deacylase activity from mouse Aars, independently verified by human editing assays. Reason: The editing domain and activity are conserved and directly present in the human target. Propagation Review Root cause: NO FAILURE CORE
GO:0002196 Ser-tRNA(Ala) deacylase activity	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl transfer of Ser-tRNA(Ala) deacylase activity from mouse Aars, independently measured for recombinant human AARS1. Reason: Direct human evidence makes this substrate-specific orthology transfer safe. Propagation Review Root cause: NO FAILURE CORE
GO:0006400 tRNA modification	IEA GO_REF:0000107	MODIFY	Summary: Ensembl transfer of tRNA modification from mouse Aars, apparently intended to represent editing of mischarged tRNA(Ala). Reason: GO:0006400 requires covalent alteration of tRNA nucleotides; AARS1 instead hydrolyzes a mischarged amino acid. Use the explicit aminoacyl-tRNA fidelity process. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Proposed replacements: aminoacyl-tRNA metabolism involved in translational fidelity
GO:0016597 amino acid binding	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl transfer of generic amino-acid binding from rat AARS1; alanine is the characterized cognate substrate. Reason: Generic amino-acid binding is not an informative independent molecular function here; the directly supported alanine-tRNA ligase annotations already capture substrate recognition in its catalytic context. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH
GO:0140018 regulation of cytoplasmic translational fidelity	IEA GO_REF:0000107	MODIFY	Summary: Ensembl transfer of regulation of cytoplasmic translational fidelity from mouse Aars. Reason: The existing term describes a valid downstream consequence of AARS1 proofreading, but the replacement more directly captures its aminoacyl-tRNA editing mechanism. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: aminoacyl-tRNA metabolism involved in translational fidelity
GO:0004813 alanine-tRNA ligase activity	TAS Reactome:R-HSA-379864	ACCEPT	Summary: Reactome assigns alanine-tRNA ligase activity to AARS1 in the cytosolic Ala-tRNA(Ala) reaction. Reason: The reaction and specificity exactly match the directly characterized core activity.
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: HPA immunofluorescence places AARS1 in the cytosol. Reason: Cytosolic localization is consistent with AARS1's core role as the cytoplasmic alanine-tRNA synthetase.
GO:0004813 alanine-tRNA ligase activity	EXP PMID:25817015 Loss-of-function alanyl-tRNA synthetase mutations cause an a...	ACCEPT	Summary: Experimental annotation from human loss-of-function variants with reduced alanyl-tRNA charging. Reason: The study supports the core catalytic activity; because the cache is abstract-only, the curator's full-text experimental assessment is retained. Supporting Evidence: PMID:25817015 demonstrating that defects of alanyl-tRNA charging can result in a wide spectrum of disease manifestations
GO:0004813 alanine-tRNA ligase activity	EXP PMID:27911835 Two crystal structures reveal design for repurposing the C-A...	ACCEPT	Summary: Experimental alanine-tRNA ligase annotation associated with structural/biochemical analysis of human AlaRS. Reason: The activity is established independently; the abstract-only cache gives no basis to overrule the curator.
GO:0005737 cytoplasm	EXP PMID:27911835 Two crystal structures reveal design for repurposing the C-A...	ACCEPT	Summary: Experimental cytoplasmic localization associated with the human AlaRS structural study. Reason: The assignment agrees with HPA, Reactome, UniProt and lactate-response localization data; retain the curator's full-text assessment.
GO:0141207 peptide lactyltransferase (ATP-dependent) activity	IDA PMID:39322678 AARS1 and AARS2 sense L-lactate to regulate cGAS as global l...	ACCEPT	Summary: Direct ATP-dependent peptide lactyltransferase annotation; AARS1/AARS2 act as intracellular lactate sensors and directly catalyze lysine lactylation. Reason: Three studies support the activity, qualified to elevated-lactate and substrate-specific contexts rather than dominant basal global lactylation. Supporting Evidence: PMID:39322678 they directly catalyse L-lactate for ATP-dependent lactylation on the lysine acceptor end
GO:0005634 nucleus	IDA PMID:38512451 The alanyl-tRNA synthetase AARS1 moonlights as a lactyltrans...	ACCEPT	Summary: Direct nuclear localization in gastric-cancer cells under elevated lactate, where AARS1 executes protein lactyltransferase activity on YAP and TEAD1. Reason: The nucleus is a directly demonstrated elevated-lactate conditional execution site for the accepted lactyltransferase function. This does not imply constitutive nuclear localization; cytoplasm remains the primary compartment for canonical tRNA charging and editing. Supporting Evidence: PMID:38512451 addition of lactate significantly promoted the nuclear localization of WT AARS1 but not the ΔNLS mutant
GO:0005737 cytoplasm	IDA PMID:38512451 The alanyl-tRNA synthetase AARS1 moonlights as a lactyltrans...	ACCEPT	Summary: Direct cytoplasmic localization with lactate-triggered shuttling to the nucleus. Reason: The cytoplasm is the primary setting for canonical AARS1 charging/editing. Supporting Evidence: PMID:38512451 AARS1, commonly understood as an enzyme residing in the cytoplasm
GO:0035332 positive regulation of hippo signaling	IDA PMID:38512451 The alanyl-tRNA synthetase AARS1 moonlights as a lactyltrans...	MODIFY	Summary: The study shows AARS1 lactylates YAP/TEAD and activates YAP-TEAD transcription, but GO:0035329 defines Hippo signaling as MST/LATS-driven YAP phosphorylation and retention/degradation. Reason: The phenotype is credible but GO:0035332 has the wrong sign; activating YAP output corresponds to negative regulation of canonical Hippo signaling. Neither sign is mechanistically ideal because AARS1 lactylates YAP/TEAD downstream of the MST/LATS kinase cascade; GO:0035331 is the least-bad existing pathway term. Proposed replacements: negative regulation of hippo signaling Supporting Evidence: PMID:38512451 AARS1 translocated into the nucleus, where it directly catalyzed lactylation of YAP at K90 and TEAD1 at K108, thereby activating downstream target gene expression to promote tumor cell proliferation.
GO:0141207 peptide lactyltransferase (ATP-dependent) activity	IDA PMID:38512451 The alanyl-tRNA synthetase AARS1 moonlights as a lactyltrans...	ACCEPT	Summary: Purified AARS1 uses lactate and ATP to lactylate protein and peptide substrates, with cellular validation. Reason: The paper directly supports the GO reaction; qualify the activity to elevated-lactate contexts and do not infer dominance over basal global Kla. Supporting Evidence: PMID:38512451 AARS1 was able to directly lactylate histone H3 and H4 in a manner dependent on both lactate and ATP
GO:0141207 peptide lactyltransferase (ATP-dependent) activity	IDA PMID:38653238 Alanyl-tRNA synthetase, AARS1, is a lactate sensor and lacty...	ACCEPT	Summary: Direct AARS1-mediated lactate-AMP formation followed by transfer to lysine acceptors. Reason: The exact reaction is corroborated independently; it is condition- and substrate-dependent rather than the principal basal-global Kla source. Supporting Evidence: PMID:38653238 AARS1 binds to lactate and catalyzes the formation of lactate-AMP, followed by transfer of lactate to the lysince acceptor residue.
GO:1901797 negative regulation of signal transduction by p53 class mediator	IDA PMID:38653238 Alanyl-tRNA synthetase, AARS1, is a lactate sensor and lacty...	KEEP AS NON CORE	Summary: AARS1-dependent lactylation of p53 K120/K139 inhibits p53 phase separation, DNA binding and transcriptional activation in tumor models. Reason: The negative effect on p53 signaling is supported but is a downstream high-lactate tumor-context consequence. Supporting Evidence: PMID:38653238 AARS1 lactylation of p53 hinders its liquid-liquid phase separation, DNA binding, and transcriptional activation.
GO:0006418 tRNA aminoacylation for protein translation	TAS Reactome:R-HSA-379716	MODIFY	Summary: Reactome places AARS1 in the broad cytosolic tRNA-aminoacylation pathway. Reason: Use the alanine-specific aminoacylation process. GO:0006419 is retained as the consistent level across the reviewed source annotations; cytosolic execution is represented separately by the accepted localization annotations. Proposed replacements: alanyl-tRNA aminoacylation
GO:0006419 alanyl-tRNA aminoacylation	IMP PMID:33909043 Protein instability associated with AARS1 and MARS1 mutation...	ACCEPT	Summary: Destabilizing AARS1 variants reduce the rate of tRNA charging in patient fibroblasts. Reason: The mutant phenotype directly supports the core alanyl-tRNA aminoacylation process. Supporting Evidence: PMID:33909043 Functional studies in skin fibroblasts from affected individuals demonstrate that these new variants also impact on the rate of tRNA charging
GO:0002196 Ser-tRNA(Ala) deacylase activity	ISS GO_REF:0000024	ACCEPT	Summary: Curator-reviewed similarity transfer of Ser-tRNA(Ala) deacylase activity from mouse Aars, independently validated by human assays. Reason: Human AARS1 directly deacylates Ser-tRNA(Ala), so the transfer captures a core editing activity. Propagation Review Root cause: NO FAILURE CORE Supporting Evidence: PMID:28493438 An in vitro editing activity assay was carried out using [3H] Ser-tRNAAla as a substrate.
GO:0006400 tRNA modification	ISS GO_REF:0000024	MODIFY	Summary: Curator-reviewed transfer of tRNA modification from mouse Aars, intended to represent AlaRS editing. Reason: Editing removes the attached amino acid rather than modifying tRNA nucleotides; use the mechanistically correct fidelity process. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Proposed replacements: aminoacyl-tRNA metabolism involved in translational fidelity
GO:0002161 aminoacyl-tRNA deacylase activity	IDA PMID:28493438 Deficient activity of alanyl-tRNA synthetase underlies an au...	ACCEPT	Summary: Direct human editing assay demonstrates AARS1 hydrolysis of mischarged Ser-tRNA(Ala), including loss of deacylation by an editing-domain disease variant. Reason: The Ser-tRNA(Ala) assay directly supports this true broader aminoacyl-tRNA deacylase parent activity. The more specific activity is already represented by existing GO:0002196 annotations, which cite this study as direct corroboration. Supporting Evidence: PMID:28493438 An in vitro editing activity assay was carried out using [3H] Ser-tRNAAla as a substrate.
GO:0004813 alanine-tRNA ligase activity	IDA PMID:28493438 Deficient activity of alanyl-tRNA synthetase underlies an au...	ACCEPT	Summary: Direct alanine-dependent aminoacylation measurements using recombinant wild-type and disease-variant human AARS1. Reason: The assay directly establishes the substrate-specific core molecular function. Supporting Evidence: PMID:28493438 The aminoacylation activities of both variants were then tested using 14C-labeled alanine with various concentrations of tRNA.
GO:0006419 alanyl-tRNA aminoacylation	IDA PMID:28493438 Deficient activity of alanyl-tRNA synthetase underlies an au...	ACCEPT	Summary: Direct human AARS1 aminoacylation data, with disease variants reducing catalytic efficiency. Reason: The measured reaction is the conserved core alanyl-tRNA aminoacylation process. Supporting Evidence: PMID:28493438 The p.Gly913Asp mutation led to a 73% decrease in catalytic efficiency.
GO:0004813 alanine-tRNA ligase activity	IDA PMID:27622773 Evolutionary Gain of Alanine Mischarging to Noncognate tRNAs...	ACCEPT	Summary: Recombinant human AARS1 charges cognate tRNA(Ala) and can also mischarge selected noncognate tRNAs. Reason: The data directly establish alanine-tRNA ligase activity; limited noncognate charging does not negate the cognate core function. Supporting Evidence: PMID:27622773 for human AlaRS, in addition to the cognate tRNAAla species, we readily detected 3H-signals for cytoplasmic tRNACys(GCA), tRNAThr(CGT/IGT)
GO:0006419 alanyl-tRNA aminoacylation	IDA PMID:27622773 Evolutionary Gain of Alanine Mischarging to Noncognate tRNAs...	ACCEPT	Summary: Direct human AARS1 assays show charging of cognate tRNA(Ala). Reason: This directly supports the core process, notwithstanding the study's additional discovery of limited noncognate charging. Supporting Evidence: PMID:27622773 Remarkably, for human AlaRS, in addition to the cognate tRNAAla species, we readily detected 3H-signals for cytoplasmic tRNACys(GCA), tRNAThr(CGT/IGT) (but not tRNAThr(TGT)), and mitochondrial tRNAAsp (mt-tRNAAsp) (Fig. 1b).
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	MARK AS OVER ANNOTATED	Summary: Membrane-enriched NK-cell proteomics detected soluble AARS1; the study recovered many nonintegral or transiently associated proteins. Reason: Fraction recovery does not establish membrane as a stable AARS1 localization; the soluble enzyme lacks a transmembrane segment. Supporting Evidence: PMID:19946888 The remaining species were largely involved in cellular processes and molecular functions that could be predicted to be transiently associated with membranes.
GO:0070062 extracellular exosome	HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote...	KEEP AS NON CORE	Summary: High-throughput mass spectrometry detected AARS1 in highly purified B-cell-derived exosomes. Reason: This credible specialized cargo observation is peripheral to intracellular AARS1 catalysis and does not establish an extracellular function. Supporting Evidence: PMID:20458337 analyzed the total proteome of highly purified B cell-derived exosomes using sensitive and accurate mass spectrometry
GO:0005829 cytosol	TAS Reactome:R-HSA-379864	ACCEPT	Summary: Reactome places AARS1 in the cytosol for its alanine-tRNA charging reaction. Reason: The compartment is appropriate for the cytoplasmic enzyme and is corroborated by HPA.
GO:0000049 tRNA binding	TAS PMID:7654687 Human alanyl-tRNA synthetase: conservation in evolution of c...	ACCEPT	Summary: Author-statement annotation for tRNA binding based on human AlaRS recognition/aminoacylation of tRNA(Ala)-derived acceptor helices. Reason: The cited biochemical work directly demonstrates recognition of tRNA-derived RNA substrates. Supporting Evidence: PMID:7654687 both the E. coli enzyme and the human enzyme purified from Pichia aminoacylate 9-base pair RNA duplexes
GO:0005737 cytoplasm	TAS PMID:7654687 Human alanyl-tRNA synthetase: conservation in evolution of c...	ACCEPT	Summary: Author-statement assignment of cloned human AlaRS to the cytoplasm. Reason: This agrees with independent cytoplasm/cytosol evidence; the abstract-only cache gives no reason to overrule the curator.
GO:0006419 alanyl-tRNA aminoacylation	TAS PMID:7761427 Wide cross-species aminoacyl-tRNA synthetase replacement in ...	ACCEPT	Summary: Author statement for alanyl-tRNA aminoacylation, supported by rescue of yeast lacking cytoplasmic AlaRS with human AARS1. Reason: Cross-species complementation demonstrates accurate AARS1 aminoacylation in vivo. Supporting Evidence: PMID:7761427 Growth of cells harboring the ala1 disrupted allele was restored by a cDNA clone encoding human alanyl-tRNA synthetase
GO:0008033 tRNA processing	TAS PMID:7654687 Human alanyl-tRNA synthetase: conservation in evolution of c...	MODIFY	Summary: The cited study establishes tRNA recognition/aminoacylation, not pre-tRNA maturation; GO:0008033 explicitly precedes aminoacyl-group addition. Reason: The tRNA-directed biology is valid but the process term is wrong; use the alanine-specific aminoacylation process. Proposed replacements: alanyl-tRNA aminoacylation Supporting Evidence: PMID:7654687 both the E. coli enzyme and the human enzyme purified from Pichia aminoacylate 9-base pair RNA duplexes

