{"gene":"GLS","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2012,"finding":"The GLS1 splice variant GAC (glutaminase C) is essential for non-small cell lung cancer cell growth. Transient knockdown of GLS1 splice variants showed that loss of GAC had the most detrimental effect on cancer cell growth, and decreased growth could be rescued by exogenous addition of downstream glutaminolysis metabolites.","method":"siRNA knockdown of GLS1 splice variants, metabolite rescue assay","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined cellular phenotype and metabolite rescue, single lab","pmids":["22892846"],"is_preprint":false},{"year":2021,"finding":"Upon oxidative stress, SUCLA2 (phosphorylated by p38 MAPK at S79) dissociates from GLS, resulting in enhanced GLS K311 succinylation, oligomerization, and enzymatic activity. Activated GLS increases glutaminolysis and production of NADPH and glutathione to counteract oxidative stress. SUCLA2 thus acts as a negative regulator of GLS succinylation.","method":"Co-IP, phosphorylation/succinylation site mutagenesis, in vitro enzymatic activity assay, mouse xenograft model","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reciprocal Co-IP, mutagenesis of modification sites, enzymatic activity assay, and in vivo validation in single rigorous study","pmids":["33991485"],"is_preprint":false},{"year":2022,"finding":"Glutamine deprivation causes GLS1 to convert from a dimer to a self-assembled filamentous polymer with enhanced catalytic activity (lower Km). Filamentous GLS1 further depletes intracellular glutamine, leading to inadequate asparagine synthesis and ROS-induced apoptosis. Asparagine supplementation rescues this apoptosis. Constitutively active filamentous mutants K320A and S482C suppress tumor growth in xenograft models.","method":"Structural/biochemical characterization of GLS1 filaments, mutagenesis (K320A, S482C), metabolite rescue (asparagine), xenograft tumor models","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution of filament formation, mutagenesis, metabolite rescue, and in vivo xenograft validation in a single rigorous study","pmids":["35381197"],"is_preprint":false},{"year":2019,"finding":"A gain-of-function de novo variant Ser482Cys in GLS causes hyperactivity of the enzyme, likely by improving the electrostatic environment of the catalytic site. This leads to increased glutamate and decreased glutamine in urine, fibroblasts, and brain, resulting in infantile cataract and profound developmental delay. Inhibition of GLS alleviated cataract in zebrafish expressing Ser482Cys-GLS.","method":"Functional analysis of patient-derived fibroblasts, zebrafish expression model, GLS inhibitor rescue, MR spectroscopy, protein sequence conservation analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — enzymatic activity measurement, multiple orthogonal methods (cell biochemistry, zebrafish model, inhibitor rescue, spectroscopy), single study","pmids":["30239721"],"is_preprint":false},{"year":2018,"finding":"GLS loss-of-function (complete knockout due to a homozygous copy number variant) causes autosomal recessive spastic ataxia with optic atrophy in humans, establishing that GLS is required for normal neurological function.","method":"Homozygosity mapping, whole-genome sequencing, confirmation of complete absence of GLS expression","journal":"Annals of clinical and translational neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — human genetic loss-of-function with defined neurological phenotype, single family report","pmids":["29468182"],"is_preprint":false},{"year":2014,"finding":"The GLS isoform (KGA/GAC) is localized to mitochondria in both neurons and astrocytes, while GLS2 appears in two locations: mitochondria and nucleus. Astrocytic glutaminase proteins encoded by both GLS and GLS2 possess enzymatic activity demonstrated by in situ activity staining.","method":"Isoform-specific immunocytochemistry, confocal microscopy, quantitative RT-PCR, in situ enzymatic activity staining in rat and human brain tissue","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization by multiple orthogonal methods (confocal, fractionation, in situ activity), single lab","pmids":["25297978"],"is_preprint":false},{"year":2021,"finding":"ARID1A inactivation upregulates GLS1 expression by releasing SWI/SNF-mediated repression of the GLS1 gene, increasing glutamine utilization through the TCA cycle to support aspartate synthesis. Pharmacological GLS1 inhibition (CB-839) selectively suppresses growth of ARID1A-mutant ovarian clear cell carcinoma in orthotopic and patient-derived xenograft models.","method":"Genetic ARID1A inactivation, ChIP (SWI/SNF binding at GLS1 locus), metabolomics (13C tracing), CB-839 treatment in xenograft models","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — genetic epistasis, chromatin occupancy, metabolic tracing, and in vivo validation in multiple model systems within single rigorous study","pmids":["34085048"],"is_preprint":false},{"year":2020,"finding":"MALT1 protease stabilizes c-Jun by cleavage, and c-Jun directly binds the GLS1 promoter to upregulate GLS1 expression. GLS1-mediated glutaminolysis promotes Th17 differentiation through enhancement of histone H3 acetylation at the Il17a promoter. IL-17A in turn enhances GLS1 expression via the MALT1/c-Jun pathway in keratinocytes.","method":"ChIP assay (c-Jun binding to GLS1 promoter and H3 acetylation at Il17a), protease inhibition, GLS1 inhibition in psoriasis mouse models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP for promoter binding and histone modification, genetic/pharmacological inhibition with defined phenotypic readout, multiple orthogonal methods in a single rigorous study","pmids":["32831293"],"is_preprint":false},{"year":2017,"finding":"Selenite promotes GLS1 protein degradation via the APC/C-CDH1 ubiquitin-proteasome pathway. Selenite promotes association of APC/C-CDH1 with GLS1, leading to GLS1 ubiquitination and degradation, which is related to induction of PTEN expression.","method":"Co-immunoprecipitation, ubiquitination assay, western blot, GLS1 activity assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating