{"gene":"GLUD1","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2000,"finding":"Human GLUD1-encoded GDH (hGDH1) displays distinct allosteric regulation compared to the nerve-specific GLUD2 isoform: hGDH1 maintains substantial basal activity (~35-40% of maximal) and is markedly inhibited by GTP (IC50 ~0.20 µM), whereas activation by L-leucine alone (~75%) requires higher concentrations without ADP. ADP synergizes with L-leucine to activate the enzyme. These properties differ from the GLUD2 enzyme, and distinct Km values for glutamate and α-ketoglutarate were determined for each isoform.","method":"Recombinant enzyme expression in Sf9 cells, in vitro kinetic and allosteric assays with purified hGDH1 and hGDH2","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified recombinant enzyme, multiple allosteric effectors tested, replicated in subsequent papers","pmids":["11032875"],"is_preprint":false},{"year":2002,"finding":"Substitution of Ser for Arg-443 in the regulatory 'antenna' domain of GLUD1 GDH virtually abolishes basal enzymatic activity and abrogates L-leucine activation in the absence of ADP. With ADP present, L-leucine can activate the R443S mutant >2000%. The Arg-443 residue lies in a helix that undergoes conformational changes during catalysis and is involved in intersubunit communication; this single substitution is sufficient to impair both catalytic and allosteric function.","method":"Site-directed mutagenesis of GLUD1, recombinant expression, in vitro enzymatic assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-directed mutagenesis with in vitro enzymatic reconstitution, multiple effector conditions tested","pmids":["12324473"],"is_preprint":false},{"year":2002,"finding":"A gain-of-function mutation Y266C in GLUD1 results in constitutively elevated GDH activity with severely impaired allosteric regulation by ADP and GTP. Overexpression of this mutant GDH (GDH266C) in insulinoma MIN6 cells causes glutamine-stimulated insulin secretion, demonstrating that unregulated GDH activity enhances oxidation of glutamate to α-ketoglutarate and thereby stimulates insulin secretion from pancreatic β-cells.","method":"Site-directed mutagenesis, COS-7 cell expression for activity assays, overexpression in MIN6 insulinoma cells, insulin secretion assays","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — enzymatic assay plus functional insulin secretion assay in relevant cell line, mechanistic link to TCA cycle established","pmids":["11872671"],"is_preprint":false},{"year":2009,"finding":"Human GLUD1 and GLUD2 GDH proteins localize primarily to mitochondria and, to a lesser extent, to the endoplasmic reticulum. Deletion of the mitochondrial signal sequence prevents mitochondrial entry and eliminates the ER-associated full-length form. Two molecular weight forms correspond to the mitochondrial (cleaved, ~90 kDa) and ER-associated (full-length, ~95 kDa) proteins.","method":"EGFP fusion constructs expressed in multiple cell lines (COS7, HeLa, CHO, HEK293, SHSY-5Y), confocal microscopy with organelle markers, Western blot fractionation, signal sequence deletion","journal":"Biochemistry and cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct live-cell imaging with organelle-specific markers, Western blot fractionation, deletion mutant analysis, multiple cell lines","pmids":["19448744"],"is_preprint":false},{"year":2009,"finding":"Transgenic (Tg) mice overexpressing Glud1 under the neuron-specific enolase promoter show increased GLUD protein activity in CNS neurons, increased in vivo depolarization-induced glutamate release in striatum, and increased frequency and amplitude of miniature EPSCs in CA1 hippocampus. This demonstrates that GLUD1 functions in the pathway of glutamate synthesis/release in nerve terminals.","method":"Transgenic mouse overexpression, in vivo glutamate microelectrode measurements, electrophysiological recordings (mEPSCs), immunohistochemistry","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo measurements and electrophysiology in transgenic model, multiple orthogonal methods, replicated in subsequent papers","pmids":["19890003"],"is_preprint":false},{"year":2009,"finding":"Activating mutations in GLUD1 (e.g., P436L, N410D, D451V) that impair GTP inhibition of GDH cause hyperinsulinism-hyperammonemia syndrome. Functional analysis confirmed that the P436L mutation abolishes GTP inhibitory regulation of the enzyme.","method":"GLUD1 gene sequencing, functional analysis of mutant GDH in patient samples","journal":"European journal of endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutation identification plus functional analysis, single-center study","pmids":["19690084"],"is_preprint":false},{"year":2012,"finding":"CNS-specific deletion of Glud1 in mice causes deficient oxidative catabolism of glutamate in astrocytes (reduced astrocytic glutamate breakdown, requiring GDH for Krebs cycle entry). Brain glutamate levels remain unchanged while glutamine levels increase. Glutamate and glutamine transporters and glutamine synthetase are upregulated. Synaptic transmission is not altered under standard conditions.","method":"CNS-conditional Glud1 knockout mice (Nestin-Cre/LoxP), enzymatic activity assays, NMR spectroscopy, immunohistochemistry, electrophysiology","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple orthogonal readouts (NMR, electrophysiology, biochemistry, IHC)","pmids":["22924626"],"is_preprint":false},{"year":2012,"finding":"GLUD1 GDH properties differ from GLUD2: hGDH1 maintains substantial basal activity and is subject to potent GTP inhibition, while hGDH2 (with the Arg443Ser evolutionary change) has low basal activity, is insensitive to GTP at physiological concentrations, and is more responsive to activation by rising ADP/L-leucine levels. These properties were confirmed using purified recombinant proteins from Sf21 cell expression.","method":"Recombinant expression in Sf21 cells, in vitro enzymatic assays, allosteric regulation studies","journal":"Neurochemistry international","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified recombinant enzymes, multiple allosteric effectors, replication of earlier findings with expanded analysis","pmids":["22658952"],"is_preprint":false},{"year":2017,"finding":"GDH1 (GLUD1) promotes anoikis resistance and tumor metastasis in LKB1-deficient lung cancer. Upon detachment, GDH1 is upregulated via PLAG1 transcription factor. The GDH1 product α-ketoglutarate (α-KG) activates CamKK2 by enhancing its binding to substrate AMPK, thereby contributing to energy production that confers anoikis resistance. This GDH1-CamKK2-AMPK axis is particularly important in LKB1-deficient tumors where AMPK activation depends predominantly on CamKK2.","method":"Cell detachment assays, gene knockdown/overexpression, Co-IP (CamKK2-AMPK interaction), metabolite measurement, patient-derived xenograft model, correlation studies","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, metabolite measurement, in vivo xenograft, genetic manipulation), mechanistic pathway defined","pmids":["29249655"],"is_preprint":false},{"year":2020,"finding":"EGFR activation upregulates GDH1 transcription through the MEK/ERK/ELK1 pathway in glioblastoma. EGFR triggers phosphorylation of ELK1 at Ser383 via MEK/ERK; phosphorylated ELK1 binds the GDH1 promoter to activate transcription. ELK1 knockdown or ELK1-Ser383 mutation prevents EGFR-induced GDH1 upregulation and glutamine metabolism activation.","method":"ChIP assay (ELK1 at GDH1 promoter), ELK1 knockdown, ELK1 Ser383 point mutation, Western blot for phosphorylation, luciferase reporter or direct measurement of GDH1 transcription","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, site-specific mutagenesis, and knockdown with multiple orthogonal readouts in a single focused study","pmids":["32034306"],"is_preprint":false},{"year":2020,"finding":"A gain-of-function GLUD1 mutation G446V reduces the energy barrier between open and closed enzyme states, impairing allosteric inhibition by GTP and activation by ADP. Patient-derived lymphoblastoid cells carrying GDH-G446V show higher mitochondrial respiration in response to GDH-dependent substrates, indicating a metabolic shift toward glutaminolysis.","method":"Computational conformational energy analysis, enzymatic activity assay in patient-derived lymphoblastoid cells, mitochondrial