Core Functions

Cytosolic AARS1 activates L-alanine with ATP and transfers alanine to tRNA(Ala), producing Ala-tRNA(Ala) for cytoplasmic protein synthesis. This substrate-specific aminoacylation reaction is the enzyme's primary conserved activity.

Molecular Function:

alanine-tRNA ligase activity

Directly Involved In:

alanyl-tRNA aminoacylation

Cellular Locations:

cytosol

Supporting Evidence:

PMID:28493438
The aminoacylation activities of both variants were then tested using 14C-labeled alanine with various concentrations of tRNA.
Reactome:R-HSA-379864
AARS (cytosolic alanyl tRNA synthetase) catalyzes the reaction of alanine, tRNA(ala), and ATP to form Ala tRNA(Ala), AMP, and pyrophosphate.

The embedded AARS1 editing apparatus proofreads mischarged tRNA(Ala) and hydrolyzes the incorrect aminoacyl ester. Ser-tRNA(Ala) deacylation is directly demonstrated with human AARS1; Gly-tRNA(Ala) is a plausible conserved substrate but remains untested with the full-length human enzyme. This post-transfer editing preserves cytoplasmic translational fidelity.

Molecular Function:

aminoacyl-tRNA deacylase activity

Directly Involved In:

aminoacyl-tRNA metabolism involved in translational fidelity

Cellular Locations:

cytosol

Supporting Evidence:

PMID:28493438
An in vitro editing activity assay was carried out using [3H] Ser-tRNAAla as a substrate.
PMID:28493438
tRNAAla can be mischarged with serine and glycine by AARS to yield Ser-tRNAAla and Gly-tRNAAla, respectively [Tsui and Fersht 1981]. To maintain the fidelity of aminoacylation, AARS possesses an editing domain that is capable of hydrolyzing the mischarged tRNAAla [Beebe et al. 2003; Guo et al. 2009].
PMID:19661429
In this way, the editing domain checks for mischarging by picking out tRNAs that have Gly or Ser and a G3•U70 pair.

As a conditional secondary activity, AARS1 senses elevated intracellular L-lactate, forms lactoyl-AMP, and transfers lactyl groups to protein lysines. This activity can operate in the cytoplasm and, after lactate-induced nuclear import, in the nucleus on substrates including YAP1, TEAD1, and TP53. It is substrate- and context-dependent; AARS1 depletion does not reduce basal global lysine lactylation in untreated HEK293T cells.

Molecular Function:

peptide lactyltransferase (ATP-dependent) activity

Cellular Locations:

cytoplasm nucleus

Supporting Evidence:

PMID:38512451
AARS1 was able to directly lactylate histone H3 and H4 in a manner dependent on both lactate and ATP
PMID:38512451
addition of lactate significantly promoted the nuclear localization of WT AARS1 but not the ΔNLS mutant
PMID:38653238
AARS1 binds to lactate and catalyzes the formation of lactate-AMP, followed by transfer of lactate to the lysince acceptor residue.
PMID:40835008
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.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000104

Electronic Gene Ontology annotations created by transferring manual GO annotations between related proteins based on shared sequence features

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

file:human/AARS1/AARS1-uniprot.txt

UniProtKB record for human AARS1 (P49588)

PMID:19946888

Defining the membrane proteome of NK cells.

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."

PMID:20458337

MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.

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."

PMID:25817015

Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect.

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."
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."

PMID:27622773

Evolutionary Gain of Alanine Mischarging to Noncognate tRNAs with a G4:U69 Base Pair.

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."
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."

PMID:27911835

Two crystal structures reveal design for repurposing the C-Ala domain of human AlaRS.

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."
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."

PMID:28493438

Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy.

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."
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."

PMID:33909043

Protein instability associated with AARS1 and MARS1 mutations causes trichothiodystrophy.

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."
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."

PMID:38512451

The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to promote YAP signaling in gastric cancer.

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."
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."

PMID:38653238

Alanyl-tRNA synthetase, AARS1, is a lactate sensor and lactyltransferase that lactylates p53 and contributes to tumorigenesis.

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."
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."

PMID:39322678

AARS1 and AARS2 sense L-lactate to regulate cGAS as global lysine lactyltransferases.

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."
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."

PMID:19661429

The C-Ala domain brings together editing and aminoacylation functions on one tRNA.

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."
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)."

PMID:29273753

Double mimicry evades tRNA synthetase editing by toxic vegetable-sourced non-proteinogenic amino acid.

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."

PMID:30124830

Hypermorphic and hypomorphic AARS alleles in patients with CMT2N expand clinical and molecular heterogeneities.

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."
The hypermorphic p.Glu337Lys allele increases tRNA charging velocity.

"Further, aminoacylation assays confirmed that the third mutation (p.Glu337Lys) increases tRNA charging velocity."

PMID:40835008

Class I histone deacetylases catalyze lysine lactylation.

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."
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)."

PMID:7654687

Human alanyl-tRNA synthetase: conservation in evolution of catalytic core and microhelix recognition.

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."
The expressed human enzyme behaves as a monomer.

"This divergence correlates with the expressed human enzyme behaving as a monomer."

PMID:7761427

Wide cross-species aminoacyl-tRNA synthetase replacement in vivo: yeast cytoplasmic alanine enzyme replaced by human polymyositis serum antigen.

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."
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."

Reactome:R-HSA-379716

Cytosolic tRNA aminoacylation

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."

Reactome:R-HSA-379864

alanine + tRNA(Ala) + ATP => Ala-tRNA(Ala) + AMP + pyrophosphate

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)."

Suggested Experiments

Experiment: Prepare homogeneous Gly-tRNA(Ala) and Ser-tRNA(Ala), then measure steady-state and single-turnover deacylation by purified full-length human AARS1. Include catalytic- site and editing-site mutants, uncharged tRNA(Ala), cognate Gly-tRNA(Gly) and Ser-tRNA(Ser), and Escherichia coli AlaRS controls to establish substrate specificity and support or reject a direct human GO:0106026 annotation.

Hypothesis: Full-length human AARS1 directly edits Gly-tRNA(Ala), but with kinetics distinct from its directly established Ser-tRNA(Ala) editing activity.

Type: biochemical enzyme kinetics

Experiment: Use acute endogenous AARS1 degradation across a calibrated intracellular lactate series, followed by isotope-resolved quantitative lactyl-proteomics and targeted measurement of YAP1, TEAD1, and TP53 sites. Rescue with matched-expression AARS1 variants that retain aminoacylation but differ in lactyltransferase activity, and compare with class I HDAC perturbation to separate AARS1-specific sites from the broader lactylome.

Hypothesis: Endogenous AARS1 contributes substantially to a restricted high-lactate, substrate-specific lactylome but not to basal global lysine lactylation.

Type: acute perturbation and quantitative proteomics

Experiment: Express P49588-1 and P49588-2 at matched endogenous levels in an AARS1-depleted human cell line and compare tRNA(Ala) charging, Ser/Gly-tRNA(Ala) editing, basal and lactate-induced localization, oligomeric state, DNA binding, and site-specific YAP1/TEAD1/TP53 lactylation. Parallel purified-protein assays should distinguish intrinsic isoform differences from cellular localization effects.

Hypothesis: The isoform-2 insertion within C-Ala changes AARS1 editing coordination or its conditional noncanonical activities without abolishing alanine charging.

Type: isoform-resolved biochemical and cell-rescue analysis

Knowledge Gaps

What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).

Gap: Whether full-length human AARS1 directly deacylates Gly-tRNA(Ala), and its kinetic specificity for Gly-tRNA(Ala) relative to Ser-tRNA(Ala), remain experimentally unresolved.