APC/C-CDH1–GLS1 interaction, ubiquitination assay, two orthogonal methods in single lab","pmids":["27902968"],"is_preprint":false},{"year":2021,"finding":"PPARγ agonists repress GLS1 expression through the CDK1-APC/C-Cdh1 signaling axis, leading to ubiquitin-proteasomal degradation of GLS1. This inhibits glutaminolysis and Th17 differentiation, reducing 2-HG production and H3K4me3 modification at the il-17 gene locus.","method":"Western blot, flow cytometry, ChIP (H3K4me3), GLS1 overexpression rescue, mouse colitis/asthma models","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for histone modification, GLS1 overexpression rescue of PPARγ-mediated effects, multiple orthogonal methods, single lab","pmids":["34267342"],"is_preprint":false},{"year":2023,"finding":"SIRT4 facilitates GLS1 degradation by hindering SIRT5's stabilizing interaction with GLS1, thereby reducing glutaminolysis and alleviating intestinal fibrosis. α-ketoglutarate produced by GLS1 acts as a key metabolite mediating ECM transcription via KDM6.","method":"Co-immunoprecipitation (SIRT4/SIRT5/GLS1 interaction), western blot, GLS1 activity assay, in vivo intestinal fibrosis models","journal":"Matrix biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating protein interaction, activity assays, in vivo model, single lab","pmids":["37541633"],"is_preprint":false},{"year":2019,"finding":"GLS1 overexpression increases phospho-AKT, phospho-GSK3β, and cyclinD1 expression in hepatocellular carcinoma cells without affecting total AKT or GSK3β, indicating GLS1 promotes proliferation via the AKT/GSK3β/CyclinD1 pathway.","method":"GLS1 overexpression/knockdown, western blot for pathway components, cell proliferation assay, GLS1 inhibitor (compound 968) treatment","journal":"Experimental cell research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — western blot correlation of pathway components after overexpression/knockdown, single lab, no direct epistasis","pmids":["31054856"],"is_preprint":false},{"year":2022,"finding":"USP6 deubiquitylase increases GLS1 ubiquitination to decrease GLS protein stability, and this process is regulated by miR-146a-5p. hucMSC exosomes deliver miR-146a-5p to suppress USP6, thereby reducing GLS1 ubiquitination and increasing GLS1 protein levels.","method":"Co-immunoprecipitation, ubiquitination assay, western blot, miRNA overexpression/inhibition","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and ubiquitination assay demonstrating USP6-GLS1 interaction and functional consequence, single lab","pmids":["35091542"],"is_preprint":false},{"year":2020,"finding":"c-Myc upregulates KGA and GAC (GLS1 isoforms) protein levels in EBV-infected cells, which in turn elevate intracellular glutamate and activate mitochondrial glutaminolysis. GLS1 isoforms are mitochondrially localized in EBV-infected cells.","method":"Western blot, GLS1 isoform inhibitors, mitochondrial fractionation/localization, cell proliferation assay","journal":"Viruses","confidence":"Low","confidence_rationale":"Tier 3 / Weak — western blot with inhibitor treatment and fractionation, single lab, limited mechanistic depth","pmids":["32727118"],"is_preprint":false},{"year":2024,"finding":"GLS1 disruption (genetic depletion or CB-839 treatment) reduces c-Myc protein stability via a ubiquitin-specific peptidase 1 (USP1)-dependent ubiquitin-proteasome pathway. Conversely, c-Myc directly binds to the GLS1 promoter and upregulates GLS1 transcription, forming a positive feedback loop. The GLS1-c-Myc axis promotes acetyl-CoA carboxylase-dependent Slug acetylation, driving cancer cell invasion.","method":"Genetic GLS1 depletion, CB-839 treatment, ChIP (c-Myc binding to GLS1 promoter), ubiquitination assay, orthotopic mouse model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP for promoter binding, ubiquitination assay for protein stability, genetic and pharmacological perturbation, in vivo orthotopic model, multiple orthogonal methods","pmids":["39024547"],"is_preprint":false},{"year":2022,"finding":"SMYD2 methylates c-Myc to increase its protein stability (reducing K48-linked polyubiquitination), which upregulates GLS1 expression. SMYD2 depletion destabilizes c-Myc and reduces GLS1 levels and glutamine metabolism in HCC cells.","method":"Co-IP, western blot for ubiquitination, GLS1 expression analysis after SMYD2 knockdown/overexpression, in vivo xenograft","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vivo validation, multiple methods in single lab","pmids":["36611819"],"is_preprint":false},{"year":2020,"finding":"NUDT21 downregulation (driven by hypoxia via HIF-1α) alters GLS1 pre-mRNA splicing, shifting expression from KGA to GAC isoforms. This links hypoxic tumor environments to aberrant glutamine metabolism.","method":"NUDT21 shRNA knockdown, RT-PCR for GLS1 splice variants, HIF-1α modulation, xenograft model","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic knockdown with isoform-specific RT-PCR, single lab, mechanistic link to splicing established","pmids":["32228887"],"is_preprint":false},{"year":2021,"finding":"YAP1 protects vascular smooth muscle cells against ferroptosis by regulating GLS1 expression to promote synthesis of glutamate and glutathione. YAP1 knockdown decreases GLS1 expression and increases ferroptosis susceptibility.","method":"YAP1 knockdown/overexpression, western blot for GLS1, glutamate/GSH measurement, ferroptosis assays in VSMCs","journal":"FASEB journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — western blot with knockdown/overexpression correlation, single lab, pathway placement inferred rather than directly demonstrated","pmids":["39091212"],"is_preprint":false},{"year":2021,"finding":"YTHDF1 binds to the 3' UTR of GLS1 mRNA (validated by RNA immunoprecipitation) and promotes GLS1 protein synthesis. YTHDF1-mediated upregulation of GLS1 drives glutamine metabolism and cisplatin resistance in colorectal cancer cells.","method":"RNA immunoprecipitation (RIP) assay, YTHDF1 overexpression/knockdown, western blot for GLS1, in vivo xenograft","journal":"Molecular therapy oncolytics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP assay directly demonstrates YTHDF1-GLS1 