respiration assay","journal":"Human genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays in patient-derived cells plus computational analysis, single study","pmids":["32143698"],"is_preprint":false},{"year":2021,"finding":"Under amino acid deprivation or mTORC1 inhibition, GDH1 translocates from mitochondria to the cytoplasm, where it is ubiquitinated and degraded via the E3 ligase RNF213. GDH1 degradation reduces intracellular α-KG levels and decreases activity of α-KG-dependent lysine demethylases (KDMs), leading to increased histone H3K9 and H3K27 methylation that suppresses ribosomal protein gene expression to preserve nutrients for cell survival.","method":"Cell fractionation, ubiquitination assays, E3 ligase identification (RNF213), metabolite measurement (α-KG), ChIP for histone methylation marks, gene expression analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, ubiquitination assay, metabolomics, ChIP), mechanistic pathway defined in single rigorous study","pmids":["34269483"],"is_preprint":false},{"year":2022,"finding":"EGFR phosphorylates GDH1 at tyrosine 135, activating it. Activated GDH1 cooperates with RSK2 to enhance CREB activity via CaMKIV signaling, promoting metastasis. GDH1, RSK2, and CREB phosphorylation positively correlate with EGFR mutation/activation in lung cancer patient tumors.","method":"Phosphorylation assays, co-immunoprecipitation, kinase assays, cell invasion/anoikis resistance assays, patient tumor correlation","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical phosphorylation and Co-IP data plus functional assays, single lab","pmids":["36516759"],"is_preprint":false},{"year":2023,"finding":"STUB1 (CHIP) is the E3 ubiquitin ligase responsible for ubiquitin-mediated proteasomal degradation of GLUD1. Lysine 503 (K503) is the primary ubiquitination site on GLUD1. Inhibiting ubiquitination at K503 promotes proliferation and tumor growth of lung adenocarcinoma cells.","method":"Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (K503), cell proliferation and xenograft assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with ubiquitination assay and mutagenesis, single lab, two orthogonal methods","pmids":["37416474"],"is_preprint":false},{"year":2024,"finding":"GLUD1 deletion in proliferating muscle stem cells (MuSCs) causes mitochondrial glutamate accumulation and inhibition of the malate-aspartate shuttle (MAS), leading to compartment-specific NAD+/NADH ratio shifts. This triggers precocious differentiation and fusion, and loss of self-renewal in vitro and in vivo. Restoring MAS activity or directly altering NAD+/NADH ratios normalizes myogenesis, placing GLUD1 as a metabolic brake on MuSC differentiation acting through mitochondrial glutamate levels and the MAS.","method":"Conditional Glud1 knockout in MuSCs, metabolomics (mitochondrial glutamate/α-KG), MAS activity rescue, NAD+/NADH manipulation, in vitro and in vivo differentiation assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with metabolomics, rescue experiments, multiple orthogonal readouts in vitro and in vivo","pmids":["39121856"],"is_preprint":false},{"year":2024,"finding":"LASP1 interacts with GLUD1 and promotes its degradation via the ubiquitin-proteasome pathway, relying on the E3 ubiquitin ligase SYVN1 (synoviolin). LASP1 enhances SYVN1-GLUD1 interaction to facilitate GLUD1 ubiquitination. In HBV-related HCC, HBX protein suppresses GLUD1 through this LASP1/SYVN1 axis. GLUD1 interacts with AKT and α-KG produced by GLUD1 suppresses AKT activation.","method":"Co-immunoprecipitation, ubiquitination assays, gene silencing, Western blot","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and ubiquitination assays, single lab","pmids":["38587834"],"is_preprint":false},{"year":2024,"finding":"Glucose starvation reduces GLUD1 acetylation at Lys84, which promotes active hexamer formation and GLUD1 enzymatic activity. Under glucose starvation, deacetylated GLUD1 translocates to the cytoplasm where it is ubiquitinated in K63-linkage by TRIM21 and binds cytoplasmic glutaminase KGA, enhancing glutamine metabolism. Cytoplasmic GLUD1 also interacts with p62, preventing p62 acetylation and blocking autophagic cell death in lung adenocarcinoma cells.","method":"Acetylation site mapping, Co-immunoprecipitation (GLUD1-KGA, GLUD1-p62), ubiquitination assays, cell fractionation, glucose starvation experiments","journal":"Cell insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assays with site-specific mapping, single lab, multiple orthogonal methods","pmids":["39144257"],"is_preprint":false},{"year":2026,"finding":"GLUD1 interacts with ARAF proto-oncogene protein and limits its ubiquitin-proteasome-mediated degradation, thereby stabilizing ARAF protein levels and sustaining MEK/ERK signaling. This represents a non-enzymatic function of GLUD1 that supports anoikis resistance during peritoneal dissemination of ovarian cancer.","method":"Co-immunoprecipitation (GLUD1-ARAF interaction), ubiquitination assays, GLUD1 knockdown/overexpression, in vitro anoikis assays, in vivo peritoneal dissemination model","journal":"NPJ precision oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assays, in vivo model, single lab","pmids":["41786885"],"is_preprint":false},{"year":2026,"finding":"PRMT7 mediates monomethylation of GLUD1 at arginine 76 (R76), which enhances GLUD1 protein stability by antagonizing ubiquitin-dependent proteasomal degradation. AKT1 phosphorylates PRMT7 at threonine 73 (T73) to promote PRMT7 activity toward GLUD1, stabilizing GLUD1 and supporting glutamine metabolism in gastric cancer cells.","method":"Co-immunoprecipitation, site-directed mutagenesis (R76, T73), ubiquitination assays, kinase assays, xenograft models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, mutagenesis, and ubiquitination assays, single lab with in vivo validation","pmids":["41876450"],"is_preprint":false},{"year":2015,"finding":"Manganese (Mn) inhibits hGDH1 (GLUD1-encoded) enzymatic activity in vitro with an IC50 of ~1.54 mM at 0.25 mM ADP, exhibiting sigmoidal inhibition kinetics. This is a less potent and less cooperative inhibition compared to hGDH2, suggesting differential sensitivity of the two isoforms to Mn at physiologically relevant ADP levels.","method":"In vitro enzymatic inhibition assay with purified recombinant hGDH1 and hGDH2, determination of IC50 and Hill coefficients","journal":"Neurochemistry international","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro assay with purified recombinant enzyme, single lab, comparative study","pmids":["25837286"],"is_preprint":false},{"year":2024,"finding":"PARP14 inhibits GLUD1 enzymatic activity via mono-ADP-ribosylation (MARylation), reducing α-KG production and suppressing energy metabolism. ECH (echinacoside) downregulates PARP14 expression, reversing this inhibition and restoring GLUD1-dependent glutamine metabolism and mitochondrial function in ovarian granulosa cells.","method":"Co-immunoprecipitation, enzymatic activity assay, siRNA knockdown, metabolomics, mitochondrial functional assays","journal":"Phytomedicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and enzymatic activity assays in a single study focused on a herbal compound, limited mechanistic validation of the MARylation site","pmids":["41895093"],"is_preprint":false},{"year":2025,"finding":"Nuclear PHGDH regulates GLUD1 transcription via interaction with the transcription factor STAT3. ChIP-qPCR and co-immunoprecipitation showed nuclear PHGDH interacts with STAT3 to repress GLUD1 (and GLS2) gene expression, affecting macrophage polarization. STAT3 inhibition reversed the effects of PHGDH on macrophage function.","method":"ChIP-qPCR, co-immunoprecipitation, gene silencing, rescue experiments","journal":"Cancer biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR and Co-IP with rescue experiments, single lab","pmids":["40434360"],"is_preprint":false},{"year":2025,"finding":"SIRT3-dependent deacetylation of GLUD1 is promoted by the SENP1-Sirt3 signaling pathway activated by A-485 (p300/CBP inhibitor). Deacetylation of GLUD1 by SIRT3 enhances its enzymatic activity and improves mitochondrial function and osteogenic differentiation. SENP1 knockdown blocks these effects.","method":"Western blot for acetylation, SENP1 knockdown, SIRT3 activity assays, osteogenic differentiation assays, in vivo OVX rat model","journal":"Journal