OPEN BIOLOGYCURATION RESIDUAL_SUBGAP

What is known: Recombinant human AARS1 directly deacylates Ser-tRNA(Ala). Conserved AlaRS-family experiments identify both glycine and serine errors, and human C-Ala restores an Escherichia coli editing construct. These observations motivate a human glycine- editing hypothesis but do not provide a verified source for a GO ISS transfer.

Significance: Direct human kinetics would determine whether GO:0106026 should be supported by IDA and whether glycine and serine errors are cleared with comparable efficiency.

What would resolve it: Measure steady-state and single-turnover deacylation of purified Gly-tRNA(Ala) and Ser-tRNA(Ala) by full-length recombinant human AARS1, with editing-site mutants and the bacterial enzyme as controls.

Provenance (the field's own admissions):

"tRNAAla can be mischarged with serine and glycine by AARS to yield Ser-tRNAAla and Gly-tRNAAla, respectively [Tsui and Fersht 1981]. To maintain the fidelity of aminoacylation, AARS possesses an editing domain that is capable of hydrolyzing the mischarged tRNAAla [Beebe et al. 2003; Guo et al. 2009]." — PMID:28493438
"In this way, the editing domain checks for mischarging by picking out tRNAs that have Gly or Ser and a G3•U70 pair." — PMID:19661429

Gap: The physiological lactate range, cell states, and substrate spectrum in which endogenous AARS1 makes a material contribution to protein lysine lactylation, relative to other enzymatic routes, remain incompletely defined.

OPEN BIOLOGYCURATION RESIDUAL_SUBGAP

What is known: ATP-dependent AARS1 lactyltransferase chemistry and several target-specific effects are reproducible under elevated-lactate tumor conditions, but AARS1 knockdown does not lower basal global lysine lactylation in untreated HEK293T cells and the reported lactoyl-AMP reaction has a millimolar lactate Km.

Significance: Resolving this boundary would distinguish physiological AARS1 substrates from high-lactate or overexpression effects and prevent substrate-specific activity from being generalized to the basal global lactylome.

What would resolve it: Quantify endogenous, site-resolved lactylation across a calibrated intracellular lactate series after acute AARS1 depletion and matched rescue, alongside perturbation of class I HDAC-dependent lactylation and measurement of AARS1 charging activity.

Provenance (the field's own admissions):

"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." — PMID:38512451
"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." — PMID:40835008
"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)." — PMID:40835008

Gap: It is unknown whether the two human AARS1 isoforms differ in aminoacylation, editing, lactate-responsive localization, or lactyltransferase activity, and whether the isoform-2 insertion within C-Ala changes the domain's cellular role.

OPEN BIOLOGY RESIDUAL_SUBGAP

What is known: UniProt records two splice isoforms, while structural work establishes distinctive DNA-binding and oligomeric surfaces for human C-Ala only in isolated-domain or structural assays; no isoform-specific core function is assigned here.

Significance: Isoform-specific activity could alter translational quality control or conditional lactylation without being visible in canonical-sequence annotations.

What would resolve it: Compare endogenous-level P49588-1 and P49588-2 rescue constructs in an AARS1-depleted human cell background for charging, editing, localization, oligomerization, DNA binding, and target-specific lactylation.

Provenance (the field's own admissions):

"Event=Alternative splicing; Named isoforms=2;" — file:human/AARS1/AARS1-uniprot.txt
"K -> KATQGPGSPPLGLISSL (in isoform 2)" — file:human/AARS1/AARS1-uniprot.txt
"Direct DNA binding by human C-Ala, but not by bacterial C-Ala, was demonstrated." — PMID:27911835

📚 Additional Documentation

Notes

(AARS1-notes.md)

AARS1 review notes

Research provenance

just deep-research-falcon human AARS1 --fallback perplexity-lite was attempted on 2026-08-08. Falcon/Edison returned an HTTP 402 payment-required response, and the configured Perplexity fallback returned an HTTP 401 insufficient-quota response. No provider-authored report was produced.
just deep-research-openai human AARS1 --timeout 600 was also attempted. It failed before research began because the configured o3-deep-research-2025-06-26 model was unavailable (HTTP 404). No partial report was retained or replaced with manually authored provider content.
The review therefore uses the fetched UniProt and GOA records, live ontology checks, cached Reactome records, and cached primary publications. The claims below are anchored directly to those sources.

Canonical aminoacylation function

AARS1 is the monomeric human cytosolic alanyl-tRNA synthetase. It recognizes the conserved G3:U70 acceptor-stem determinant and attaches alanine to tRNA(Ala). Recombinant human enzyme expressed in Pichia aminoacylated RNA duplexes derived from either bacterial or human tRNA(Ala) acceptor stems, and behaved as a monomer [PMID:7654687, "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."] [PMID:7654687, "This divergence correlates with the expressed human enzyme behaving as a monomer."]. Human disease variants have also been tested with purified recombinant AARS1, directly confirming loss of alanine-charging efficiency for specific recessive alleles [PMID:28493438, "The aminoacylation activities of both variants were then tested using 14C-labeled alanine with various concentrations of tRNA."] [PMID:28493438, "The results showed that the p.Tyr690Leufs*3 mutation caused a 86% decrease in catalytic efficiency (kcat/Km) (Fig. 1D)."]

Post-transfer editing and translational fidelity

The editing domain hydrolyzes incorrectly charged tRNA(Ala), preventing serine and related near-cognate amino acids from entering proteins at alanine codons. Direct human assays used Ser-tRNA(Ala) and showed that an editing-domain truncation sharply reduced deacylation and increased serine misacylation [PMID:28493438, "An in vitro editing activity assay was carried out using [3H] Ser-tRNAAla as a substrate."] [PMID:28493438, "Compared with the wild-type, more than 3-fold higher accumulation of [3H] Ser-tRNAAla was observed in the p.Tyr690Leufs*3 mutant (Fig. 1F), confirming that misacylation resulted from the editing deficiency."]. An independent structural and biochemical study found that the human AlaRS editing system rejects more than 99% of activated azetidine-2-carboxylic acid, illustrating broader substrate-quality control [PMID:29273753, "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."].

This editing is aminoacyl-tRNA quality control, not covalent modification of tRNA nucleotides and not pre-tRNA maturation. Accordingly, the source annotations to tRNA modification and tRNA processing should be redirected to translational-fidelity metabolism and alanyl-tRNA aminoacylation, respectively.

Conditional protein lactyltransferase activity

At high intracellular lactate, AARS1 can use lactate and ATP to form lactoyl-AMP and transfer the lactyl group to protein lysines. Purified recombinant AARS1 directly lactylated histones and an H3 peptide in a lactate- and ATP-dependent reaction [PMID:38512451, "The results showed that AARS1 was able to directly lactylate histone H3 and H4 in a manner dependent on both lactate and ATP (Figure 1C and Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/JCI174587DS1)."] [PMID:38512451, "Subsequent mass spectrometry also confirmed that AARS1 was indeed able to directly lactylate the H3 peptide at K18 in the presence of lactate and ATP (Figure 1D)."]. This is a genuine second catalytic activity, but it is conditional and should not displace aminoacylation/editing as the constitutive core.

Lactate promotes KPNA4-dependent AARS1 nuclear import in gastric-cancer models [PMID:38512451, "Moreover, lactate promoted the interaction of AARS1 with KPNA4, while deletion of the NLS in AARS1 abolished such interaction (Supplemental Figure 1M), results suggesting that KPNA4 binds to the NLS motif of AARS1 to mediate its nuclear translocation."]. In the nucleus, AARS1 lactylates YAP1 and TEAD1 and increases their transcriptional output. Because the GO Hippo pathway is defined by kinase-cascade phosphorylation that retains or degrades YAP, activation and nuclear retention of YAP-TEAD represents negative, not positive, regulation of Hippo signaling. The paper itself describes the downstream output directly [PMID:38512451, "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."]. A separate study supports AARS1-dependent TP53 lactylation and inhibition, but that tumor-context output remains non-core.

The breadth of AARS1's contribution to cellular lactylation is context dependent. In untreated proliferating HEK293T cells, depletion of AARS1 or AARS2 did not reduce basal global lysine lactylation [PMID:40835008, "To compare the relative contribution of AARS enzymes towards global basal levels of Kla in cells, we used siRNA to knockdown AARS1 and AARS2. 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."]. This scopes the activity to high-lactate and substrate-specific settings; it does not negate the direct enzymology.

Disease-mechanism boundary

AARS1-associated disease cannot be reduced to a single simple loss-of-function mechanism. Recessive neurodevelopmental alleles can reduce protein abundance, aminoacylation, or editing. Dominant neuropathy alleles include both hypoactive and hyperactive charging variants: two tested alleles were loss of function, whereas p.Glu337Lys increased tRNA-charging velocity [PMID:30124830, "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."] [PMID:30124830, "Further, aminoacylation assays confirmed that the third mutation (p.Glu337Lys) increases tRNA charging velocity."]. These findings support the centrality of accurately regulated charging/editing but do not justify a disease-process GO annotation as a general molecular function.

Annotation boundaries

The membrane HDA observation comes from a proteome-wide fractionation study and is not a defining location for this soluble cytosolic enzyme.
Extracellular-exosome detection is retained only as contextual/non-core evidence; it does not establish a secreted AARS1 function.
Nuclear localization and YAP1/TEAD1/TP53 signaling are lactate- and disease-model-dependent outputs of the conditional lactyltransferase activity.
AARS1 is monomeric; KPNA4, YAP1, TEAD1, TP53, and ANKRD16 relationships do not establish a constitutive stable AARS1 complex.
The cGAS-inhibition experiments in PMID:39322678 specifically assign the functional cGAS substrate role to AARS2. They support shared AARS1/AARS2 lactyltransferase chemistry but should not be converted into an AARS1-specific cGAS regulatory function.