mRNA binding, protein synthesis validated, in vivo confirmation, single lab","pmids":["33614908"],"is_preprint":false},{"year":2024,"finding":"GLS1 interacts with NFS1 (iron-sulfur cluster assembly enzyme) and regulates Fe2+ homeostasis. GLS1-driven glutamine metabolism facilitates acetyl-CoA production, which promotes histone acetylation of NFS1, establishing a link between GLS1 activity and iron homeostasis in nucleus pulposus cells.","method":"Co-immunoprecipitation (GLS1-NFS1 interaction), GLS1 overexpression, metabolite measurement, histone acetylation assay","journal":"Free radical biology & medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP demonstrating interaction, single lab, mechanistic link between acetyl-CoA and NFS1 acetylation not fully validated","pmids":["39710108"],"is_preprint":false},{"year":2019,"finding":"GLS1 knockdown in prostate cancer cells suppresses the Wnt/β-catenin pathway (decreased cyclinD1 and Bcl-2, increased Bax), inducing apoptosis and cell cycle arrest.","method":"GLS1 siRNA knockdown, western blot for Wnt/β-catenin pathway components, apoptosis and cell cycle assays","journal":"Bioscience reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — western blot with knockdown, correlation of pathway components, single lab, no direct mechanistic linkage demonstrated","pmids":["31196962"],"is_preprint":false}],"current_model":"GLS (kidney-type glutaminase) is a mitochondrial enzyme that catalyzes the deamidation of glutamine to glutamate and ammonia, supporting TCA cycle anaplerosis, redox homeostasis (glutathione production), and biosynthesis; its activity is regulated post-translationally by succinylation at K311 (controlled by SUCLA2-p38MAPK signaling), ubiquitin-proteasomal degradation via APC/C-CDH1 (promoted by SIRT4, selenite, and bergenin/PPARγ), and by self-assembly into catalytically hyperactive filaments under glutamine deprivation; its expression is transcriptionally driven by c-Myc (which directly binds the GLS1 promoter) in a positive feedback loop, and GLS in turn stabilizes c-Myc through USP1; a gain-of-function variant (S482C) causes hyperactivity leading to glutamate excess and neurological disease, while complete loss of GLS causes spastic ataxia, confirming its essential role in maintaining glutamate homeostasis in the nervous system."},"narrative":{"mechanistic_narrative":"GLS (kidney-type glutaminase) is a mitochondrial enzyme that initiates glutaminolysis, converting glutamine to glutamate to feed the TCA cycle, redox defense, and biosynthesis; its splice isoforms KGA and GAC are mitochondrially localized in neurons, astrocytes, and tumor cells [PMID:25297978, PMID:32727118], and the GAC variant in particular is required for cancer cell proliferation, with growth defects upon knockdown rescued by downstream glutaminolysis metabolites [PMID:22892846]. Catalytic output is tuned by post-translational regulation: under oxidative stress, p38-MAPK-phosphorylated SUCLA2 dissociates from GLS, enabling K311 succinylation, oligomerization, and elevated activity that drives NADPH and glutathione production [PMID:33991485], while glutamine deprivation triggers conversion of dimeric GLS into hyperactive self-assembled filaments that further deplete glutamine and provoke ROS-induced apoptosis rescued by asparagine [PMID:35381197]. GLS protein abundance is set by competing ubiquitin-proteasome inputs through APC/C-CDH1, promoted by selenite and by PPARγ agonists acting via the CDK1-APC/C-Cdh1 axis [PMID:27902968, PMID:34267342], and by SIRT4-, SIRT5-, USP6-, and YTHDF1-dependent control of stability and translation [PMID:37541633, PMID:35091542, PMID:33614908]. Transcriptionally, GLS1 is induced by c-Myc, which binds the GLS1 promoter, and GLS1 reciprocally stabilizes c-Myc through a USP1-dependent mechanism, forming a feed-forward loop that drives cancer cell invasion [PMID:39024547]; additional inputs include c-Jun downstream of MALT1 in Th17/psoriasis settings and ARID1A loss releasing SWI/SNF repression of the locus [PMID:32831293, PMID:34085048]. In the nervous system, a de novo gain-of-function S482C variant causes enzyme hyperactivity, glutamate excess, infantile cataract and developmental delay [PMID:30239721], whereas complete GLS loss causes autosomal recessive spastic ataxia with optic atrophy, establishing GLS as essential for glutamate homeostasis [PMID:29468182].","teleology":[{"year":2012,"claim":"Established that a specific GLS1 splice isoform, GAC, is the metabolically critical product driving cancer cell growth, framing glutaminase as a dependency rather than a housekeeping enzyme.","evidence":"isoform-specific siRNA knockdown with downstream metabolite rescue in NSCLC cells","pmids":["22892846"],"confidence":"Medium","gaps":["Does not resolve which downstream metabolite is rate-limiting","Single cell-line context","No in vivo validation"]},{"year":2014,"claim":"Resolved the subcellular distribution of GLS, confirming mitochondrial localization of KGA/GAC in neurons and astrocytes and distinguishing it from nuclear-capable GLS2.","evidence":"isoform-specific immunocytochemistry, confocal microscopy and in situ activity staining in rat and human brain","pmids":["25297978"],"confidence":"Medium","gaps":["Does not address regulation of localization","Functional consequence of compartmentalization not tested"]},{"year":2018,"claim":"Demonstrated that complete loss of GLS causes a human neurological disease, establishing GLS as essential for normal nervous system function.","evidence":"homozygosity mapping and whole-genome sequencing of a family with spastic ataxia and confirmed absence of GLS expression","pmids":["29468182"],"confidence":"Medium","gaps":["Single family report","Mechanism linking glutaminase loss to optic atrophy/spasticity not defined"]},{"year":2019,"claim":"Showed that a gain-of-function point mutation in the catalytic environment produces enzyme hyperactivity and glutamate excess, defining the opposite disease pole from loss-of-function and pinpointing a regulatory residue.","evidence":"patient fibroblast biochemistry, zebrafish expression model with GLS-inhibitor rescue, and MR