of orthopaedic surgery and research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — acetylation/deacetylation assay with knockdown, single lab, indirect evidence for SIRT3-GLUD1 axis","pmids":["40442713"],"is_preprint":false}],"current_model":"GLUD1 encodes the housekeeping mitochondrial glutamate dehydrogenase (hGDH1) that catalyzes the reversible oxidative deamination of glutamate to α-ketoglutarate (α-KG) and ammonia; its activity is tightly regulated by allosteric effectors—potently inhibited by GTP (IC50 ~0.20 µM) and activated by ADP and L-leucine through the 'antenna' regulatory domain (critical residue Arg-443)—and gain-of-function mutations that impair GTP inhibition cause hyperinsulinism-hyperammonemia syndrome by driving excess insulin secretion; beyond its canonical mitochondrial matrix role in glutamate catabolism and anaplerosis (required for astrocytic glutamate metabolism), GLUD1 can translocate to the cytoplasm under nutrient stress where it is ubiquitinated by RNF213 and STUB1 (at K503) for proteasomal degradation; its protein stability is further controlled by PRMT7-mediated arginine methylation (R76) downstream of AKT1 and by acetylation at K84; in cancer contexts GLUD1 is phosphorylated by EGFR at Y135 to activate CaMKIV-CREB signaling, transcriptionally induced via EGFR-MEK-ERK-ELK1, and mediates anoikis resistance through α-KG-CamKK2-AMPK signaling (in LKB1-deficient cells) and through a non-enzymatic stabilization of ARAF to sustain MEK/ERK; in muscle stem cells, GLUD1 prevents mitochondrial glutamate accumulation and malate-aspartate shuttle inhibition to act as a metabolic brake on differentiation."},"narrative":{"mechanistic_narrative":"GLUD1 encodes the mitochondrial glutamate dehydrogenase (hGDH1) that catalyzes the reversible oxidative deamination of glutamate to α-ketoglutarate (α-KG), feeding glutamate carbon into the TCA cycle for anaplerosis and energy production [PMID:11032875, PMID:22924626]. The enzyme maintains substantial basal activity and is tightly governed by allosteric effectors—potently inhibited by GTP and activated by L-leucine and ADP—with the regulatory 'antenna' residue Arg-443 being essential for both catalytic and allosteric function [PMID:11032875, PMID:12324473]. Loss of allosteric control is pathogenic: gain-of-function mutations that impair GTP inhibition (e.g., Y266C, P436L, G446V) drive unregulated glutamate oxidation and glutamine-stimulated insulin secretion, causing hyperinsulinism-hyperammonemia syndrome [PMID:11872671, PMID:19690084, PMID:32143698]. The protein localizes principally to mitochondria, with a minor ER-associated pool, directed by an N-terminal mitochondrial signal sequence [PMID:19448744]. In the nervous system GLUD1 supports glutamate synthesis/release at nerve terminals and is required for astrocytic oxidative catabolism of glutamate for Krebs cycle entry [PMID:19890003, PMID:22924626], while in muscle stem cells it acts as a metabolic brake on differentiation by preventing mitochondrial glutamate accumulation and malate-aspartate shuttle inhibition [PMID:39121856]. GLUD1 abundance and localization are extensively controlled post-translationally: it translocates to the cytoplasm under amino-acid or glucose deprivation, where it is ubiquitinated and degraded by RNF213, with degradation lowering α-KG, reducing α-KG-dependent histone demethylase activity, and reprogramming gene expression to conserve nutrients [PMID:34269483]. Additional E3 ligases (STUB1 at K503; the LASP1/SYVN1 axis) target GLUD1 for proteasomal degradation, whereas PRMT7-mediated arginine methylation at R76 (downstream of AKT1) and K84 deacetylation stabilize and activate the enzyme [PMID:37416474, PMID:38587834, PMID:39144257, PMID:41876450]. In cancer, GLUD1 is transcriptionally induced via EGFR-MEK-ERK-ELK1 and phosphorylated by EGFR at Y135 to activate CaMKIV-CREB signaling, and it promotes anoikis resistance both enzymatically—through α-KG-driven CaMKK2-AMPK activation in LKB1-deficient cells—and non-enzymatically, by stabilizing ARAF to sustain MEK/ERK signaling [PMID:29249655, PMID:32034306, PMID:36516759, PMID:41786885].","teleology":[{"year":2000,"claim":"Established that the GLUD1-encoded enzyme is a distinct allosterically regulated GDH isoform, defining its baseline catalytic and regulatory parameters.","evidence":"In vitro kinetic and allosteric assays with purified recombinant hGDH1 expressed in Sf9 cells","pmids":["11032875"],"confidence":"High","gaps":["Does not address in vivo regulation or physiological effector concentrations","Allosteric structural basis not resolved"]},{"year":2002,"claim":"Identified Arg-443 in the antenna domain as essential for basal activity and L-leucine activation, linking a single residue to intersubunit communication and allosteric control.","evidence":"Site-directed mutagenesis (R443S) with recombinant expression and in vitro enzymatic assays","pmids":["12324473"],"confidence":"High","gaps":["No structural model of the conformational change","Physiological consequence of antenna-domain regulation in cells untested here"]},{"year":2002,"claim":"Connected loss of GDH allosteric regulation to disease by showing a gain-of-function mutation drives glutamine-stimulated insulin secretion.","evidence":"Y266C mutagenesis, activity assays in COS-7, overexpression and insulin secretion assays in MIN6 insulinoma cells","pmids":["11872671"],"confidence":"High","gaps":["Does not establish in vivo β-cell phenotype","Ammonemia mechanism not directly addressed"]},{"year":2009,"claim":"Defined GLUD1 subcellular distribution, establishing a dominant mitochondrial pool and a minor ER-associated full-length form dependent on the signal sequence.","evidence":"EGFP fusions in multiple cell lines, confocal microscopy, fractionation, signal-sequence deletion","pmids":["19448744"],"confidence":"High","gaps":["Functional role of the ER-associated form unknown","No evidence yet for regulated cytoplasmic translocation"]},{"year":2009,"claim":"Demonstrated in vivo neuronal roles for GLUD1 in depolarization-induced glutamate release and synaptic transmission.","evidence":"Neuron-specific Glud1 transgenic overexpression, in vivo glutamate microelectrode measurements, mEPSC electrophysiology","pmids":["19890003"],"confidence":"High","gaps":["Overexpression model may not reflect endogenous levels","Mechanism of release coupling not resolved"]},{"year":2012,"claim":"Established the requirement of GLUD1 for astrocytic oxidative glutamate catabolism and Krebs cycle entry in the brain in vivo.","evidence":"CNS-conditional Glud1 knockout (Nestin-Cre), NMR spectroscopy, enzymatic assays, electrophysiology, IHC","pmids":["22924626"],"confidence":"High","gaps":["Compensatory transporter/glutamine synthetase upregulation complicates interpretation","No synaptic defect under standard conditions"]},{"year":2009,"claim":"Expanded the spectrum of GTP-insensitive activating mutations causing hyperinsulinism-hyperammonemia syndrome.","evidence":"GLUD1 sequencing and functional analysis of mutant GDH (P436L, N410D, D451V) in patient samples","pmids":["19690084"],"confidence":"Medium","gaps":["Single-center cohort","Functional analysis limited to subset of mutations"]},{"year":2020,"claim":"Linked GLUD1 to oncogenic transcription and a structural basis for impaired GTP regulation in disease.","evidence":"ChIP and ELK1-Ser383 mutagenesis showing EGFR-MEK-ERK-ELK1 induction of GDH1; computational and patient-cell analysis of the G446V activating mutation","pmids":["32034306","32143698"],"confidence":"High","gaps":["G446V functional data from single study in patient-derived cells","Transcriptional control mapped in glioblastoma only"]},{"year":2017,"claim":"Defined an enzymatic, α-KG-dependent mechanism by which GLUD1 confers anoikis resistance in LKB1-deficient cancer.","evidence":"Detachment assays, knockdown/overexpression, Co-IP of CamKK2-AMPK, metabolite measurement, patient-derived xenografts","pmids":["29249655"],"confidence":"High","gaps":["Dependence on LKB1 status limits generality","PLAG1 induction mechanism not fully resolved"]},{"year":2021,"claim":"Revealed stress-induced cytoplasmic translocation and RNF213-mediated degradation of GLUD1 as a nutrient-conservation program coupling α-KG to epigenetic gene control.","evidence":"Fractionation, ubiquitination assays, RNF213 identification, α-KG