📄 View Raw YAML

id: P49588
gene_symbol: AARS1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  AARS1 is a predominantly cytosolic, monomeric class II alanyl-tRNA synthetase
  that activates L-alanine with ATP and transfers it to cytosolic tRNA(Ala). Its
  editing domain hydrolyzes incorrectly charged Ser-tRNA(Ala), while the C-terminal
  C-Ala region helps coordinate tRNA recognition, aminoacylation, and post-transfer
  editing to preserve translational fidelity. Under high intracellular L-lactate,
  AARS1 can also generate lactoyl-AMP and transfer lactyl groups to protein lysines.
  Lactate-dependent nuclear import enables context-specific lactylation of YAP1,
  TEAD1, and TP53, increasing YAP-TEAD transcriptional output and suppressing p53
  signaling in tumor models; this activity is not required for basal global lysine
  lactylation in untreated HEK293T cells. Pathogenic AARS1 variants cause recessive
  neurodevelopmental syndromes and dominant axonal neuropathy through heterogeneous
  effects on protein abundance, aminoacylation, editing, or charging kinetics.
alternative_products:
- name: '1'
  id: P49588-1
- name: '2'
  id: P49588-2
  sequence_note: VSP_057201, VSP_057202
existing_annotations:
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  supporting_entities:
  - PANTHER:PTN002622950
  - UniProtKB:P49588
  review:
    summary: >-
      IBA cytosol assignment, consistent with AARS1's identity as the cytoplasmic AlaRS
      and with independent HPA and experimental cytoplasmic localization.
    action: ACCEPT
    reason: >-
      The cytosol is the primary compartment for the core tRNA-charging and editing
      functions.
    additional_reference_ids:
    - PMID:27911835
    - PMID:38512451
    propagation_review:
      root_cause: NO_FAILURE_CORE
- term:
    id: GO:0004813
    label: alanine-tRNA ligase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  supporting_entities:
  - CGD:CAL0000182169
  - MGI:MGI:2384560
  - PANTHER:PTN000206950
  - RGD:1304832
  - SGD:S000005862
  - UniProtKB:P00957
  - UniProtKB:P49588
  - UniProtKB:Q5JTZ9
  review:
    summary: >-
      IBA assignment of substrate-specific alanine-tRNA ligase activity, corroborated by
      multiple human biochemical studies.
    action: ACCEPT
    reason: >-
      This is AARS1's principal conserved molecular function.
    additional_reference_ids:
    - PMID:25817015
    - PMID:27622773
    - PMID:28493438
    propagation_review:
      root_cause: NO_FAILURE_CORE
    supported_by:
    - reference_id: PMID:28493438
      supporting_text: >-
        The aminoacylation activities of both variants were then tested using 14C-labeled
        alanine with various concentrations of tRNA.
- term:
    id: GO:0002161
    label: aminoacyl-tRNA deacylase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  supporting_entities:
  - MGI:MGI:2384560
  - PANTHER:PTN000206950
  - UniProtKB:P00957
  - UniProtKB:P49588
  - UniProtKB:Q57984
  review:
    summary: >-
      IBA assignment of the editing-domain deacylase activity; human AARS1 editing was
      directly measured with Ser-tRNA(Ala).
    action: ACCEPT
    reason: >-
      Post-transfer editing is a conserved core function and is directly verified in the
      human target.
    additional_reference_ids:
    - PMID:28493438
    propagation_review:
      root_cause: NO_FAILURE_CORE
    supported_by:
    - reference_id: PMID:28493438
      supporting_text: >-
        AARS possesses an editing domain that is capable of hydrolyzing the mischarged
        tRNAAla
- term:
    id: GO:0006419
    label: alanyl-tRNA aminoacylation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  supporting_entities:
  - CGD:CAL0000182169
  - MGI:MGI:2384560
  - PANTHER:PTN000206950
  - RGD:1304832
  - SGD:S000005862
  - UniProtKB:P00957
  - UniProtKB:P49588
  - UniProtKB:Q5JTZ9
  review:
    summary: >-
      IBA assignment of the process producing Ala-tRNA(Ala), supported by human
      enzymology and cross-species complementation.
    action: ACCEPT
    reason: >-
      Alanyl-tRNA aminoacylation is the central conserved process executed by AARS1.
    additional_reference_ids:
    - PMID:27622773
    - PMID:28493438
    - PMID:7761427
    propagation_review:
      root_cause: NO_FAILURE_CORE
- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  supporting_entities:
  - InterPro:IPR002318
  - InterPro:IPR018162
  - InterPro:IPR018163
  - InterPro:IPR018164
  review:
    summary: >-
      InterPro inference of generic nucleotide binding from AlaRS catalytic/editing
      domains; the relevant nucleotide substrate is ATP.
    action: MODIFY
    reason: >-
      The parent binding term is true but too broad; ATP binding is the mechanistically
      relevant specificity.
    proposed_replacement_terms:
    - id: GO:0005524
      label: ATP binding
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
- term:
    id: GO:0003676
    label: nucleic acid binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  supporting_entities:
  - InterPro:IPR003156
  - InterPro:IPR018165
  review:
    summary: >-
      InterPro inference of generic nucleic-acid binding; the core physiological
      nucleic-acid ligand is tRNA.
    action: MODIFY
    reason: >-
      Use informative tRNA binding. Isolated C-Ala can bind DNA in vitro, but that does
      not justify generic nucleic-acid binding as the core annotation.
    proposed_replacement_terms:
    - id: GO:0000049
      label: tRNA binding
    additional_reference_ids:
    - PMID:7654687
    - PMID:27911835
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
- term:
    id: GO:0004812
    label: aminoacyl-tRNA ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  supporting_entities:
  - InterPro:IPR012947
  review:
    summary: >-
      InterPro inference of broad aminoacyl-tRNA ligase activity from the class-II
      synthetase fold.
    action: MODIFY
    reason: >-
      The activity is correct but too general for a protein with established alanine
      specificity.
    proposed_replacement_terms:
    - id: GO:0004813
      label: alanine-tRNA ligase activity
    additional_reference_ids:
    - PMID:25817015
    - PMID:28493438
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
- term:
    id: GO:0004813
    label: alanine-tRNA ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  supporting_entities:
  - ARBA:ARBA00087807
  - UniProtKB:P50475
  - ensembl:ENSRNOP00000025051
  - UniProtKB:Q8BGQ7
  - ensembl:ENSMUSP00000034441
  - InterPro:IPR018162
  - InterPro:IPR018164
  - InterPro:IPR018165
  - InterPro:IPR023033
  - RHEA:12540
  - EC:6.1.1.7
  - UniRule:UR000375824
  review:
    summary: >-
      Convergent ARBA, UniRule, InterPro, EC 6.1.1.7 and RHEA:12540 assignment of
      alanine-tRNA ligase activity.
    action: ACCEPT
    reason: >-
      The electronic mapping exactly matches the directly characterized core reaction.
    additional_reference_ids:
    - PMID:25817015
    - PMID:27622773
    - PMID:28493438
    propagation_review:
      root_cause: NO_FAILURE_CORE
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  supporting_entities:
  - UniProtKB:P50475
  - ensembl:ENSRNOP00000025051
  - InterPro:IPR012947
  - InterPro:IPR018162
  - InterPro:IPR018164
  - InterPro:IPR018165
  - UniRule:UR000375824
  review:
    summary: >-
      Electronic ATP-binding assignment from conserved AlaRS catalytic domains and
      UniRule.
    action: ACCEPT
    reason: >-
      ATP binding is obligatory for adenylate-intermediate formation in AARS1 catalysis.
    additional_reference_ids:
    - PMID:38512451
    propagation_review:
      root_cause: NO_FAILURE_CORE
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  supporting_entities:
  - UniProtKB-SubCell:SL-0191
  review:
    summary: >-
      Electronic nuclear localization mapped from reviewed UniProt localization and
      corroborated by lactate-induced, KPNA4-dependent nuclear entry in human cells.
    action: ACCEPT
    reason: >-
      The nucleus is a bona fide elevated-lactate conditional execution site for
      AARS1 protein lactyltransferase activity. Acceptance does not imply that AARS1
      is constitutively nuclear or that the nucleus replaces its primary cytoplasmic
      localization.
    additional_reference_ids:
    - PMID:38512451
    propagation_review:
      root_cause: NO_FAILURE_CORE
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  supporting_entities:
  - InterPro:IPR002318
  - InterPro:IPR018162
  - UniProtKB-SubCell:SL-0086
  review:
    summary: >-
      Electronic cytoplasmic localization inferred from AlaRS domains and reviewed
      UniProt localization.
    action: ACCEPT
    reason: >-
      The cytoplasm is the primary setting for AARS1 tRNA charging/editing and is
      independently observed in human cells.
    additional_reference_ids:
    - PMID:27911835
    - PMID:38512451
    propagation_review:
      root_cause: NO_FAILURE_CORE
- term:
    id: GO:0006419
    label: alanyl-tRNA aminoacylation
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  supporting_entities:
  - ARBA:ARBA00085735
  - UniProtKB:P50475
  - ensembl:ENSRNOP00000025051
  - UniProtKB:Q8BGQ7
  - ensembl:ENSMUSP00000034441
  - InterPro:IPR018162
  - InterPro:IPR018164
  - InterPro:IPR018165
  review:
    summary: >-
      Electronic assignment of alanyl-tRNA aminoacylation from convergent family,
      orthology and domain evidence.
    action: ACCEPT
    reason: >-
      This is AARS1's core process and is directly established by human enzymology and
      loss-of-function studies.
    additional_reference_ids:
    - PMID:25817015
    - PMID:27622773
    - PMID:28493438
    - PMID:33909043
    propagation_review:
      root_cause: NO_FAILURE_CORE
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  qualifier: enables
  supporting_entities:
  - UniRule:UR000375824
  review:
    summary: >-
      UniRule transfer of zinc-ion binding; the reviewed AARS1 record specifies one zinc
      ion per subunit.
    action: ACCEPT
    reason: >-
      Zinc binding is a conserved component of AlaRS architecture with no evidence of
      target-specific loss.
    propagation_review:
      root_cause: NO_FAILURE_CORE
- term:
    id: GO:0043039
    label: tRNA aminoacylation
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  supporting_entities:
  - InterPro:IPR012947
  review:
    summary: >-
      InterPro inference of broad tRNA aminoacylation from the tRNA-synthetase
      additional domain.
    action: MODIFY
    reason: >-
      Use the alanine-specific child process established for AARS1.
    proposed_replacement_terms:
    - id: GO:0006419
      label: alanyl-tRNA aminoacylation
    additional_reference_ids:
    - PMID:27622773
    - PMID:28493438
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
- term:
    id: GO:0106074
    label: aminoacyl-tRNA metabolism involved in translational fidelity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  supporting_entities:
  - GO:0002161
  - GO:0002196
  review:
    summary: >-
      Electronic inference of aminoacyl-tRNA quality-control metabolism from AARS1's
      deacylase activities.
    action: ACCEPT
    reason: >-
      The term accurately captures editing that removes incorrect amino acids from
      charged tRNA.
    additional_reference_ids:
    - PMID:28493438
    propagation_review:
      root_cause: NO_FAILURE_CORE
- term:
    id: GO:0141207
    label: peptide lactyltransferase (ATP-dependent) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  supporting_entities:
  - ARBA:ARBA00085408
  - RHEA:80271
  - RHEA:80275
  review:
    summary: >-
      Electronic assignment of ATP-dependent peptide lactyltransferase activity from the
      exact Rhea reactions, corroborated by three independent 2024 studies.
    action: ACCEPT
    reason: >-
      This is a real intrinsic AARS1 activity under elevated-lactate and
      substrate-specific conditions; PMID:40835008 shows it is not required for basal
      global Kla in HEK293T cells.
    additional_reference_ids:
    - PMID:38512451
    - PMID:38653238
    - PMID:39322678
    - PMID:40835008
    propagation_review:
      root_cause: NO_FAILURE_CORE
    supported_by:
    - reference_id: PMID:38512451
      supporting_text: >-
        AARS1 was able to directly lactylate histone H3 and H4 in a manner dependent on
        both lactate and ATP
    - reference_id: PMID:40835008
      supporting_text: >-
        However, the knockdown of either enzyme did not alter Kla levels
- term:
    id: GO:0000049
    label: tRNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  supporting_entities:
  - UniProtKB:P50475
  - ensembl:ENSRNOP00000025051
  review:
    summary: >-
      Ensembl orthology transfer of tRNA binding from rat AARS1, concordant with human
      tRNA/microhelix recognition experiments.
    action: ACCEPT
    reason: >-
      tRNA binding is essential to aminoacylation/editing and is conserved in
      cytoplasmic AlaRS.
    additional_reference_ids:
    - PMID:7654687
    propagation_review:
      root_cause: NO_FAILURE_CORE
- term:
    id: GO:0002161
    label: aminoacyl-tRNA deacylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  supporting_entities:
  - UniProtKB:Q8BGQ7
  - ensembl:ENSMUSP00000034441
  review:
    summary: >-
      Ensembl transfer of aminoacyl-tRNA deacylase activity from mouse Aars,
      independently verified by human editing assays.
    action: ACCEPT
    reason: >-
      The editing domain and activity are conserved and directly present in the human
      target.
    additional_reference_ids:
    - PMID:28493438
    propagation_review:
      root_cause: NO_FAILURE_CORE
- term:
    id: GO:0002196
    label: Ser-tRNA(Ala) deacylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  supporting_entities:
  - UniProtKB:Q8BGQ7
  - ensembl:ENSMUSP00000034441
  review:
    summary: >-
      Ensembl transfer of Ser-tRNA(Ala) deacylase activity from mouse Aars,
      independently measured for recombinant human AARS1.
    action: ACCEPT
    reason: >-
      Direct human evidence makes this substrate-specific orthology transfer safe.
    additional_reference_ids:
    - PMID:28493438
    propagation_review:
      root_cause: NO_FAILURE_CORE
- term:
    id: GO:0006400
    label: tRNA modification
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  supporting_entities:
  - UniProtKB:Q8BGQ7
  - ensembl:ENSMUSP00000034441
  review:
    summary: >-
      Ensembl transfer of tRNA modification from mouse Aars, apparently intended to
      represent editing of mischarged tRNA(Ala).
    action: MODIFY
    reason: >-
      GO:0006400 requires covalent alteration of tRNA nucleotides; AARS1 instead
      hydrolyzes a mischarged amino acid. Use the explicit aminoacyl-tRNA fidelity
      process.
    proposed_replacement_terms:
    - id: GO:0106074
      label: aminoacyl-tRNA metabolism involved in translational fidelity
    additional_reference_ids:
    - PMID:28493438
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - ROLE_CONFLATION
- term:
    id: GO:0016597
    label: amino acid binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  supporting_entities:
  - UniProtKB:P50475
  - ensembl:ENSRNOP00000025051
  review:
    summary: >-
      Ensembl transfer of generic amino-acid binding from rat AARS1; alanine is the
      characterized cognate substrate.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic amino-acid binding is not an informative independent molecular function
      here; the directly supported alanine-tRNA ligase annotations already capture
      substrate recognition in its catalytic context.
    additional_reference_ids:
    - PMID:25817015
    - PMID:28493438
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
- term:
    id: GO:0140018
    label: regulation of cytoplasmic translational fidelity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  supporting_entities:
  - UniProtKB:Q8BGQ7
  - ensembl:ENSMUSP00000034441
  review:
    summary: >-
      Ensembl transfer of regulation of cytoplasmic translational fidelity from mouse
      Aars.
    action: MODIFY
    reason: >-
      The existing term describes a valid downstream consequence of AARS1 proofreading,
      but the replacement more directly captures its aminoacyl-tRNA editing mechanism.
    proposed_replacement_terms:
    - id: GO:0106074
      label: aminoacyl-tRNA metabolism involved in translational fidelity
    additional_reference_ids:
    - PMID:28493438
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
- term:
    id: GO:0004813
    label: alanine-tRNA ligase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-379864
  qualifier: enables
  review:
    summary: >-
      Reactome assigns alanine-tRNA ligase activity to AARS1 in the cytosolic
      Ala-tRNA(Ala) reaction.
    action: ACCEPT
    reason: >-
      The reaction and specificity exactly match the directly characterized core
      activity.
    additional_reference_ids:
    - PMID:25817015
    - PMID:28493438
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      HPA immunofluorescence places AARS1 in the cytosol.
    action: ACCEPT
    reason: >-
      Cytosolic localization is consistent with AARS1's core role as the cytoplasmic
      alanine-tRNA synthetase.
- term:
    id: GO:0004813
    label: alanine-tRNA ligase activity
  evidence_type: EXP
  original_reference_id: PMID:25817015
  qualifier: enables
  review:
    summary: >-
      Experimental annotation from human loss-of-function variants with reduced
      alanyl-tRNA charging.
    action: ACCEPT
    reason: >-
      The study supports the core catalytic activity; because the cache is
      abstract-only, the curator's full-text experimental assessment is retained.
    supported_by:
    - reference_id: PMID:25817015
      supporting_text: >-
        demonstrating that defects of alanyl-tRNA charging can result in a wide spectrum
        of disease manifestations
- term:
    id: GO:0004813
    label: alanine-tRNA ligase activity
  evidence_type: EXP
  original_reference_id: PMID:27911835
  qualifier: enables
  review:
    summary: >-
      Experimental alanine-tRNA ligase annotation associated with structural/biochemical
      analysis of human AlaRS.
    action: ACCEPT
    reason: >-
      The activity is established independently; the abstract-only cache gives no basis
      to overrule the curator.
    additional_reference_ids:
    - PMID:27622773
    - PMID:28493438
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:27911835
  qualifier: located_in
  review:
    summary: >-
      Experimental cytoplasmic localization associated with the human AlaRS structural
      study.
    action: ACCEPT
    reason: >-
      The assignment agrees with HPA, Reactome, UniProt and lactate-response
      localization data; retain the curator's full-text assessment.
    additional_reference_ids:
    - PMID:38512451
- term:
    id: GO:0141207
    label: peptide lactyltransferase (ATP-dependent) activity
  evidence_type: IDA
  original_reference_id: PMID:39322678
  qualifier: enables
  review:
    summary: >-
      Direct ATP-dependent peptide lactyltransferase annotation; AARS1/AARS2 act as
      intracellular lactate sensors and directly catalyze lysine lactylation.
    action: ACCEPT
    reason: >-
      Three studies support the activity, qualified to elevated-lactate and
      substrate-specific contexts rather than dominant basal global lactylation.
    additional_reference_ids:
    - PMID:38512451
    - PMID:38653238
    - PMID:40835008
    supported_by:
    - reference_id: PMID:39322678
      supporting_text: >-
        they directly catalyse L-lactate for ATP-dependent lactylation on the lysine
        acceptor end
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:38512451
  qualifier: is_active_in
  review:
    summary: >-
      Direct nuclear localization in gastric-cancer cells under elevated lactate,
      where AARS1 executes protein lactyltransferase activity on YAP and TEAD1.
    action: ACCEPT
    reason: >-
      The nucleus is a directly demonstrated elevated-lactate conditional execution
      site for the accepted lactyltransferase function. This does not imply
      constitutive nuclear localization; cytoplasm remains the primary compartment
      for canonical tRNA charging and editing.
    supported_by:
    - reference_id: PMID:38512451
      supporting_text: >-
        addition of lactate significantly promoted the nuclear localization of WT AARS1
        but not the ΔNLS mutant
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:38512451
  qualifier: is_active_in
  review:
    summary: >-
      Direct cytoplasmic localization with lactate-triggered shuttling to the nucleus.
    action: ACCEPT
    reason: >-
      The cytoplasm is the primary setting for canonical AARS1 charging/editing.
    supported_by:
    - reference_id: PMID:38512451
      supporting_text: >-
        AARS1, commonly understood as an enzyme residing in the cytoplasm
- term:
    id: GO:0035332
    label: positive regulation of hippo signaling
  evidence_type: IDA
  original_reference_id: PMID:38512451
  qualifier: involved_in
  review:
    summary: >-
      The study shows AARS1 lactylates YAP/TEAD and activates YAP-TEAD transcription,
      but GO:0035329 defines Hippo signaling as MST/LATS-driven YAP phosphorylation and
      retention/degradation.
    action: MODIFY
    reason: >-
      The phenotype is credible but GO:0035332 has the wrong sign; activating YAP output
      corresponds to negative regulation of canonical Hippo signaling. Neither sign is
      mechanistically ideal because AARS1 lactylates YAP/TEAD downstream of the MST/LATS
      kinase cascade; GO:0035331 is the least-bad existing pathway term.
    proposed_replacement_terms:
    - id: GO:0035331
      label: negative regulation of hippo signaling
    supported_by:
    - reference_id: PMID:38512451
      supporting_text: >-
        AARS1 translocated into the nucleus, where it directly catalyzed lactylation of
        YAP at K90 and TEAD1 at K108, thereby activating downstream target gene expression
        to promote tumor cell proliferation.
- term:
    id: GO:0141207
    label: peptide lactyltransferase (ATP-dependent) activity
  evidence_type: IDA
  original_reference_id: PMID:38512451
  qualifier: enables
  review:
    summary: >-
      Purified AARS1 uses lactate and ATP to lactylate protein and peptide substrates,
      with cellular validation.
    action: ACCEPT
    reason: >-
      The paper directly supports the GO reaction; qualify the activity to
      elevated-lactate contexts and do not infer dominance over basal global Kla.
    additional_reference_ids:
    - PMID:38653238
    - PMID:39322678
    - PMID:40835008
    supported_by:
    - reference_id: PMID:38512451
      supporting_text: >-
        AARS1 was able to directly lactylate histone H3 and H4 in a manner dependent on
        both lactate and ATP
- term:
    id: GO:0141207
    label: peptide lactyltransferase (ATP-dependent) activity
  evidence_type: IDA
  original_reference_id: PMID:38653238
  qualifier: enables
  review:
    summary: >-
      Direct AARS1-mediated lactate-AMP formation followed by transfer to lysine
      acceptors.
    action: ACCEPT
    reason: >-
      The exact reaction is corroborated independently; it is condition- and
      substrate-dependent rather than the principal basal-global Kla source.
    additional_reference_ids:
    - PMID:38512451
    - PMID:39322678
    - PMID:40835008
    supported_by:
    - reference_id: PMID:38653238
      supporting_text: >-
        AARS1 binds to lactate and catalyzes the formation of lactate-AMP, followed by
        transfer of lactate to the lysince acceptor residue.
- term:
    id: GO:1901797
    label: negative regulation of signal transduction by p53 class mediator
  evidence_type: IDA
  original_reference_id: PMID:38653238
  qualifier: involved_in
  review:
    summary: >-
      AARS1-dependent lactylation of p53 K120/K139 inhibits p53 phase separation, DNA
      binding and transcriptional activation in tumor models.
    action: KEEP_AS_NON_CORE
    reason: >-
      The negative effect on p53 signaling is supported but is a downstream high-lactate
      tumor-context consequence.
    supported_by:
    - reference_id: PMID:38653238
      supporting_text: >-
        AARS1 lactylation of p53 hinders its liquid-liquid phase separation, DNA binding,
        and transcriptional activation.
- term:
    id: GO:0006418
    label: tRNA aminoacylation for protein translation
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-379716
  qualifier: involved_in
  review:
    summary: >-
      Reactome places AARS1 in the broad cytosolic tRNA-aminoacylation pathway.
    action: MODIFY
    reason: >-
      Use the alanine-specific aminoacylation process. GO:0006419 is retained as the
      consistent level across the reviewed source annotations; cytosolic execution is
      represented separately by the accepted localization annotations.
    proposed_replacement_terms:
    - id: GO:0006419
      label: alanyl-tRNA aminoacylation
- term:
    id: GO:0006419
    label: alanyl-tRNA aminoacylation
  evidence_type: IMP
  original_reference_id: PMID:33909043
  qualifier: involved_in
  review:
    summary: >-
      Destabilizing AARS1 variants reduce the rate of tRNA charging in patient
      fibroblasts.
    action: ACCEPT
    reason: >-
      The mutant phenotype directly supports the core alanyl-tRNA aminoacylation
      process.
    supported_by:
    - reference_id: PMID:33909043
      supporting_text: >-
        Functional studies in skin fibroblasts from affected individuals demonstrate that
        these new variants also impact on the rate of tRNA charging
- term:
    id: GO:0002196
    label: Ser-tRNA(Ala) deacylase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  supporting_entities:
  - UniProtKB:Q8BGQ7
  review:
    summary: >-
      Curator-reviewed similarity transfer of Ser-tRNA(Ala) deacylase activity from
      mouse Aars, independently validated by human assays.
    action: ACCEPT
    reason: >-