spectroscopy","pmids":["30239721"],"confidence":"High","gaps":["Structural basis inferred rather than crystallographically resolved","Single de novo variant"]},{"year":2021,"claim":"Defined a stress-responsive post-translational switch in which SUCLA2 release permits K311 succinylation, oligomerization, and activation of GLS to fuel antioxidant output.","evidence":"reciprocal Co-IP, phospho/succinyl-site mutagenesis, in vitro activity assays, and mouse xenografts","pmids":["33991485"],"confidence":"High","gaps":["Identity of the succinyltransferase not established","Relationship between succinylation and filament assembly unclear"]},{"year":2022,"claim":"Established that glutamine deprivation drives GLS dimer-to-filament conversion as a self-amplifying hyperactive state with cell-fate consequences, linking enzyme assembly to apoptosis.","evidence":"biochemical filament reconstitution, K320A/S482C mutants, asparagine rescue and xenograft tumor models","pmids":["35381197"],"confidence":"High","gaps":["High-resolution filament architecture not provided","Physiological triggers beyond glutamine deprivation untested"]},{"year":2020,"claim":"Connected upstream signaling to GLS1 transcription and downstream chromatin output, showing MALT1/c-Jun-driven GLS1 expression supports Th17 differentiation via histone acetylation at Il17a.","evidence":"ChIP for c-Jun promoter binding and H3 acetylation, protease and GLS1 inhibition in psoriasis mouse models","pmids":["32831293"],"confidence":"High","gaps":["Does not quantify metabolite flux to acetyl-CoA in vivo","Generality beyond skin inflammation unknown"]},{"year":2021,"claim":"Identified ARID1A/SWI/SNF as a chromatin repressor of GLS1, creating a synthetic-lethal vulnerability to glutaminase inhibition in ARID1A-mutant cancer.","evidence":"ARID1A genetic inactivation, ChIP, 13C metabolic tracing and CB-839 in orthotopic and PDX models","pmids":["34085048"],"confidence":"High","gaps":["Direct SWI/SNF occupancy dynamics over time not resolved","Restricted to ovarian clear cell context"]},{"year":2024,"claim":"Demonstrated a reciprocal GLS1-c-Myc feedback loop in which c-Myc transcribes GLS1 and GLS1 stabilizes c-Myc via USP1, coupling glutamine metabolism to oncogenic invasion.","evidence":"genetic and CB-839 perturbation, ChIP, ubiquitination assays and orthotopic mouse model","pmids":["39024547"],"confidence":"High","gaps":["Mechanism by which GLS1 controls USP1 not defined","Whether the loop operates outside the studied cancers untested"]},{"year":2023,"claim":"Mapped sirtuin- and deubiquitinase-based control of GLS1 stability, showing SIRT4 antagonizes SIRT5 stabilization to limit glutaminolysis and α-ketoglutarate-driven ECM transcription.","evidence":"Co-IP of SIRT4/SIRT5/GLS1, activity assays and in vivo intestinal fibrosis models","pmids":["37541633"],"confidence":"Medium","gaps":["Direct enzymatic modification of GLS1 by these sirtuins not shown","Single disease model"]},{"year":null,"claim":"How the multiple regulatory layers — succinylation, filament assembly, APC/C-CDH1 degradation, and transcriptional feedback — are integrated into a single quantitative control scheme for GLS activity in normal versus diseased tissue remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking PTM state to assembly state to flux","Tissue-specific regulatory hierarchy undefined","Structural mechanism of catalytic-site mutations and filament gating not crystallographically resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,2,3,5]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1,5]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[5,13]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,6]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1,2,17]}],"complexes":[],"partners":["SUCLA2","SIRT5","SIRT4","USP6","YTHDF1","NFS1","MYC","CDH1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O94925","full_name":"Glutaminase kidney isoform, mitochondrial","aliases":["K-glutaminase","L-glutamine amidohydrolase"],"length_aa":669,"mass_kda":73.5,"function":"Catalyzes the first reaction in the primary pathway for the renal catabolism of glutamine. Plays a role in maintaining acid-base homeostasis. Regulates the levels of the neurotransmitter glutamate, the main excitatory neurotransmitter in the brain (PubMed:30239721, PubMed:30575854, PubMed:30970188) Lacks catalytic activity","subcellular_location":"Mitochondrion matrix","url":"https://www.uniprot.org/uniprotkb/O94925/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GLS","classification":"Not Classified","n_dependent_lines":145,"n_total_lines":1208,"dependency_fraction":0.12003311258278146},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GLS","total_profiled":1310},"omim":[{"mim_id":"618412","title":"GLOBAL DEVELOPMENTAL DELAY, PROGRESSIVE ATAXIA, AND ELEVATED GLUTAMINE; GDPAG","url":"https://www.omim.org/entry/618412"},{"mim_id":"618339","title":"CASGID SYNDROME; CASGID","url":"https://www.omim.org/entry/618339"},{"mim_id":"618328","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 71; DEE71","url":"https://www.omim.org/entry/618328"},{"mim_id":"610723","title":"MICRO RNA 23B; MIR23B","url":"https://www.omim.org/entry/610723"},{"mim_id":"608179","title":"CAYTAXIN; ATCAY","url":"https://www.omim.org/entry/608179"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"kidney","ntpm":144.3}],"url":"https://www.proteinatlas.org/search/GLS"},"hgnc":{"alias_symbol":["KIAA0838","GLS1","GAC","GAM","KGA"],"prev_symbol":[]},"alphafold":{"accession":"O94925","domains":[{"cath_id":"1.10.238.210","chopping":"138-215","consensus_level":"high","plddt":91.325,"start":138,"end":215},{"cath_id":"3.40.710.10","chopping":"230-523","consensus_level":"medium","plddt":96.2895,"start":230,"end":523},{"cath_id":"1.25.40.20","chopping":"545-646","consensus_level":"high","plddt":90.6089,"start":545,"end":646}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94925","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94925-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94925-F1-predicted_aligned_error_v6.png","plddt_mean":80.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GLS","jax_strain_url":"https://www.jax.org/strain/search?query=GLS"},"sequence":{"accession":"O94925","fasta_url":"https://rest.uniprot.org/uniprotkb/O94925.