metabolomics, histone-methylation ChIP","pmids":["34269483"],"confidence":"High","gaps":["Trigger for mitochondria-to-cytosol relocation not fully defined","Reversibility of degradation upon refeeding untested"]},{"year":2022,"claim":"Identified EGFR phosphorylation of GLUD1 at Y135 as an activating modification driving CaMKIV-CREB pro-metastatic signaling.","evidence":"Phosphorylation and kinase assays, Co-IP, invasion/anoikis assays, patient tumor correlation","pmids":["36516759"],"confidence":"Medium","gaps":["Single-lab biochemistry","Direct structural consequence of Y135 phosphorylation not shown"]},{"year":2023,"claim":"Mapped a second degradation route, identifying STUB1 as an E3 ligase and K503 as the primary GLUD1 ubiquitination site controlling tumor growth.","evidence":"Co-IP, ubiquitination assays, K503 mutagenesis, proliferation and xenograft assays","pmids":["37416474"],"confidence":"Medium","gaps":["Single-lab, two orthogonal methods","Relationship to RNF213 pathway unresolved"]},{"year":2024,"claim":"Placed GLUD1 as a metabolic brake on muscle stem cell differentiation acting through mitochondrial glutamate and the malate-aspartate shuttle.","evidence":"Conditional Glud1 knockout in MuSCs, metabolomics, MAS rescue, NAD+/NADH manipulation, in vitro and in vivo differentiation assays","pmids":["39121856"],"confidence":"High","gaps":["Compartment-specific NAD+/NADH measurement is inferential","Generalizability to other stem cell types unknown"]},{"year":2024,"claim":"Extended GLUD1 stability control to additional ligase axes and identified acetylation-coupled cytoplasmic functions and an AKT-suppressive role.","evidence":"Co-IP and ubiquitination assays defining LASP1/SYVN1-mediated degradation and GLUD1-AKT interaction; K84 acetylation mapping with TRIM21, KGA, and p62 interactions under glucose starvation","pmids":["38587834","39144257"],"confidence":"Medium","gaps":["Single-lab Co-IP datasets","Functional integration of multiple competing ligases unclear","K63-ubiquitination role mechanistically incomplete"]},{"year":2026,"claim":"Established a non-enzymatic scaffolding function of GLUD1 (ARAF stabilization) and a stabilizing methylation modification (PRMT7/R76 downstream of AKT1).","evidence":"Co-IP and ubiquitination assays for GLUD1-ARAF stabilization with in vivo dissemination model; PRMT7 R76 methylation mapping with AKT1-T73 phosphorylation and xenografts","pmids":["41786885","41876450"],"confidence":"Medium","gaps":["Single-lab biochemistry for each axis","Structural basis of ARAF binding and R76 methylation not resolved"]},{"year":null,"claim":"How the multiple competing post-translational modifications, ligases, and the enzymatic versus non-enzymatic activities of GLUD1 are integrated in a single cell to set its abundance, localization, and signaling output remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling RNF213, STUB1, SYVN1, and TRIM21 ubiquitination","Relative contribution of enzymatic α-KG output versus scaffolding functions in tumors unquantified","Structural basis of mitochondria-to-cytoplasm translocation unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,1,2,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[17]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[3,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[11,16]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,6,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,12,17]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[11,13,18]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[4,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,5,10]}],"complexes":[],"partners":["RNF213","STUB1","SYVN1","LASP1","PRMT7","ARAF","AKT1","EGFR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P00367","full_name":"Glutamate dehydrogenase 1, mitochondrial","aliases":[],"length_aa":558,"mass_kda":61.4,"function":"Mitochondrial glutamate dehydrogenase that catalyzes the conversion of L-glutamate into alpha-ketoglutarate. Plays a key role in glutamine anaplerosis by producing alpha-ketoglutarate, an important intermediate in the tricarboxylic acid cycle (PubMed:11032875, PubMed:11254391, PubMed:16023112, PubMed:16959573). Plays a role in insulin homeostasis (PubMed:11297618, PubMed:9571255). 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activating mutations in GLUD1.","date":"2023","source":"Endocrine connections","url":"https://pubmed.ncbi.nlm.nih.gov/35951311","citation_count":4,"is_preprint":false},{"pmid":"38754351","id":"PMC_38754351","title":"Dynamic behaviors of protein and water associated with fresh noodle quality during processing based on different HMW-GSs at Glu-D1.","date":"2024","source":"Food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38754351","citation_count":4,"is_preprint":false},{"pmid":"25781533","id":"PMC_25781533","title":"Hyperinsulinemic hypoglycemia: think of hyperinsulinism/hyperammonemia (HI/HA) syndrome caused by mutations in the GLUD1 gene.","date":"2015","source":"Journal of pediatric endocrinology & metabolism : JPEM","url":"https://pubmed.ncbi.nlm.nih.gov/25781533","citation_count":4,"is_preprint":false},{"pmid":"26656609","id":"PMC_26656609","title":"A novel mutation in the glutamate dehydrogenase (GLUD1) of a patient with congenital hyperinsulinism-hyperammonemia (HI/HA).","date":"2016","source":"Journal of pediatric endocrinology & metabolism : JPEM","url":"https://pubmed.ncbi.nlm.nih.gov/26656609","citation_count":4,"is_preprint":false},{"pmid":"21932603","id":"PMC_21932603","title":"Biochemical evaluation of an infant with hypoglycemia resulting from a novel de novo mutation of the GLUD1 gene and hyperinsulinism-hyperammonemia syndrome.","date":"2011","source":"Journal of pediatric endocrinology & metabolism : JPEM","url":"https://pubmed.ncbi.nlm.nih.gov/21932603","citation_count":4,"is_preprint":false},{"pmid":"40442713","id":"PMC_40442713","title":"A-485 alleviates postmenopausal osteoporosis by activating GLUD1 deacetylation through the SENP1-Sirt3 signal pathway.","date":"2025","source":"Journal of orthopaedic surgery and research","url":"https://pubmed.ncbi.nlm.nih.gov/40442713","citation_count":3,"is_preprint":false},{"pmid":"35342475","id":"PMC_35342475","title":"Diazoxide-Induced Neutropenia and Long-Term Follow-up in a Patient with Hyperinsulinemia-Hyperammonemia due to GLUD1 Mutation.","date":"2021","source":"Acta endocrinologica (Bucharest, Romania : 2005)","url":"https://pubmed.ncbi.nlm.nih.gov/35342475","citation_count":3,"is_preprint":false},{"pmid":"26839063","id":"PMC_26839063","title":"A novel mutation in GLUD1 causing hyperinsulinism-hyperammonemia in a patient with high density of homozygosity on microarray: a case report.","date":"2016","source":"Journal of medical case reports","url":"https://pubmed.ncbi.nlm.nih.gov/26839063","citation_count":3,"is_preprint":false},{"pmid":"25746627","id":"PMC_25746627","title":"Characterization of a thermostable glucose dehydrogenase with strict substrate specificity from a hyperthermophilic archaeon Thermoproteus sp. GDH-1.","date":"2015","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25746627","citation_count":3,"is_preprint":false},{"pmid":"39136063","id":"PMC_39136063","title":"GDH1 exacerbates renal fibrosis by inhibiting the transcriptional activity of peroxisome proliferator-activated receptor gamma.","date":"2024","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/39136063","citation_count":2,"is_preprint":false},{"pmid":"41345253","id":"PMC_41345253","title":"GluD1 at the synaptic crossroads: from domain structure to circuit dysfunction.","date":"2025","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/41345253","citation_count":2,"is_preprint":false},{"pmid":"39272024","id":"PMC_39272024","title":"Energy metabolism-related GLUD1 contributes to favorable clinical outcomes of IDH-mutant glioma.","date":"2024","source":"BMC neurology","url":"https://pubmed.ncbi.nlm.nih.gov/39272024","citation_count":2,"is_preprint":false},{"pmid":"36909588","id":"PMC_36909588","title":"UBE3A and transsynaptic complex NRXN1-CBLN1-GluD1 in a hypothalamic VMHvl-arcuate feedback circuit regulates aggression.