      Human AARS1 directly deacylates Ser-tRNA(Ala), so the transfer captures a core
      editing activity.
    additional_reference_ids:
    - PMID:28493438
    propagation_review:
      root_cause: NO_FAILURE_CORE
    supported_by:
    - reference_id: PMID:28493438
      supporting_text: >-
        An in vitro editing activity assay was carried out using [3H] Ser-tRNAAla as a
        substrate.
- term:
    id: GO:0006400
    label: tRNA modification
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  supporting_entities:
  - UniProtKB:Q8BGQ7
  review:
    summary: >-
      Curator-reviewed transfer of tRNA modification from mouse Aars, intended to
      represent AlaRS editing.
    action: MODIFY
    reason: >-
      Editing removes the attached amino acid rather than modifying tRNA nucleotides;
      use the mechanistically correct fidelity process.
    proposed_replacement_terms:
    - id: GO:0106074
      label: aminoacyl-tRNA metabolism involved in translational fidelity
    additional_reference_ids:
    - PMID:28493438
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - ROLE_CONFLATION
- term:
    id: GO:0002161
    label: aminoacyl-tRNA deacylase activity
  evidence_type: IDA
  original_reference_id: PMID:28493438
  qualifier: enables
  review:
    summary: >-
      Direct human editing assay demonstrates AARS1 hydrolysis of mischarged
      Ser-tRNA(Ala), including loss of deacylation by an editing-domain disease
      variant.
    action: ACCEPT
    reason: >-
      The Ser-tRNA(Ala) assay directly supports this true broader
      aminoacyl-tRNA deacylase parent activity. The more specific activity is
      already represented by existing GO:0002196 annotations, which cite this
      study as direct corroboration.
    supported_by:
    - reference_id: PMID:28493438
      supporting_text: >-
        An in vitro editing activity assay was carried out using [3H] Ser-tRNAAla as a
        substrate.
- term:
    id: GO:0004813
    label: alanine-tRNA ligase activity
  evidence_type: IDA
  original_reference_id: PMID:28493438
  qualifier: enables
  review:
    summary: >-
      Direct alanine-dependent aminoacylation measurements using recombinant wild-type
      and disease-variant human AARS1.
    action: ACCEPT
    reason: >-
      The assay directly establishes the substrate-specific core molecular function.
    supported_by:
    - reference_id: PMID:28493438
      supporting_text: >-
        The aminoacylation activities of both variants were then tested using 14C-labeled
        alanine with various concentrations of tRNA.
- term:
    id: GO:0006419
    label: alanyl-tRNA aminoacylation
  evidence_type: IDA
  original_reference_id: PMID:28493438
  qualifier: involved_in
  review:
    summary: >-
      Direct human AARS1 aminoacylation data, with disease variants reducing catalytic
      efficiency.
    action: ACCEPT
    reason: >-
      The measured reaction is the conserved core alanyl-tRNA aminoacylation process.
    supported_by:
    - reference_id: PMID:28493438
      supporting_text: >-
        The p.Gly913Asp mutation led to a 73% decrease in catalytic efficiency.
- term:
    id: GO:0004813
    label: alanine-tRNA ligase activity
  evidence_type: IDA
  original_reference_id: PMID:27622773
  qualifier: enables
  review:
    summary: >-
      Recombinant human AARS1 charges cognate tRNA(Ala) and can also mischarge selected
      noncognate tRNAs.
    action: ACCEPT
    reason: >-
      The data directly establish alanine-tRNA ligase activity; limited noncognate
      charging does not negate the cognate core function.
    supported_by:
    - reference_id: PMID:27622773
      supporting_text: >-
        for human AlaRS, in addition to the cognate tRNAAla species, we readily detected
        3H-signals for cytoplasmic tRNACys(GCA), tRNAThr(CGT/IGT)
- term:
    id: GO:0006419
    label: alanyl-tRNA aminoacylation
  evidence_type: IDA
  original_reference_id: PMID:27622773
  qualifier: involved_in
  review:
    summary: >-
      Direct human AARS1 assays show charging of cognate tRNA(Ala).
    action: ACCEPT
    reason: >-
      This directly supports the core process, notwithstanding the study's additional
      discovery of limited noncognate charging.
    supported_by:
    - reference_id: PMID:27622773
      supporting_text: >-
        Remarkably, for human AlaRS, in addition to the cognate tRNAAla species, we
        readily detected 3H-signals for cytoplasmic tRNACys(GCA), tRNAThr(CGT/IGT)
        (but not tRNAThr(TGT)), and mitochondrial tRNAAsp (mt-tRNAAsp) (Fig. 1b).
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: >-
      Membrane-enriched NK-cell proteomics detected soluble AARS1; the study recovered
      many nonintegral or transiently associated proteins.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Fraction recovery does not establish membrane as a stable AARS1 localization; the
      soluble enzyme lacks a transmembrane segment.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: >-
        The remaining species were largely involved in cellular processes and molecular
        functions that could be predicted to be transiently associated with membranes.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:20458337
  qualifier: located_in
  review:
    summary: >-
      High-throughput mass spectrometry detected AARS1 in highly purified B-cell-derived
      exosomes.
    action: KEEP_AS_NON_CORE
    reason: >-
      This credible specialized cargo observation is peripheral to intracellular AARS1
      catalysis and does not establish an extracellular function.
    supported_by:
    - reference_id: PMID:20458337
      supporting_text: >-
        analyzed the total proteome of highly purified B cell-derived exosomes using
        sensitive and accurate mass spectrometry
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-379864
  qualifier: located_in
  review:
    summary: >-
      Reactome places AARS1 in the cytosol for its alanine-tRNA charging reaction.
    action: ACCEPT
    reason: >-
      The compartment is appropriate for the cytoplasmic enzyme and is corroborated by
      HPA.
- term:
    id: GO:0000049
    label: tRNA binding
  evidence_type: TAS
  original_reference_id: PMID:7654687
  qualifier: enables
  review:
    summary: >-
      Author-statement annotation for tRNA binding based on human AlaRS
      recognition/aminoacylation of tRNA(Ala)-derived acceptor helices.
    action: ACCEPT
    reason: >-
      The cited biochemical work directly demonstrates recognition of tRNA-derived RNA
      substrates.
    supported_by:
    - reference_id: PMID:7654687
      supporting_text: >-
        both the E. coli enzyme and the human enzyme purified from Pichia aminoacylate
        9-base pair RNA duplexes
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: TAS
  original_reference_id: PMID:7654687
  qualifier: located_in
  review:
    summary: >-
      Author-statement assignment of cloned human AlaRS to the cytoplasm.
    action: ACCEPT
    reason: >-
      This agrees with independent cytoplasm/cytosol evidence; the abstract-only cache
      gives no reason to overrule the curator.
- term:
    id: GO:0006419
    label: alanyl-tRNA aminoacylation
  evidence_type: TAS
  original_reference_id: PMID:7761427
  qualifier: involved_in
  review:
    summary: >-
      Author statement for alanyl-tRNA aminoacylation, supported by rescue of yeast
      lacking cytoplasmic AlaRS with human AARS1.
    action: ACCEPT
    reason: >-
      Cross-species complementation demonstrates accurate AARS1 aminoacylation in vivo.
    supported_by:
    - reference_id: PMID:7761427
      supporting_text: >-
        Growth of cells harboring the ala1 disrupted allele was restored by a cDNA clone
        encoding human alanyl-tRNA synthetase
- term:
    id: GO:0008033
    label: tRNA processing
  evidence_type: TAS
  original_reference_id: PMID:7654687
  qualifier: involved_in
  review:
    summary: >-
      The cited study establishes tRNA recognition/aminoacylation, not pre-tRNA
      maturation; GO:0008033 explicitly precedes aminoacyl-group addition.
    action: MODIFY
    reason: >-
      The tRNA-directed biology is valid but the process term is wrong; use the
      alanine-specific aminoacylation process.
    proposed_replacement_terms:
    - id: GO:0006419
      label: alanyl-tRNA aminoacylation
    supported_by:
    - reference_id: PMID:7654687
      supporting_text: >-
        both the E. coli enzyme and the human enzyme purified from Pichia aminoacylate
        9-base pair RNA duplexes
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000104
  title: Electronic Gene Ontology annotations created by transferring manual GO annotations
    between related proteins based on shared sequence features
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/AARS1/AARS1-uniprot.txt
  title: UniProtKB record for human AARS1 (P49588)
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reviewed UniProtKB record for human cytosolic alanyl-tRNA synthetase. It
      consolidates the alanine-charging and editing reactions, conditional
      lactyltransferase activity, monomeric state, cytoplasmic and
      lactate-responsive nuclear localization, isoforms, and disease variants,
      while preserving evidence provenance for each assertion.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  full_text_unavailable: true
  findings:
  - statement: >-
      The NK-cell membrane-fraction survey cautions that many detected proteins
      were nonintegral and potentially only transiently membrane associated.
    supporting_text: >-
      The remaining species were largely involved in cellular processes and
      molecular functions that could be predicted to be transiently associated
      with membranes.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      PubMed identity and abstract verified. This high-throughput fractionation
      study is relevant only to the broad HDA membrane tuple; its own caveat makes
      it unsuitable evidence that soluble AARS1 has a functional membrane location.
- id: PMID:20458337
  title: MHC class II-associated proteins in B-cell exosomes and potential functional
    implications for exosome biogenesis.
  full_text_unavailable: true
  findings:
  - statement: >-
      The source is a high-throughput proteomic survey of purified B-cell-derived
      exosomes that identified 539 proteins.
    supporting_text: >-
      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.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      PubMed identity and abstract verified. This source supports context-specific
      high-throughput detection in a B-cell exosome preparation, not a constitutive
      exosomal role for AARS1.
- id: PMID:25817015
  title: Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive
    early-onset epileptic encephalopathy with persistent myelination defect.
  full_text_unavailable: true
  findings:
  - statement: >-
      Biallelic AARS1 variants caused severe infantile encephalopathy and reduced
      enzyme function, linking defective alanyl-tRNA charging to recessive disease.
    supporting_text: >-
      The two identified mutations were found to result in a significant reduction
      in function.
    reference_section_type: ABSTRACT
  - statement: >-
      The authors explicitly concluded that impaired alanyl-tRNA charging can produce
      a broad spectrum of neurological disease.
    supporting_text: >-
      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.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed identity and abstract verified. Direct human genetic and functional
      evidence for recessive loss of AARS1 charging function; the cache is
      abstract-only, so no more detailed assay interpretation is asserted.
- id: PMID:27622773
  title: Evolutionary Gain of Alanine Mischarging to Noncognate tRNAs with a G4:U69
    Base Pair.
  findings:
  - statement: >-
      Human AARS1 can mischarge alanine onto noncognate tRNAs, including tRNA(Cys),
      when their acceptor stems contain a G4:U69 identity element.
    supporting_text: >-
      Here we found human and not E. coli AlaRS has an intrinsic capacity for
      mispairing alanine onto nonalanyl-tRNAs including tRNACys.
    reference_section_type: ABSTRACT
  - statement: >-
      The G4:U69 acceptor-stem base pair is required for this expanded human AARS1
      substrate specificity.
    supporting_text: >-
      All human AlaRS-mischarged tRNAs have a G4:U69 base pair in the acceptor stem.
      The base pair is required for the mischarging.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Full-text primary study with recombinant human enzyme, cellular reporter data,
      and structural analysis. It establishes a noncanonical mischarging capacity,
      but this is secondary to cognate tRNA(Ala) charging and editing.
- id: PMID:27911835
  title: Two crystal structures reveal design for repurposing the C-Ala domain of
    human AlaRS.
  full_text_unavailable: true
  findings:
  - statement: >-
      Human C-Ala adopts a divergent architecture that forms a dimer interface and
      DNA-binding groove rather than retaining the prokaryotic tRNA-docking role.
    supporting_text: >-
      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.
    reference_section_type: ABSTRACT
  - statement: >-
      Purified human C-Ala, but not the bacterial orthologous domain, bound DNA directly.
    supporting_text: >-
      Direct DNA binding by human C-Ala, but not by bacterial C-Ala, was demonstrated.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed identity and abstract verified. Direct structural and binding evidence
      for human C-Ala architecture, but the isolated-domain DNA-binding result does not
      by itself establish a physiological DNA-binding function for full-length AARS1.
- id: PMID:28493438
  title: Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive
    syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy.
  findings:
  - statement: >-
      Two recessive human AARS1 variants reduced recombinant aminoacylation catalytic
      efficiency by 73% to 86%.
    supporting_text: >-
      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.
    reference_section_type: RESULTS
  - statement: >-
      Human AARS1 directly deacylates Ser-tRNA(Ala); the editing-domain truncation
      markedly impaired that activity while another disease variant retained
      wild-type-like deacylation.
    supporting_text: >-
      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.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full-text primary study directly assaying recombinant human AARS1 alanine
      charging and Ser-tRNA(Ala) editing. It strongly supports both canonical
      enzymatic functions and loss-of-function disease mechanisms.
- id: PMID:33909043
  title: Protein instability associated with AARS1 and MARS1 mutations causes trichothiodystrophy.
  full_text_unavailable: true
  findings:
  - statement: >-
      Trichothiodystrophy-associated AARS1 variants destabilize the protein and reduce
      tRNA charging in patient fibroblasts.
    supporting_text: >-
      These variants result in the instability of the respective gene products
      alanyl- and methionyl-tRNA synthetase.
    reference_section_type: ABSTRACT
  - statement: >-
      Patient-fibroblast studies showed that the variants alter the rate of tRNA charging.
    supporting_text: >-
      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.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed identity and abstract verified. Direct patient-cell evidence for an
      AARS1 disease mechanism combining protein instability with impaired charging;
      the source is not needed to define the normal catalytic reaction.
- id: PMID:38512451
  title: The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to promote
    YAP signaling in gastric cancer.
  findings:
  - statement: >-
      AARS1 directly uses lactate and ATP to catalyze protein lysine lactylation.
    supporting_text: >-
      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.
    reference_section_type: ABSTRACT
  - statement: >-
      Intracellular lactate drives AARS1 nuclear translocation, where AARS1 lactylates
      and activates the YAP-TEAD complex.
    supporting_text: >-
      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.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full-text primary study with purified-protein, cellular, and tumor-model
      evidence for AARS1 lactyltransferase activity and lactate-responsive nuclear
      YAP1/TEAD1 regulation. The paper is sound; because YAP activation follows
      inhibition of the upstream Hippo kinase cascade, it supports negative rather
      than positive regulation of GO-defined Hippo signaling.
- id: PMID:38653238
  title: Alanyl-tRNA synthetase, AARS1, is a lactate sensor and lactyltransferase
    that lactylates p53 and contributes to tumorigenesis.
  full_text_unavailable: true
  findings:
  - statement: >-
      AARS1 binds lactate, forms lactate-AMP, and transfers the lactyl group to protein
      lysine residues.
    supporting_text: >-
      AARS1 binds to lactate and catalyzes the formation of lactate-AMP, followed by
      transfer of lactate to the lysince acceptor residue.
    reference_section_type: ABSTRACT
  - statement: >-
      AARS1 lactylates TP53 at Lys-120 and Lys-139, impairing TP53 phase separation,
      DNA binding, and transcriptional activation.
    supporting_text: >-
      AARS1 lactylation of p53 hinders its liquid-liquid phase separation, DNA binding,
      and transcriptional activation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed identity and abstract verified. Direct mechanistic support for the
      lactate-AMP intermediate, protein lactyltransferase activity, and TP53 inhibition.
      Its tumor-cell global-lactylation framing is context dependent in light of
      PMID:40835008; the substrate-specific findings remain supported.
- id: PMID:39322678
  title: AARS1 and AARS2 sense L-lactate to regulate cGAS as global lysine lactyltransferases.
  full_text_unavailable: true
  findings:
  - statement: >-
      AARS1 and AARS2 bind L-lactate and directly catalyze ATP-dependent lysine
      lactylation.
    supporting_text: >-
      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.
    reference_section_type: ABSTRACT
  - statement: >-
      The cGAS association, lactylation, and inactivation experiments in this paper
      identify AARS2, not AARS1, as the responsible paralog.
    supporting_text: >-
      In response to L-lactate, AARS2 associates with cyclic GMP-AMP synthase (cGAS)
      and mediates its lactylation and inactivation in cells and in mice.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed identity and abstract verified. It independently supports shared
      ATP-dependent AARS1/AARS2 lactyltransferase chemistry. The downstream cGAS
      mechanism is explicitly AARS2-specific and must not be assigned to AARS1.
- id: PMID:19661429
  title: The C-Ala domain brings together editing and aminoacylation functions on one
    tRNA.
  findings:
  - statement: >-
      AlaRS editing recognizes tRNA(Ala) mischarged with either glycine or serine.
    supporting_text: >-
      In this way, the editing domain checks for mischarging by picking out tRNAs
      that have Gly or Ser and a G3•U70 pair.
    reference_section_type: DISCUSSION
  - statement: >-
      Human C-Ala and its linker restored nearly full Ser-tRNA(Ala) clearance when
      grafted onto the E. coli AlaRS editing domain.
    supporting_text: >-
      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).
    reference_section_type: RESULTS
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Full-text mechanistic study. It supports conserved Gly/Ser-tRNA(Ala) editing
      specificity and functional conservation of human C-Ala, but the human evidence
      is a cross-species domain graft rather than a direct full-length human
      Gly-tRNA(Ala) deacylation assay; it therefore supports only a cautious ISS claim.
- id: PMID:29273753
  title: Double mimicry evades tRNA synthetase editing by toxic vegetable-sourced
    non-proteinogenic amino acid.
  findings:
  - statement: >-
      Human AARS1 activates the alanine mimic azetidine-2-carboxylic acid but its
      editing system rejects more than 99% of the activated nonproteinogenic substrate.
    supporting_text: >-
      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.
    reference_section_type: INTRODUCTION
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Full-text primary study directly characterizing human AlaRS substrate activation
      and editing selectivity. It corroborates the editing function but addresses a
      dietary nonproteinogenic amino acid rather than the normal Ser/Gly error substrates.
- id: PMID:30124830
  title: Hypermorphic and hypomorphic AARS alleles in patients with CMT2N expand clinical
    and molecular heterogeneities.
  full_text_unavailable: true
  findings:
  - statement: >-
      Dominant CMT2N AARS1 alleles can be hypomorphic or hypermorphic rather than
      sharing one uniform loss-of-function mechanism.
    supporting_text: >-
      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.
    reference_section_type: ABSTRACT
  - statement: >-
      The hypermorphic p.Glu337Lys allele increases tRNA charging velocity.
    supporting_text: >-
      Further, aminoacylation assays confirmed that the third mutation (p.Glu337Lys)
      increases tRNA charging velocity.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed identity and abstract verified. It establishes heterogeneous dominant
      neuropathy mechanisms and prevents overgeneralizing all pathogenic AARS1 alleles
      as simple loss of charging activity.
- id: PMID:40835008
  title: Class I histone deacetylases catalyze lysine lactylation.
  findings:
  - statement: >-
      AARS1 or AARS2 depletion did not reduce basal global lysine lactylation in
      untreated proliferating HEK293T cells.
    supporting_text: >-
      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.
    reference_section_type: RESULTS
  - statement: >-
      The reported AARS1 lactyl-AMP reaction has a millimolar Km, making substantial
      activity unlikely at healthy lactate concentrations.
    supporting_text: >-
      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).
    reference_section_type: DISCUSSION
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Full-text independent counter-scope study. It does not refute purified-enzyme
      activity or high-lactate substrate-specific effects, but shows that AARS1 is not
      required for basal global lactylation in HEK293T cells and constrains broad claims.
- id: PMID:7654687
  title: 'Human alanyl-tRNA synthetase: conservation in evolution of catalytic core
    and microhelix recognition.'
  full_text_unavailable: true
  findings:
  - statement: >-
      Active human AARS1 recognizes the conserved tRNA(Ala) acceptor-stem G3:U70 base
      pair and aminoacylates acceptor-stem RNA duplexes.
    supporting_text: >-
      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.
    reference_section_type: ABSTRACT
  - statement: >-
      The expressed human enzyme behaves as a monomer.
    supporting_text: >-
      This divergence correlates with the expressed human enzyme behaving as a monomer.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: MISCITED
    review_notes: >-
      PubMed identity and abstract verified. The study directly supports human AARS1
      tRNA binding, aminoacylation, acceptor-helix recognition, and monomeric state.
      It does not establish pre-tRNA processing, so its source GO:0008033 use is
      miscited. The separate cytoplasm TAS annotation is retained with curator deference
      because only the abstract is available locally and independent localization
      evidence is concordant.
- id: PMID:7761427
  title: 'Wide cross-species aminoacyl-tRNA synthetase replacement in vivo: yeast
    cytoplasmic alanine enzyme replaced by human polymyositis serum antigen.'
  full_text_unavailable: true
  findings:
  - statement: >-
      Human AARS1 restored growth of yeast lacking its essential cytoplasmic AlaRS,
      demonstrating accurate in-vivo aminoacylation across species.
    supporting_text: >-
      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.
    reference_section_type: ABSTRACT
  - statement: >-
      Conservation of the G3:U70 recognition system is sufficient for accurate
      cross-species aminoacylation in vivo.
    supporting_text: >-
      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.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed identity and abstract verified. This is direct in-vivo complementation
      evidence that human AARS1 supports cytoplasmic alanyl-tRNA aminoacylation,
      although the experimental cellular context is yeast.
- id: Reactome:R-HSA-379716
  title: Cytosolic tRNA aminoacylation
  findings:
  - statement: >-
      Reactome places cytosolic AARS1 in the pathway that charges nuclear-encoded tRNAs
      with their cognate amino acids using ATP.
    supporting_text: >-
      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.
    reference_section_type: DATABASE_ENTRY
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Curated human Reactome pathway entry for cytosolic tRNA aminoacylation. It
      provides pathway context; the AARS1-specific reaction is captured in
      R-HSA-379864.
- id: Reactome:R-HSA-379864
  title: alanine + tRNA(Ala) + ATP => Ala-tRNA(Ala) + AMP + pyrophosphate
  findings:
  - statement: >-
      Reactome assigns monomeric cytosolic AARS1 the alanine-tRNA(Ala) ligation reaction.
    supporting_text: >-
      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).
    reference_section_type: DATABASE_ENTRY
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Curated human Reactome reaction entry directly representing the canonical AARS1