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94925/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94925"}},"corpus_meta":[{"pmid":"28875174","id":"PMC_28875174","title":"Improved 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Axis.","date":"2023","source":"Nutrition and cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37401860","citation_count":11,"is_preprint":false},{"pmid":"33542341","id":"PMC_33542341","title":"Increased C reactive protein, cardiac troponin I and GLS are associated with myocardial inflammation in patients with non-ischemic heart failure.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33542341","citation_count":11,"is_preprint":false},{"pmid":"35110645","id":"PMC_35110645","title":"Immune responses following the first dose of the Sputnik V (Gam-COVID-Vac).","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35110645","citation_count":11,"is_preprint":false},{"pmid":"35041497","id":"PMC_35041497","title":"Direct Inhibition of RetS Synthesis by RsmA Contributes to Homeostasis of the Pseudomonas aeruginosa Gac/Rsm Signaling System.","date":"2022","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/35041497","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51620,"output_tokens":5156,"usd":0.1161,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13547,"output_tokens":3486,"usd":0.077442,"stage2_stop_reason":"end_turn"},"total_usd":0.193542,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"The GLS1 splice variant GAC (glutaminase C) is essential for non-small cell lung cancer cell growth. Transient knockdown of GLS1 splice variants showed that loss of GAC had the most detrimental effect on cancer cell growth, and decreased growth could be rescued by exogenous addition of downstream glutaminolysis metabolites.\",\n      \"method\": \"siRNA knockdown of GLS1 splice variants, metabolite rescue assay\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined cellular phenotype and metabolite rescue, single lab\",\n      \"pmids\": [\"22892846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Upon oxidative stress, SUCLA2 (phosphorylated by p38 MAPK at S79) dissociates from GLS, resulting in enhanced GLS K311 succinylation, oligomerization, and enzymatic activity. Activated GLS increases glutaminolysis and production of NADPH and glutathione to counteract oxidative stress. SUCLA2 thus acts as a negative regulator of GLS succinylation.\",\n      \"method\": \"Co-IP, phosphorylation/succinylation site mutagenesis, in vitro enzymatic activity assay, mouse xenograft model\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reciprocal Co-IP, mutagenesis of modification sites, enzymatic activity assay, and in vivo validation in single rigorous study\",\n      \"pmids\": [\"33991485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Glutamine deprivation causes GLS1 to convert from a dimer to a self-assembled filamentous polymer with enhanced catalytic activity (lower Km). Filamentous GLS1 further depletes intracellular glutamine, leading to inadequate asparagine synthesis and ROS-induced apoptosis. Asparagine supplementation rescues this apoptosis. Constitutively active filamentous mutants K320A and S482C suppress tumor growth in xenograft models.\",\n      \"method\": \"Structural/biochemical characterization of GLS1 filaments, mutagenesis (K320A, S482C), metabolite rescue (asparagine), xenograft tumor models\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution of filament formation, mutagenesis, metabolite rescue, and in vivo xenograft validation in a single rigorous study\",\n      \"pmids\": [\"35381197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A gain-of-function de novo variant Ser482Cys in GLS causes hyperactivity of the enzyme, likely by improving the electrostatic environment of the catalytic site. This leads to increased glutamate and decreased glutamine in urine, fibroblasts, and brain, resulting in infantile cataract and profound developmental delay. Inhibition of GLS alleviated cataract in zebrafish expressing Ser482Cys-GLS.\",\n      \"method\": \"Functional analysis of patient-derived fibroblasts, zebrafish expression model, GLS inhibitor rescue, MR spectroscopy, protein sequence conservation analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — enzymatic activity measurement, multiple orthogonal methods (cell biochemistry, zebrafish model, inhibitor rescue, spectroscopy), single study\",\n      \"pmids\": [\"30239721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GLS loss-of-function (complete knockout due to a homozygous copy number variant) causes autosomal recessive spastic ataxia with optic atrophy in humans, establishing that GLS is required for normal neurological function.\",\n      \"method\": \"Homozygosity mapping, whole-genome sequencing, confirmation of complete absence of GLS expression\",\n      \"journal\": \"Annals of clinical and translational neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — human genetic loss-of-function with defined neurological phenotype, single family report\",\n      \"pmids\": [\"29468182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The GLS isoform (KGA/GAC) is localized to mitochondria in both neurons and astrocytes, while GLS2 appears in two locations: mitochondria and nucleus. Astrocytic glutaminase proteins encoded by both GLS and GLS2 possess enzymatic activity demonstrated by in situ activity staining.\",\n      \"method\": \"Isoform-specific immunocytochemistry, confocal microscopy, quantitative RT-PCR, in situ enzymatic activity staining in rat and human brain tissue\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization by multiple orthogonal methods (confocal, fractionation, in situ activity), single lab\",\n      \"pmids\": [\"25297978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ARID1A inactivation upregulates GLS1 expression by releasing SWI/SNF-mediated repression of the GLS1 gene, increasing glutamine utilization through the TCA cycle to support aspartate synthesis. Pharmacological GLS1 inhibition (CB-839) selectively suppresses growth of ARID1A-mutant ovarian clear cell carcinoma in orthotopic and patient-derived xenograft models.