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36909588","citation_count":2,"is_preprint":false},{"pmid":"29199326","id":"PMC_29199326","title":"[Effect of GLUD1 on proliferation, osteogenic differentiation and mineralization of human dental pulp stem cells].","date":"2017","source":"Shanghai kou qiang yi xue = Shanghai journal of stomatology","url":"https://pubmed.ncbi.nlm.nih.gov/29199326","citation_count":2,"is_preprint":false},{"pmid":"23902843","id":"PMC_23902843","title":"[ABCC8, KCNJ11 and GLUD1 gene mutation analysis in congenital hyperinsulinism pedigree].","date":"2013","source":"Zhonghua yi xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/23902843","citation_count":1,"is_preprint":false},{"pmid":"38124277","id":"PMC_38124277","title":"Increases in anterograde axoplasmic transport in neurons of the hyper-glutamatergic, glutamate dehydrogenase 1 (Glud1) transgenic mouse: Effects of glutamate receptors on transport.","date":"2023","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38124277","citation_count":1,"is_preprint":false},{"pmid":"40652260","id":"PMC_40652260","title":"Hyperinsulinism-hyperammonemia syndrome associated with GLUD1 gene mutation: a case series.","date":"2025","source":"Journal of medical case reports","url":"https://pubmed.ncbi.nlm.nih.gov/40652260","citation_count":0,"is_preprint":false},{"pmid":"41786885","id":"PMC_41786885","title":"GLUD1 supports ovarian cancer progression by counteracting anoikis via ARAF/MEK/ERK signaling.","date":"2026","source":"NPJ precision oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41786885","citation_count":0,"is_preprint":false},{"pmid":"37345272","id":"PMC_37345272","title":"Structural insights into the ligand binding domain of GluD1 and GluD2 receptors.","date":"2023","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/37345272","citation_count":0,"is_preprint":false},{"pmid":"41895093","id":"PMC_41895093","title":"Echinacoside modulates PARP14-GLUD1 axis to mediate energy metabolism reprogramming and mitochondrial function in diminished ovarian reserve.","date":"2026","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41895093","citation_count":0,"is_preprint":false},{"pmid":"41529805","id":"PMC_41529805","title":"Integrated network pharmacology and multi-omics reveals GLUD1-mediated α-KG/Glu conversion in regulating amino acid metabolism: a mechanism of Dangua Fang against type 2 diabetes mellitus.","date":"2026","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41529805","citation_count":0,"is_preprint":false},{"pmid":"41876450","id":"PMC_41876450","title":"AKT1 phosphorylates PRMT7 to promote GLUD1 methylation and gastric cancer progression.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41876450","citation_count":0,"is_preprint":false},{"pmid":"20931523","id":"PMC_20931523","title":"[Mutation analysis of the GLUD1 gene in patients with glutamate dehydrogenase congenital hyperinsulinism].","date":"2010","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20931523","citation_count":0,"is_preprint":false},{"pmid":"41973845","id":"PMC_41973845","title":"Chronic stress promotes oral squamous cell carcinoma progression via GLUD1-mediated metabolic reprogramming.","date":"2026","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/41973845","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50950,"output_tokens":6446,"usd":0.12477,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15299,"output_tokens":4872,"usd":0.099147,"stage2_stop_reason":"end_turn"},"total_usd":0.223917,"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\": 2000,\n      \"finding\": \"Human GLUD1-encoded GDH (hGDH1) displays distinct allosteric regulation compared to the nerve-specific GLUD2 isoform: hGDH1 maintains substantial basal activity (~35-40% of maximal) and is markedly inhibited by GTP (IC50 ~0.20 µM), whereas activation by L-leucine alone (~75%) requires higher concentrations without ADP. ADP synergizes with L-leucine to activate the enzyme. These properties differ from the GLUD2 enzyme, and distinct Km values for glutamate and α-ketoglutarate were determined for each isoform.\",\n      \"method\": \"Recombinant enzyme expression in Sf9 cells, in vitro kinetic and allosteric assays with purified hGDH1 and hGDH2\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified recombinant enzyme, multiple allosteric effectors tested, replicated in subsequent papers\",\n      \"pmids\": [\"11032875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Substitution of Ser for Arg-443 in the regulatory 'antenna' domain of GLUD1 GDH virtually abolishes basal enzymatic activity and abrogates L-leucine activation in the absence of ADP. With ADP present, L-leucine can activate the R443S mutant >2000%. The Arg-443 residue lies in a helix that undergoes conformational changes during catalysis and is involved in intersubunit communication; this single substitution is sufficient to impair both catalytic and allosteric function.\",\n      \"method\": \"Site-directed mutagenesis of GLUD1, recombinant expression, in vitro enzymatic assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-directed mutagenesis with in vitro enzymatic reconstitution, multiple effector conditions tested\",\n      \"pmids\": [\"12324473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A gain-of-function mutation Y266C in GLUD1 results in constitutively elevated GDH activity with severely impaired allosteric regulation by ADP and GTP. Overexpression of this mutant GDH (GDH266C) in insulinoma MIN6 cells causes glutamine-stimulated insulin secretion, demonstrating that unregulated GDH activity enhances oxidation of glutamate to α-ketoglutarate and thereby stimulates insulin secretion from pancreatic β-cells.\",\n      \"method\": \"Site-directed mutagenesis, COS-7 cell expression for activity assays, overexpression in MIN6 insulinoma cells, insulin secretion assays\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — enzymatic assay plus functional insulin secretion assay in relevant cell line, mechanistic link to TCA cycle established\",\n      \"pmids\": [\"11872671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Human GLUD1 and GLUD2 GDH proteins localize primarily to mitochondria and, to a lesser extent, to the endoplasmic reticulum. Deletion of the mitochondrial signal sequence prevents mitochondrial entry and eliminates the ER-associated full-length form. Two molecular weight forms correspond to the mitochondrial (cleaved, ~90 kDa) and ER-associated (full-length, ~95 kDa) proteins.\",\n      \"method\": \"EGFP fusion constructs expressed in multiple cell lines (COS7, HeLa, CHO, HEK293, SHSY-5Y), confocal microscopy with organelle markers, Western blot fractionation, signal sequence deletion\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct live-cell imaging with organelle-specific markers, Western blot fractionation, deletion mutant analysis, multiple cell lines\",\n      \"pmids\": [\"19448744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Transgenic (Tg) mice overexpressing Glud1 under the neuron-specific enolase promoter show increased GLUD protein activity in CNS neurons, increased in vivo depolarization-induced glutamate release in striatum, and increased frequency and amplitude of miniature EPSCs in CA1 hippocampus. This demonstrates that GLUD1 functions in the pathway of glutamate synthesis/release in nerve terminals.\",\n      \"method\": \"Transgenic mouse overexpression, in vivo glutamate microelectrode measurements, electrophysiological recordings (mEPSCs), immunohistochemistry\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo measurements and electrophysiology in transgenic model, multiple orthogonal methods, replicated in subsequent papers\",\n      \"pmids\": [\"19890003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Activating mutations in GLUD1 (e.g., P436L, N410D, D451V) that impair GTP inhibition of GDH cause hyperinsulinism-hyperammonemia syndrome. Functional analysis confirmed that the P436L mutation abolishes GTP inhibitory regulation of the enzyme.\",\n      \"method\": \"GLUD1 gene sequencing, functional analysis of mutant GDH in patient samples\",\n      \"journal\": \"European journal of endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutation identification plus functional analysis, single-center study\",\n      \"pmids\": [\"19690084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CNS-specific deletion of Glud1 in mice causes deficient oxidative catabolism of glutamate in astrocytes (reduced astrocytic glutamate breakdown, requiring GDH for Krebs cycle entry). Brain glutamate levels remain unchanged while glutamine levels increase. Glutamate and glutamine transporters and glutamine synthetase are upregulated. Synaptic transmission is not altered under standard conditions.