      charging reaction and cytosolic location; the supporting human primary study is
      PMID:7654687.
core_functions:
- description: >-
    Cytosolic AARS1 activates L-alanine with ATP and transfers alanine to tRNA(Ala),
    producing Ala-tRNA(Ala) for cytoplasmic protein synthesis. This substrate-specific
    aminoacylation reaction is the enzyme's primary conserved activity.
  supported_by:
  - reference_id: PMID:28493438
    supporting_text: >-
      The aminoacylation activities of both variants were then tested using 14C-labeled
      alanine with various concentrations of tRNA.
  - reference_id: Reactome:R-HSA-379864
    supporting_text: >-
      AARS (cytosolic alanyl tRNA synthetase) catalyzes the reaction of alanine,
      tRNA(ala), and ATP to form Ala tRNA(Ala), AMP, and pyrophosphate.
  molecular_function:
    id: GO:0004813
    label: alanine-tRNA ligase activity
  directly_involved_in:
  - id: GO:0006419
    label: alanyl-tRNA aminoacylation
  locations:
  - id: GO:0005829
    label: cytosol
- description: >-
    The embedded AARS1 editing apparatus proofreads mischarged tRNA(Ala) and hydrolyzes
    the incorrect aminoacyl ester. Ser-tRNA(Ala) deacylation is directly demonstrated
    with human AARS1; Gly-tRNA(Ala) is a plausible conserved substrate but remains
    untested with the full-length human enzyme. This post-transfer editing preserves
    cytoplasmic translational fidelity.
  supported_by:
  - reference_id: PMID:28493438
    supporting_text: >-
      An in vitro editing activity assay was carried out using [3H] Ser-tRNAAla as a
      substrate.
  - reference_id: PMID:28493438
    supporting_text: >-
      tRNAAla can be mischarged with serine and glycine by AARS to yield Ser-tRNAAla
      and Gly-tRNAAla, respectively [Tsui and Fersht 1981]. To maintain the fidelity
      of aminoacylation, AARS possesses an editing domain that is capable of hydrolyzing
      the mischarged tRNAAla [Beebe et al. 2003; Guo et al. 2009].
  - reference_id: PMID:19661429
    supporting_text: >-
      In this way, the editing domain checks for mischarging by picking out tRNAs
      that have Gly or Ser and a G3•U70 pair.
  molecular_function:
    id: GO:0002161
    label: aminoacyl-tRNA deacylase activity
  directly_involved_in:
  - id: GO:0106074
    label: aminoacyl-tRNA metabolism involved in translational fidelity
  locations:
  - id: GO:0005829
    label: cytosol
- description: >-
    As a conditional secondary activity, AARS1 senses elevated intracellular L-lactate,
    forms lactoyl-AMP, and transfers lactyl groups to protein lysines. This activity can
    operate in the cytoplasm and, after lactate-induced nuclear import, in the nucleus on
    substrates including YAP1, TEAD1, and TP53. It is substrate- and context-dependent;
    AARS1 depletion does not reduce basal global lysine lactylation in untreated HEK293T
    cells.
  supported_by:
  - reference_id: PMID:38512451
    supporting_text: >-
      AARS1 was able to directly lactylate histone H3 and H4 in a manner dependent on
      both lactate and ATP
  - reference_id: PMID:38512451
    supporting_text: >-
      addition of lactate significantly promoted the nuclear localization of WT AARS1
      but not the ΔNLS mutant
  - reference_id: PMID:38653238
    supporting_text: >-
      AARS1 binds to lactate and catalyzes the formation of lactate-AMP, followed by
      transfer of lactate to the lysince acceptor residue.
  - reference_id: PMID:40835008
    supporting_text: >-
      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.
  molecular_function:
    id: GO:0141207
    label: peptide lactyltransferase (ATP-dependent) activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  - id: GO:0005634
    label: nucleus
knowledge_gaps:
- gap_statement: >-
    Whether full-length human AARS1 directly deacylates Gly-tRNA(Ala), and its kinetic
    specificity for Gly-tRNA(Ala) relative to Ser-tRNA(Ala), remain experimentally
    unresolved.
  boundary: >-
    Recombinant human AARS1 directly deacylates Ser-tRNA(Ala). Conserved AlaRS-family
    experiments identify both glycine and serine errors, and human C-Ala restores an
    Escherichia coli editing construct. These observations motivate a human glycine-
    editing hypothesis but do not provide a verified source for a GO ISS transfer.
  gap_kind:
  - BIOLOGY
  - CURATION
  dark_aspect: RESIDUAL_SUBGAP
  status: OPEN
  significance: >-
    Direct human kinetics would determine whether GO:0106026 should be supported by
    IDA and whether glycine and serine errors are cleared with comparable efficiency.
  resolution: >-
    Measure steady-state and single-turnover deacylation of purified Gly-tRNA(Ala) and
    Ser-tRNA(Ala) by full-length recombinant human AARS1, with editing-site mutants and
    the bacterial enzyme as controls.
  provenance:
  - reference_id: PMID:28493438
    supporting_text: >-
      tRNAAla can be mischarged with serine and glycine by AARS to yield Ser-tRNAAla
      and Gly-tRNAAla, respectively [Tsui and Fersht 1981]. To maintain the fidelity
      of aminoacylation, AARS possesses an editing domain that is capable of hydrolyzing
      the mischarged tRNAAla [Beebe et al. 2003; Guo et al. 2009].
  - reference_id: PMID:19661429
    supporting_text: >-
      In this way, the editing domain checks for mischarging by picking out tRNAs
      that have Gly or Ser and a G3•U70 pair.
- gap_statement: >-
    The physiological lactate range, cell states, and substrate spectrum in which
    endogenous AARS1 makes a material contribution to protein lysine lactylation,
    relative to other enzymatic routes, remain incompletely defined.
  boundary: >-
    ATP-dependent AARS1 lactyltransferase chemistry and several target-specific effects
    are reproducible under elevated-lactate tumor conditions, but AARS1 knockdown does
    not lower basal global lysine lactylation in untreated HEK293T cells and the reported
    lactoyl-AMP reaction has a millimolar lactate Km.
  gap_kind:
  - BIOLOGY
  - CURATION
  dark_aspect: RESIDUAL_SUBGAP
  status: OPEN
  significance: >-
    Resolving this boundary would distinguish physiological AARS1 substrates from
    high-lactate or overexpression effects and prevent substrate-specific activity from
    being generalized to the basal global lactylome.
  resolution: >-
    Quantify endogenous, site-resolved lactylation across a calibrated intracellular
    lactate series after acute AARS1 depletion and matched rescue, alongside perturbation
    of class I HDAC-dependent lactylation and measurement of AARS1 charging activity.
  provenance:
  - reference_id: PMID:38512451
    supporting_text: >-
      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.
  - reference_id: PMID:40835008
    supporting_text: >-
      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.
  - reference_id: PMID:40835008
    supporting_text: >-
      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).
- gap_statement: >-
    It is unknown whether the two human AARS1 isoforms differ in aminoacylation,
    editing, lactate-responsive localization, or lactyltransferase activity, and whether
    the isoform-2 insertion within C-Ala changes the domain's cellular role.
  boundary: >-
    UniProt records two splice isoforms, while structural work establishes distinctive
    DNA-binding and oligomeric surfaces for human C-Ala only in isolated-domain or
    structural assays; no isoform-specific core function is assigned here.
  gap_kind:
  - BIOLOGY
  dark_aspect: RESIDUAL_SUBGAP
  status: OPEN
  significance: >-
    Isoform-specific activity could alter translational quality control or conditional
    lactylation without being visible in canonical-sequence annotations.
  resolution: >-
    Compare endogenous-level P49588-1 and P49588-2 rescue constructs in an AARS1-depleted
    human cell background for charging, editing, localization, oligomerization, DNA
    binding, and target-specific lactylation.
  provenance:
  - reference_id: file:human/AARS1/AARS1-uniprot.txt
    supporting_text: >-
      Event=Alternative splicing; Named isoforms=2;
  - reference_id: file:human/AARS1/AARS1-uniprot.txt
    supporting_text: >-
      K -> KATQGPGSPPLGLISSL (in isoform 2)
  - reference_id: PMID:27911835
    supporting_text: >-
      Direct DNA binding by human C-Ala, but not by bacterial C-Ala, was demonstrated.
proposed_new_terms:
- proposed_name: peptidyl-lysine lactylation
  proposed_definition: >-
    A peptidyl-lysine modification process in which a lactyl group is covalently added
    to the epsilon-amino group of a lysine residue within a protein.
  justification: >-
    GO:0141207 captures the ATP-dependent molecular activity but no current biological
    process term captures its immediate protein-modification outcome. The proposed term
    should be placed under GO:0018205 peptidyl-lysine modification and related to the
    broader GO:0043543 protein acylation branch; it would support curation of AARS1 and
    other experimentally established lysine lactylation mechanisms without conflating
    them with downstream signaling phenotypes.
  proposed_parent:
    id: GO:0018205
    label: peptidyl-lysine modification
  supported_by:
  - reference_id: PMID:38512451
    supporting_text: >-
      AARS1 translocated into the nucleus, where it directly catalyzed lactylation of
      YAP at K90 and TEAD1 at K108, thereby activating downstream target gene expression
      to promote tumor cell proliferation.
  - reference_id: PMID:38653238
    supporting_text: >-
      AARS1 binds to lactate and catalyzes the formation of lactate-AMP, followed by
      transfer of lactate to the lysince acceptor residue.
suggested_questions:
- question: >-
    Does full-length human AARS1 directly hydrolyze Gly-tRNA(Ala), and how do its
    catalytic efficiency and discrimination compare with Ser-tRNA(Ala) editing?
  experts: []
- question: >-
    Across physiological and pathological lactate concentrations, which endogenous
    protein substrates depend materially on AARS1 rather than class I HDACs or other
    lactylation routes, and in which cell states?
  experts: []
- question: >-
    Do AARS1 isoforms P49588-1 and P49588-2 differ in C-Ala-dependent editing,
    localization, oligomerization, DNA binding, or lactyltransferase activity?
  experts: []
suggested_experiments:
- hypothesis: >-
    Full-length human AARS1 directly edits Gly-tRNA(Ala), but with kinetics distinct
    from its directly established Ser-tRNA(Ala) editing activity.
  description: >-
    Prepare homogeneous Gly-tRNA(Ala) and Ser-tRNA(Ala), then measure steady-state and
    single-turnover deacylation by purified full-length human AARS1. Include catalytic-
    site and editing-site mutants, uncharged tRNA(Ala), cognate Gly-tRNA(Gly) and
    Ser-tRNA(Ser), and Escherichia coli AlaRS controls to establish substrate specificity
    and support or reject a direct human GO:0106026 annotation.
  experiment_type: biochemical enzyme kinetics
- hypothesis: >-
    Endogenous AARS1 contributes substantially to a restricted high-lactate,
    substrate-specific lactylome but not to basal global lysine lactylation.
  description: >-
    Use acute endogenous AARS1 degradation across a calibrated intracellular lactate
    series, followed by isotope-resolved quantitative lactyl-proteomics and targeted
    measurement of YAP1, TEAD1, and TP53 sites. Rescue with matched-expression AARS1
    variants that retain aminoacylation but differ in lactyltransferase activity, and
    compare with class I HDAC perturbation to separate AARS1-specific sites from the
    broader lactylome.
  experiment_type: acute perturbation and quantitative proteomics
- hypothesis: >-
    The isoform-2 insertion within C-Ala changes AARS1 editing coordination or its
    conditional noncanonical activities without abolishing alanine charging.
  description: >-
    Express P49588-1 and P49588-2 at matched endogenous levels in an AARS1-depleted
    human cell line and compare tRNA(Ala) charging, Ser/Gly-tRNA(Ala) editing, basal and
    lactate-induced localization, oligomeric state, DNA binding, and site-specific
    YAP1/TEAD1/TP53 lactylation. Parallel purified-protein assays should distinguish
    intrinsic isoform differences from cellular localization effects.
  experiment_type: isoform-resolved biochemical and cell-rescue analysis

AARS1

Gene Description

Proposed New Ontology Terms

peptidyl-lysine lactylation

Existing Annotations Review

Core Functions

Cytosolic AARS1 activates L-alanine with ATP and transfers alanine to tRNA(Ala), producing Ala-tRNA(Ala) for cytoplasmic protein synthesis. This substrate-specific aminoacylation reaction is the enzyme's primary conserved activity.

References

Suggested Questions for Experts

Suggested Experiments

Knowledge Gaps

📚 Additional Documentation

Notes

AARS1 review notes

Research provenance

Canonical aminoacylation function

Post-transfer editing and translational fidelity

Conditional protein lactyltransferase activity

Disease-mechanism boundary

Annotation boundaries

📄 View Raw YAML