\",\n      \"method\": \"Genetic ARID1A inactivation, ChIP (SWI/SNF binding at GLS1 locus), metabolomics (13C tracing), CB-839 treatment in xenograft models\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — genetic epistasis, chromatin occupancy, metabolic tracing, and in vivo validation in multiple model systems within single rigorous study\",\n      \"pmids\": [\"34085048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MALT1 protease stabilizes c-Jun by cleavage, and c-Jun directly binds the GLS1 promoter to upregulate GLS1 expression. GLS1-mediated glutaminolysis promotes Th17 differentiation through enhancement of histone H3 acetylation at the Il17a promoter. IL-17A in turn enhances GLS1 expression via the MALT1/c-Jun pathway in keratinocytes.\",\n      \"method\": \"ChIP assay (c-Jun binding to GLS1 promoter and H3 acetylation at Il17a), protease inhibition, GLS1 inhibition in psoriasis mouse models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP for promoter binding and histone modification, genetic/pharmacological inhibition with defined phenotypic readout, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"32831293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Selenite promotes GLS1 protein degradation via the APC/C-CDH1 ubiquitin-proteasome pathway. Selenite promotes association of APC/C-CDH1 with GLS1, leading to GLS1 ubiquitination and degradation, which is related to induction of PTEN expression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, western blot, GLS1 activity assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating APC/C-CDH1–GLS1 interaction, ubiquitination assay, two orthogonal methods in single lab\",\n      \"pmids\": [\"27902968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PPARγ agonists repress GLS1 expression through the CDK1-APC/C-Cdh1 signaling axis, leading to ubiquitin-proteasomal degradation of GLS1. This inhibits glutaminolysis and Th17 differentiation, reducing 2-HG production and H3K4me3 modification at the il-17 gene locus.\",\n      \"method\": \"Western blot, flow cytometry, ChIP (H3K4me3), GLS1 overexpression rescue, mouse colitis/asthma models\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for histone modification, GLS1 overexpression rescue of PPARγ-mediated effects, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"34267342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SIRT4 facilitates GLS1 degradation by hindering SIRT5's stabilizing interaction with GLS1, thereby reducing glutaminolysis and alleviating intestinal fibrosis. α-ketoglutarate produced by GLS1 acts as a key metabolite mediating ECM transcription via KDM6.\",\n      \"method\": \"Co-immunoprecipitation (SIRT4/SIRT5/GLS1 interaction), western blot, GLS1 activity assay, in vivo intestinal fibrosis models\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating protein interaction, activity assays, in vivo model, single lab\",\n      \"pmids\": [\"37541633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GLS1 overexpression increases phospho-AKT, phospho-GSK3β, and cyclinD1 expression in hepatocellular carcinoma cells without affecting total AKT or GSK3β, indicating GLS1 promotes proliferation via the AKT/GSK3β/CyclinD1 pathway.\",\n      \"method\": \"GLS1 overexpression/knockdown, western blot for pathway components, cell proliferation assay, GLS1 inhibitor (compound 968) treatment\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — western blot correlation of pathway components after overexpression/knockdown, single lab, no direct epistasis\",\n      \"pmids\": [\"31054856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP6 deubiquitylase increases GLS1 ubiquitination to decrease GLS protein stability, and this process is regulated by miR-146a-5p. hucMSC exosomes deliver miR-146a-5p to suppress USP6, thereby reducing GLS1 ubiquitination and increasing GLS1 protein levels.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, western blot, miRNA overexpression/inhibition\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and ubiquitination assay demonstrating USP6-GLS1 interaction and functional consequence, single lab\",\n      \"pmids\": [\"35091542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"c-Myc upregulates KGA and GAC (GLS1 isoforms) protein levels in EBV-infected cells, which in turn elevate intracellular glutamate and activate mitochondrial glutaminolysis. GLS1 isoforms are mitochondrially localized in EBV-infected cells.\",\n      \"method\": \"Western blot, GLS1 isoform inhibitors, mitochondrial fractionation/localization, cell proliferation assay\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — western blot with inhibitor treatment and fractionation, single lab, limited mechanistic depth\",\n      \"pmids\": [\"32727118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GLS1 disruption (genetic depletion or CB-839 treatment) reduces c-Myc protein stability via a ubiquitin-specific peptidase 1 (USP1)-dependent ubiquitin-proteasome pathway. Conversely, c-Myc directly binds to the GLS1 promoter and upregulates GLS1 transcription, forming a positive feedback loop. The GLS1-c-Myc axis promotes acetyl-CoA carboxylase-dependent Slug acetylation, driving cancer cell invasion.\",\n      \"method\": \"Genetic GLS1 depletion, CB-839 treatment, ChIP (c-Myc binding to GLS1 promoter), ubiquitination assay, orthotopic mouse model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP for promoter binding, ubiquitination assay for protein stability, genetic and pharmacological perturbation, in vivo orthotopic model, multiple orthogonal methods\",\n      \"pmids\": [\"39024547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SMYD2 methylates c-Myc to increase its protein stability (reducing K48-linked polyubiquitination), which upregulates GLS1 expression. SMYD2 depletion destabilizes c-Myc and reduces GLS1 levels and glutamine metabolism in HCC cells.