\",\n      \"method\": \"CNS-conditional Glud1 knockout mice (Nestin-Cre/LoxP), enzymatic activity assays, NMR spectroscopy, immunohistochemistry, electrophysiology\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple orthogonal readouts (NMR, electrophysiology, biochemistry, IHC)\",\n      \"pmids\": [\"22924626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"GLUD1 GDH properties differ from GLUD2: hGDH1 maintains substantial basal activity and is subject to potent GTP inhibition, while hGDH2 (with the Arg443Ser evolutionary change) has low basal activity, is insensitive to GTP at physiological concentrations, and is more responsive to activation by rising ADP/L-leucine levels. These properties were confirmed using purified recombinant proteins from Sf21 cell expression.\",\n      \"method\": \"Recombinant expression in Sf21 cells, in vitro enzymatic assays, allosteric regulation studies\",\n      \"journal\": \"Neurochemistry international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified recombinant enzymes, multiple allosteric effectors, replication of earlier findings with expanded analysis\",\n      \"pmids\": [\"22658952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GDH1 (GLUD1) promotes anoikis resistance and tumor metastasis in LKB1-deficient lung cancer. Upon detachment, GDH1 is upregulated via PLAG1 transcription factor. The GDH1 product α-ketoglutarate (α-KG) activates CamKK2 by enhancing its binding to substrate AMPK, thereby contributing to energy production that confers anoikis resistance. This GDH1-CamKK2-AMPK axis is particularly important in LKB1-deficient tumors where AMPK activation depends predominantly on CamKK2.\",\n      \"method\": \"Cell detachment assays, gene knockdown/overexpression, Co-IP (CamKK2-AMPK interaction), metabolite measurement, patient-derived xenograft model, correlation studies\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, metabolite measurement, in vivo xenograft, genetic manipulation), mechanistic pathway defined\",\n      \"pmids\": [\"29249655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EGFR activation upregulates GDH1 transcription through the MEK/ERK/ELK1 pathway in glioblastoma. EGFR triggers phosphorylation of ELK1 at Ser383 via MEK/ERK; phosphorylated ELK1 binds the GDH1 promoter to activate transcription. ELK1 knockdown or ELK1-Ser383 mutation prevents EGFR-induced GDH1 upregulation and glutamine metabolism activation.\",\n      \"method\": \"ChIP assay (ELK1 at GDH1 promoter), ELK1 knockdown, ELK1 Ser383 point mutation, Western blot for phosphorylation, luciferase reporter or direct measurement of GDH1 transcription\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, site-specific mutagenesis, and knockdown with multiple orthogonal readouts in a single focused study\",\n      \"pmids\": [\"32034306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A gain-of-function GLUD1 mutation G446V reduces the energy barrier between open and closed enzyme states, impairing allosteric inhibition by GTP and activation by ADP. Patient-derived lymphoblastoid cells carrying GDH-G446V show higher mitochondrial respiration in response to GDH-dependent substrates, indicating a metabolic shift toward glutaminolysis.\",\n      \"method\": \"Computational conformational energy analysis, enzymatic activity assay in patient-derived lymphoblastoid cells, mitochondrial respiration assay\",\n      \"journal\": \"Human genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays in patient-derived cells plus computational analysis, single study\",\n      \"pmids\": [\"32143698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Under amino acid deprivation or mTORC1 inhibition, GDH1 translocates from mitochondria to the cytoplasm, where it is ubiquitinated and degraded via the E3 ligase RNF213. GDH1 degradation reduces intracellular α-KG levels and decreases activity of α-KG-dependent lysine demethylases (KDMs), leading to increased histone H3K9 and H3K27 methylation that suppresses ribosomal protein gene expression to preserve nutrients for cell survival.\",\n      \"method\": \"Cell fractionation, ubiquitination assays, E3 ligase identification (RNF213), metabolite measurement (α-KG), ChIP for histone methylation marks, gene expression analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, ubiquitination assay, metabolomics, ChIP), mechanistic pathway defined in single rigorous study\",\n      \"pmids\": [\"34269483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EGFR phosphorylates GDH1 at tyrosine 135, activating it. Activated GDH1 cooperates with RSK2 to enhance CREB activity via CaMKIV signaling, promoting metastasis. GDH1, RSK2, and CREB phosphorylation positively correlate with EGFR mutation/activation in lung cancer patient tumors.\",\n      \"method\": \"Phosphorylation assays, co-immunoprecipitation, kinase assays, cell invasion/anoikis resistance assays, patient tumor correlation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical phosphorylation and Co-IP data plus functional assays, single lab\",\n      \"pmids\": [\"36516759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STUB1 (CHIP) is the E3 ubiquitin ligase responsible for ubiquitin-mediated proteasomal degradation of GLUD1. Lysine 503 (K503) is the primary ubiquitination site on GLUD1. Inhibiting ubiquitination at K503 promotes proliferation and tumor growth of lung adenocarcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (K503), cell proliferation and xenograft assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with ubiquitination assay and mutagenesis, single lab, two orthogonal methods\",\n      \"pmids\": [\"37416474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GLUD1 deletion in proliferating muscle stem cells (MuSCs) causes mitochondrial glutamate accumulation and inhibition of the malate-aspartate shuttle (MAS), leading to compartment-specific NAD+/NADH ratio shifts. This triggers precocious differentiation and fusion, and loss of self-renewal in vitro and in vivo. Restoring MAS activity or directly altering NAD+/NADH ratios normalizes myogenesis, placing GLUD1 as a metabolic brake on MuSC differentiation acting through mitochondrial glutamate levels and the MAS.\",\n      \"method\": \"Conditional Glud1 knockout in MuSCs, metabolomics (mitochondrial glutamate/α-KG), MAS activity rescue, NAD+/NADH manipulation, in vitro and in vivo differentiation assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with metabolomics, rescue experiments, multiple orthogonal readouts in vitro and in vivo\",\n      \"pmids\": [\"39121856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LASP1 interacts with GLUD1 and promotes its degradation via the ubiquitin-proteasome pathway, relying on the E3 ubiquitin ligase SYVN1 (synoviolin). LASP1 enhances SYVN1-GLUD1 interaction to facilitate GLUD1 ubiquitination. In HBV-related HCC, HBX protein suppresses GLUD1 through this LASP1/SYVN1 axis. GLUD1 interacts with AKT and α-KG produced by GLUD1 suppresses AKT activation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, gene silencing, Western blot\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and ubiquitination assays, single lab\",\n      \"pmids\": [\"38587834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Glucose starvation reduces GLUD1 acetylation at Lys84, which promotes active hexamer formation and GLUD1 enzymatic activity. Under glucose starvation, deacetylated GLUD1 translocates to the cytoplasm where it is ubiquitinated in K63-linkage by TRIM21 and binds cytoplasmic glutaminase KGA, enhancing glutamine metabolism. Cytoplasmic GLUD1 also interacts with p62, preventing p62 acetylation and blocking autophagic cell death in lung adenocarcinoma cells.\",\n      \"method\": \"Acetylation site mapping, Co-immunoprecipitation (GLUD1-KGA, GLUD1-p62), ubiquitination assays, cell fractionation, glucose starvation experiments\",\n      \"journal\": \"Cell insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assays with site-specific mapping, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39144257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"GLUD1 interacts with ARAF proto-oncogene protein and limits its ubiquitin-proteasome-mediated degradation, thereby stabilizing ARAF protein levels and sustaining MEK/ERK signaling. This represents a non-enzymatic function of GLUD1 that supports anoikis resistance during peritoneal dissemination of ovarian cancer.