\",\n      \"method\": \"Co-IP, western blot for ubiquitination, GLS1 expression analysis after SMYD2 knockdown/overexpression, in vivo xenograft\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vivo validation, multiple methods in single lab\",\n      \"pmids\": [\"36611819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NUDT21 downregulation (driven by hypoxia via HIF-1α) alters GLS1 pre-mRNA splicing, shifting expression from KGA to GAC isoforms. This links hypoxic tumor environments to aberrant glutamine metabolism.\",\n      \"method\": \"NUDT21 shRNA knockdown, RT-PCR for GLS1 splice variants, HIF-1α modulation, xenograft model\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic knockdown with isoform-specific RT-PCR, single lab, mechanistic link to splicing established\",\n      \"pmids\": [\"32228887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YAP1 protects vascular smooth muscle cells against ferroptosis by regulating GLS1 expression to promote synthesis of glutamate and glutathione. YAP1 knockdown decreases GLS1 expression and increases ferroptosis susceptibility.\",\n      \"method\": \"YAP1 knockdown/overexpression, western blot for GLS1, glutamate/GSH measurement, ferroptosis assays in VSMCs\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — western blot with knockdown/overexpression correlation, single lab, pathway placement inferred rather than directly demonstrated\",\n      \"pmids\": [\"39091212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDF1 binds to the 3' UTR of GLS1 mRNA (validated by RNA immunoprecipitation) and promotes GLS1 protein synthesis. YTHDF1-mediated upregulation of GLS1 drives glutamine metabolism and cisplatin resistance in colorectal cancer cells.\",\n      \"method\": \"RNA immunoprecipitation (RIP) assay, YTHDF1 overexpression/knockdown, western blot for GLS1, in vivo xenograft\",\n      \"journal\": \"Molecular therapy oncolytics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP assay directly demonstrates YTHDF1-GLS1 mRNA binding, protein synthesis validated, in vivo confirmation, single lab\",\n      \"pmids\": [\"33614908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GLS1 interacts with NFS1 (iron-sulfur cluster assembly enzyme) and regulates Fe2+ homeostasis. GLS1-driven glutamine metabolism facilitates acetyl-CoA production, which promotes histone acetylation of NFS1, establishing a link between GLS1 activity and iron homeostasis in nucleus pulposus cells.\",\n      \"method\": \"Co-immunoprecipitation (GLS1-NFS1 interaction), GLS1 overexpression, metabolite measurement, histone acetylation assay\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP demonstrating interaction, single lab, mechanistic link between acetyl-CoA and NFS1 acetylation not fully validated\",\n      \"pmids\": [\"39710108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GLS1 knockdown in prostate cancer cells suppresses the Wnt/β-catenin pathway (decreased cyclinD1 and Bcl-2, increased Bax), inducing apoptosis and cell cycle arrest.\",\n      \"method\": \"GLS1 siRNA knockdown, western blot for Wnt/β-catenin pathway components, apoptosis and cell cycle assays\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — western blot with knockdown, correlation of pathway components, single lab, no direct mechanistic linkage demonstrated\",\n      \"pmids\": [\"31196962\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GLS (kidney-type glutaminase) is a mitochondrial enzyme that catalyzes the deamidation of glutamine to glutamate and ammonia, supporting TCA cycle anaplerosis, redox homeostasis (glutathione production), and biosynthesis; its activity is regulated post-translationally by succinylation at K311 (controlled by SUCLA2-p38MAPK signaling), ubiquitin-proteasomal degradation via APC/C-CDH1 (promoted by SIRT4, selenite, and bergenin/PPARγ), and by self-assembly into catalytically hyperactive filaments under glutamine deprivation; its expression is transcriptionally driven by c-Myc (which directly binds the GLS1 promoter) in a positive feedback loop, and GLS in turn stabilizes c-Myc through USP1; a gain-of-function variant (S482C) causes hyperactivity leading to glutamate excess and neurological disease, while complete loss of GLS causes spastic ataxia, confirming its essential role in maintaining glutamate homeostasis in the nervous system.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GLS (kidney-type glutaminase) is a mitochondrial enzyme that initiates glutaminolysis, converting glutamine to glutamate to feed the TCA cycle, redox defense, and biosynthesis; its splice isoforms KGA and GAC are mitochondrially localized in neurons, astrocytes, and tumor cells [#5, #13], and the GAC variant in particular is required for cancer cell proliferation, with growth defects upon knockdown rescued by downstream glutaminolysis metabolites [#0]. Catalytic output is tuned by post-translational regulation: under oxidative stress, p38-MAPK-phosphorylated SUCLA2 dissociates from GLS, enabling K311 succinylation, oligomerization, and elevated activity that drives NADPH and glutathione production [#1], while glutamine deprivation triggers conversion of dimeric GLS into hyperactive self-assembled filaments that further deplete glutamine and provoke ROS-induced apoptosis rescued by asparagine [#2]. GLS protein abundance is set by competing ubiquitin-proteasome inputs through APC/C-CDH1, promoted by selenite and by PPARγ agonists acting via the CDK1-APC/C-Cdh1 axis [#8, #9], and by SIRT4-, SIRT5-, USP6-, and YTHDF1-dependent control of stability and translation [#10, #12, #18]. Transcriptionally, GLS1 is induced by c-Myc, which binds the GLS1 promoter, and GLS1 reciprocally stabilizes c-Myc through a USP1-dependent mechanism, forming a feed-forward loop that drives cancer cell invasion [#14]; additional inputs include c-Jun downstream of MALT1 in Th17/psoriasis settings and ARID1A loss releasing SWI/SNF repression of the locus [#7, #6]. In the nervous system, a de novo gain-of-function S482C variant causes enzyme hyperactivity, glutamate excess, infantile cataract and developmental delay [#3], whereas complete GLS loss causes autosomal recessive spastic ataxia with optic atrophy, establishing GLS as essential for glutamate homeostasis [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that a specific GLS1 splice isoform, GAC, is the metabolically critical product driving cancer cell growth, framing glutaminase as a dependency rather than a housekeeping enzyme.\",\n      \"evidence\": \"isoform-specific siRNA knockdown with downstream metabolite rescue in NSCLC cells\",\n      \"pmids\": [\"22892846\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not resolve which downstream metabolite is rate-limiting\", \"Single cell-line context\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved the subcellular distribution of GLS, confirming mitochondrial localization of KGA/GAC in neurons and astrocytes and distinguishing it from nuclear-capable GLS2.\",\n      \"evidence\": \"isoform-specific immunocytochemistry, confocal microscopy and in situ activity staining in rat and human brain\",\n      \"pmids\": [\"25297978\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address regulation of localization\", \"Functional consequence of compartmentalization not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated that complete loss of GLS causes a human neurological disease, establishing GLS as essential for normal nervous system function.\",\n      \"evidence\": \"homozygosity mapping and whole-genome sequencing of a family with spastic ataxia and confirmed absence of GLS expression\",\n      \"pmids\": [\"29468182\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single family report\", \"Mechanism linking glutaminase loss to optic atrophy/spasticity not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed that a gain-of-function point mutation in the catalytic environment produces enzyme hyperactivity and glutamate excess, defining the opposite disease pole from loss-of-function and pinpointing a regulatory residue.\",\n      \"evidence\": \"patient fibroblast biochemistry, zebrafish expression model with GLS-inhibitor rescue, and MR spectroscopy\",\n      \"pmids\": [\"30239721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis inferred rather than crystallographically resolved\", \"Single de novo variant\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a stress-responsive post-translational switch in which SUCLA2 release permits K311 succinylation, oligomerization, and activation of GLS to fuel antioxidant output.\",\n      \"evidence\": \"reciprocal Co-IP, phospho/succinyl-site mutagenesis, in vitro activity assays, and mouse xenografts\",\n      \"pmids\": [\"33991485\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the succinyltransferase not established\", \"Relationship between succinylation and filament assembly unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established that glutamine deprivation drives GLS dimer-to-filament conversion as a self-amplifying hyperactive state with cell-fate consequences, linking enzyme assembly to apoptosis.\",\n      \"evidence\": \"biochemical filament reconstitution, K320A/S482C mutants, asparagine rescue and xenograft tumor models\",\n      \"pmids\": [\"35381197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution filament architecture not provided\", \"Physiological triggers beyond glutamine deprivation untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected upstream signaling to GLS1 transcription and downstream chromatin output, showing MALT1/c-Jun-driven GLS1 expression supports Th17 differentiation via histone acetylation at Il17a.\",\n      \"evidence\": \"ChIP for c-Jun promoter binding and H3 acetylation, protease and GLS1 inhibition in psoriasis mouse models\",\n      \"pmids\": [\"32831293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not quantify metabolite flux to acetyl-CoA in vivo\", \"Generality beyond skin inflammation unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified ARID1A/SWI/SNF as a chromatin repressor of GLS1, creating a synthetic-lethal vulnerability to glutaminase inhibition in ARID1A-mutant cancer.\",\n      \"evidence\": \"ARID1A genetic inactivation, ChIP, 13C metabolic tracing and CB-839 in orthotopic and PDX models\",\n      \"pmids\": [\"34085048\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct SWI/SNF occupancy dynamics over time not resolved\", \"Restricted to ovarian clear cell context\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated a reciprocal GLS1-c-Myc feedback loop in which c-Myc transcribes GLS1 and GLS1 stabilizes c-Myc via USP1, coupling glutamine metabolism to oncogenic invasion.\",\n      \"evidence\": \"genetic and CB-839 perturbation, ChIP, ubiquitination assays and orthotopic mouse model\",\n      \"pmids\": [\"39024547\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which GLS1 controls USP1 not defined\", \"Whether the loop operates outside the studied cancers untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapped sirtuin- and deubiquitinase-based control of GLS1 stability, showing SIRT4 antagonizes SIRT5 stabilization to limit glutaminolysis and α-ketoglutarate-driven ECM transcription.\",\n      \"evidence\": \"Co-IP of SIRT4/SIRT5/GLS1, activity assays and in vivo intestinal fibrosis models\",\n      \"pmids\": [\"37541633\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic modification of GLS1 by these sirtuins not shown\", \"Single disease model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple regulatory layers — succinylation, filament assembly, APC/C-CDH1 degradation, and transcriptional feedback — are integrated into a single quantitative control scheme for GLS activity in normal versus diseased tissue remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking PTM state to assembly state to flux\", \"Tissue-specific regulatory hierarchy undefined\", \"Structural mechanism of catalytic-site mutations and filament gating not crystallographically resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 2, 3, 5]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [5, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1, 2, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SUCLA2\",\n      \"SIRT5\",\n      \"SIRT4\",\n      \"USP6\",\n      \"YTHDF1\",\n      \"NFS1\",\n      \"MYC\",\n      \"CDH1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}