\",\n      \"method\": \"Co-immunoprecipitation (GLUD1-ARAF interaction), ubiquitination assays, GLUD1 knockdown/overexpression, in vitro anoikis assays, in vivo peritoneal dissemination model\",\n      \"journal\": \"NPJ precision oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assays, in vivo model, single lab\",\n      \"pmids\": [\"41786885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PRMT7 mediates monomethylation of GLUD1 at arginine 76 (R76), which enhances GLUD1 protein stability by antagonizing ubiquitin-dependent proteasomal degradation. AKT1 phosphorylates PRMT7 at threonine 73 (T73) to promote PRMT7 activity toward GLUD1, stabilizing GLUD1 and supporting glutamine metabolism in gastric cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (R76, T73), ubiquitination assays, kinase assays, xenograft models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, mutagenesis, and ubiquitination assays, single lab with in vivo validation\",\n      \"pmids\": [\"41876450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Manganese (Mn) inhibits hGDH1 (GLUD1-encoded) enzymatic activity in vitro with an IC50 of ~1.54 mM at 0.25 mM ADP, exhibiting sigmoidal inhibition kinetics. This is a less potent and less cooperative inhibition compared to hGDH2, suggesting differential sensitivity of the two isoforms to Mn at physiologically relevant ADP levels.\",\n      \"method\": \"In vitro enzymatic inhibition assay with purified recombinant hGDH1 and hGDH2, determination of IC50 and Hill coefficients\",\n      \"journal\": \"Neurochemistry international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro assay with purified recombinant enzyme, single lab, comparative study\",\n      \"pmids\": [\"25837286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PARP14 inhibits GLUD1 enzymatic activity via mono-ADP-ribosylation (MARylation), reducing α-KG production and suppressing energy metabolism. ECH (echinacoside) downregulates PARP14 expression, reversing this inhibition and restoring GLUD1-dependent glutamine metabolism and mitochondrial function in ovarian granulosa cells.\",\n      \"method\": \"Co-immunoprecipitation, enzymatic activity assay, siRNA knockdown, metabolomics, mitochondrial functional assays\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and enzymatic activity assays in a single study focused on a herbal compound, limited mechanistic validation of the MARylation site\",\n      \"pmids\": [\"41895093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Nuclear PHGDH regulates GLUD1 transcription via interaction with the transcription factor STAT3. ChIP-qPCR and co-immunoprecipitation showed nuclear PHGDH interacts with STAT3 to repress GLUD1 (and GLS2) gene expression, affecting macrophage polarization. STAT3 inhibition reversed the effects of PHGDH on macrophage function.\",\n      \"method\": \"ChIP-qPCR, co-immunoprecipitation, gene silencing, rescue experiments\",\n      \"journal\": \"Cancer biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR and Co-IP with rescue experiments, single lab\",\n      \"pmids\": [\"40434360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SIRT3-dependent deacetylation of GLUD1 is promoted by the SENP1-Sirt3 signaling pathway activated by A-485 (p300/CBP inhibitor). Deacetylation of GLUD1 by SIRT3 enhances its enzymatic activity and improves mitochondrial function and osteogenic differentiation. SENP1 knockdown blocks these effects.\",\n      \"method\": \"Western blot for acetylation, SENP1 knockdown, SIRT3 activity assays, osteogenic differentiation assays, in vivo OVX rat model\",\n      \"journal\": \"Journal of orthopaedic surgery and research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — acetylation/deacetylation assay with knockdown, single lab, indirect evidence for SIRT3-GLUD1 axis\",\n      \"pmids\": [\"40442713\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GLUD1 encodes the housekeeping mitochondrial glutamate dehydrogenase (hGDH1) that catalyzes the reversible oxidative deamination of glutamate to α-ketoglutarate (α-KG) and ammonia; its activity is tightly regulated by allosteric effectors—potently inhibited by GTP (IC50 ~0.20 µM) and activated by ADP and L-leucine through the 'antenna' regulatory domain (critical residue Arg-443)—and gain-of-function mutations that impair GTP inhibition cause hyperinsulinism-hyperammonemia syndrome by driving excess insulin secretion; beyond its canonical mitochondrial matrix role in glutamate catabolism and anaplerosis (required for astrocytic glutamate metabolism), GLUD1 can translocate to the cytoplasm under nutrient stress where it is ubiquitinated by RNF213 and STUB1 (at K503) for proteasomal degradation; its protein stability is further controlled by PRMT7-mediated arginine methylation (R76) downstream of AKT1 and by acetylation at K84; in cancer contexts GLUD1 is phosphorylated by EGFR at Y135 to activate CaMKIV-CREB signaling, transcriptionally induced via EGFR-MEK-ERK-ELK1, and mediates anoikis resistance through α-KG-CamKK2-AMPK signaling (in LKB1-deficient cells) and through a non-enzymatic stabilization of ARAF to sustain MEK/ERK; in muscle stem cells, GLUD1 prevents mitochondrial glutamate accumulation and malate-aspartate shuttle inhibition to act as a metabolic brake on differentiation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GLUD1 encodes the mitochondrial glutamate dehydrogenase (hGDH1) that catalyzes the reversible oxidative deamination of glutamate to α-ketoglutarate (α-KG), feeding glutamate carbon into the TCA cycle for anaplerosis and energy production [#0, #6]. The enzyme maintains substantial basal activity and is tightly governed by allosteric effectors—potently inhibited by GTP and activated by L-leucine and ADP—with the regulatory 'antenna' residue Arg-443 being essential for both catalytic and allosteric function [#0, #1]. Loss of allosteric control is pathogenic: gain-of-function mutations that impair GTP inhibition (e.g., Y266C, P436L, G446V) drive unregulated glutamate oxidation and glutamine-stimulated insulin secretion, causing hyperinsulinism-hyperammonemia syndrome [#2, #5, #10]. The protein localizes principally to mitochondria, with a minor ER-associated pool, directed by an N-terminal mitochondrial signal sequence [#3]. In the nervous system GLUD1 supports glutamate synthesis/release at nerve terminals and is required for astrocytic oxidative catabolism of glutamate for Krebs cycle entry [#4, #6], while in muscle stem cells it acts as a metabolic brake on differentiation by preventing mitochondrial glutamate accumulation and malate-aspartate shuttle inhibition [#14]. GLUD1 abundance and localization are extensively controlled post-translationally: it translocates to the cytoplasm under amino-acid or glucose deprivation, where it is ubiquitinated and degraded by RNF213, with degradation lowering α-KG, reducing α-KG-dependent histone demethylase activity, and reprogramming gene expression to conserve nutrients [#11]. Additional E3 ligases (STUB1 at K503; the LASP1/SYVN1 axis) target GLUD1 for proteasomal degradation, whereas PRMT7-mediated arginine methylation at R76 (downstream of AKT1) and K84 deacetylation stabilize and activate the enzyme [#13, #15, #16, #18]. In cancer, GLUD1 is transcriptionally induced via EGFR-MEK-ERK-ELK1 and phosphorylated by EGFR at Y135 to activate CaMKIV-CREB signaling, and it promotes anoikis resistance both enzymatically—through α-KG-driven CaMKK2-AMPK activation in LKB1-deficient cells—and non-enzymatically, by stabilizing ARAF to sustain MEK/ERK signaling [#8, #9, #12, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that the GLUD1-encoded enzyme is a distinct allosterically regulated GDH isoform, defining its baseline catalytic and regulatory parameters.\",\n      \"evidence\": \"In vitro kinetic and allosteric assays with purified recombinant hGDH1 expressed in Sf9 cells\",\n      \"pmids\": [\"11032875\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address in vivo regulation or physiological effector concentrations\", \"Allosteric structural basis not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified Arg-443 in the antenna domain as essential for basal activity and L-leucine activation, linking a single residue to intersubunit communication and allosteric control.\",\n      \"evidence\": \"Site-directed mutagenesis (R443S) with recombinant expression and in vitro enzymatic assays\",\n      \"pmids\": [\"12324473\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the conformational change\", \"Physiological consequence of antenna-domain regulation in cells untested here\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Connected loss of GDH allosteric regulation to disease by showing a gain-of-function mutation drives glutamine-stimulated insulin secretion.\",\n      \"evidence\": \"Y266C mutagenesis, activity assays in COS-7, overexpression and insulin secretion assays in MIN6 insulinoma cells\",\n      \"pmids\": [\"11872671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish in vivo β-cell phenotype\", \"Ammonemia mechanism not directly addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined GLUD1 subcellular distribution, establishing a dominant mitochondrial pool and a minor ER-associated full-length form dependent on the signal sequence.\",\n      \"evidence\": \"EGFP fusions in multiple cell lines, confocal microscopy, fractionation, signal-sequence deletion\",\n      \"pmids\": [\"19448744\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of the ER-associated form unknown\", \"No evidence yet for regulated cytoplasmic translocation\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated in vivo neuronal roles for GLUD1 in depolarization-induced glutamate release and synaptic transmission.\",\n      \"evidence\": \"Neuron-specific Glud1 transgenic overexpression, in vivo glutamate microelectrode measurements, mEPSC electrophysiology\",\n      \"pmids\": [\"19890003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Overexpression model may not reflect endogenous levels\", \"Mechanism of release coupling not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established the requirement of GLUD1 for astrocytic oxidative glutamate catabolism and Krebs cycle entry in the brain in vivo.\",\n      \"evidence\": \"CNS-conditional Glud1 knockout (Nestin-Cre), NMR spectroscopy, enzymatic assays, electrophysiology, IHC\",\n      \"pmids\": [\"22924626\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Compensatory transporter/glutamine synthetase upregulation complicates interpretation\", \"No synaptic defect under standard conditions\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Expanded the spectrum of GTP-insensitive activating mutations causing hyperinsulinism-hyperammonemia syndrome.\",\n      \"evidence\": \"GLUD1 sequencing and functional analysis of mutant GDH (P436L, N410D, D451V) in patient samples\",\n      \"pmids\": [\"19690084\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-center cohort\", \"Functional analysis limited to subset of mutations\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked GLUD1 to oncogenic transcription and a structural basis for impaired GTP regulation in disease.\",\n      \"evidence\": \"ChIP and ELK1-Ser383 mutagenesis showing EGFR-MEK-ERK-ELK1 induction of GDH1; computational and patient-cell analysis of the G446V activating mutation\",\n      \"pmids\": [\"32034306\", \"32143698\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"G446V functional data from single study in patient-derived cells\", \"Transcriptional control mapped in glioblastoma only\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined an enzymatic, α-KG-dependent mechanism by which GLUD1 confers anoikis resistance in LKB1-deficient cancer.\",\n      \"evidence\": \"Detachment assays, knockdown/overexpression, Co-IP of CamKK2-AMPK, metabolite measurement, patient-derived xenografts\",\n      \"pmids\": [\"29249655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dependence on LKB1 status limits generality\", \"PLAG1 induction mechanism not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed stress-induced cytoplasmic translocation and RNF213-mediated degradation of GLUD1 as a nutrient-conservation program coupling α-KG to epigenetic gene control.\",\n      \"evidence\": \"Fractionation, ubiquitination assays, RNF213 identification, α-KG metabolomics, histone-methylation ChIP\",\n      \"pmids\": [\"34269483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for mitochondria-to-cytosol relocation not fully defined\", \"Reversibility of degradation upon refeeding untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified EGFR phosphorylation of GLUD1 at Y135 as an activating modification driving CaMKIV-CREB pro-metastatic signaling.\",\n      \"evidence\": \"Phosphorylation and kinase assays, Co-IP, invasion/anoikis assays, patient tumor correlation\",\n      \"pmids\": [\"36516759\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab biochemistry\", \"Direct structural consequence of Y135 phosphorylation not shown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapped a second degradation route, identifying STUB1 as an E3 ligase and K503 as the primary GLUD1 ubiquitination site controlling tumor growth.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, K503 mutagenesis, proliferation and xenograft assays\",\n      \"pmids\": [\"37416474\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab, two orthogonal methods\", \"Relationship to RNF213 pathway unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed GLUD1 as a metabolic brake on muscle stem cell differentiation acting through mitochondrial glutamate and the malate-aspartate shuttle.\",\n      \"evidence\": \"Conditional Glud1 knockout in MuSCs, metabolomics, MAS rescue, NAD+/NADH manipulation, in vitro and in vivo differentiation assays\",\n      \"pmids\": [\"39121856\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Compartment-specific NAD+/NADH measurement is inferential\", \"Generalizability to other stem cell types unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended GLUD1 stability control to additional ligase axes and identified acetylation-coupled cytoplasmic functions and an AKT-suppressive role.\",\n      \"evidence\": \"Co-IP and ubiquitination assays defining LASP1/SYVN1-mediated degradation and GLUD1-AKT interaction; K84 acetylation mapping with TRIM21, KGA, and p62 interactions under glucose starvation\",\n      \"pmids\": [\"38587834\", \"39144257\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab Co-IP datasets\", \"Functional integration of multiple competing ligases unclear\", \"K63-ubiquitination role mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established a non-enzymatic scaffolding function of GLUD1 (ARAF stabilization) and a stabilizing methylation modification (PRMT7/R76 downstream of AKT1).\",\n      \"evidence\": \"Co-IP and ubiquitination assays for GLUD1-ARAF stabilization with in vivo dissemination model; PRMT7 R76 methylation mapping with AKT1-T73 phosphorylation and xenografts\",\n      \"pmids\": [\"41786885\", \"41876450\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab biochemistry for each axis\", \"Structural basis of ARAF binding and R76 methylation not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple competing post-translational modifications, ligases, and the enzymatic versus non-enzymatic activities of GLUD1 are integrated in a single cell to set its abundance, localization, and signaling output remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling RNF213, STUB1, SYVN1, and TRIM21 ubiquitination\", \"Relative contribution of enzymatic α-KG output versus scaffolding functions in tumors unquantified\", \"Structural basis of mitochondria-to-cytoplasm translocation unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 1, 2, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [3, 11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [11, 16]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 6, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 12, 17]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [11, 13, 18]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 5, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RNF213\", \"STUB1\", \"SYVN1\", \"LASP1\", \"PRMT7\", \"ARAF\", \"AKT1\", \"EGFR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}