{"gene":"GCDH","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2008,"finding":"GCDH forms homotetramers and also interacts with distinct heterologous polypeptides to form novel 97, 130, and 200 kDa GCDH complexes. Disease-causing missense mutations (p.Arg138Gly, p.Met263Val, p.Arg402Trp, p.Glu414Lys) render the enzyme enzymatically inactive (except p.Met263Val which retains 10% activity). p.Arg402Trp undergoes rapid intramitochondrial degradation. p.Met263Val and p.Arg402Trp strongly impair homotetrameric assembly. Molecular modeling suggests Met263 is at the surface contact interface with interacting proteins.","method":"Mammalian cell expression, western blot, pulse-chase analysis, cross-linking, biochemical enzyme activity assays, molecular modeling","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (activity assay, cross-linking, pulse-chase, modeling) in a single rigorous study establishing oligomerization, stability, and catalytic mechanism","pmids":["18775954"],"is_preprint":false},{"year":2017,"finding":"GCDH acts downstream of DHTKD1 in the L-lysine degradation pathway. Genetic inhibition of DHTKD1 (upstream of GCDH) in Dhtkd1-/-/Gcdh-/- double knockout mice did not rescue the GA-I phenotype or prevent accumulation of glutaric acid in brain and liver, indicating that a DHTKD1-independent mechanism generates glutaryl-CoA substrates for GCDH.","method":"Gcdh-/- and Dhtkd1-/- mouse models, Dhtkd1-/-/Gcdh-/- double knockout, biochemical metabolite measurement (GA, 3-OHGA, glutarylcarnitine) in brain and liver","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via double-knockout mouse with quantitative metabolite readouts, reveals a previously unknown lysine-to-glutaryl-CoA route","pmids":["28545977"],"is_preprint":false},{"year":2022,"finding":"GCDH controls protein glutarylation (a post-translational modification); its knockdown induces NRF2 glutarylation, increasing NRF2 stability and DNA-binding activity, which transcriptionally upregulates ATF4, ATF3, DDIT3, and CHAC1, resulting in melanoma cell death. Inhibition of the upstream lysine catabolism enzyme DHTKD1 blocks GCDH-knockdown-induced cell death, confirming pathway placement. In vivo, inducible GCDH inactivation inhibits melanoma tumor growth.","method":"siRNA knockdown, in vivo inducible inactivation (mouse xenograft), glutarylation mass spectrometry, transcriptional reporter assays, DHTKD1 epistasis rescue experiments","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KD, KO, in vivo, mass spec, epistasis) establishing GCDH's role in controlling NRF2 glutarylation and downstream apoptotic signaling","pmids":["36050469"],"is_preprint":false},{"year":2014,"finding":"In the murine brain, L-pipecolate is the major L-lysine degradation product, generated predominantly via α-deamination along the pipecolate pathway. L-pipecolate oxidation was detectable only in brain peroxisomes (not mitochondria), and L-pipecolate oxidase activity was low, situating GCDH's substrates downstream of these pathways in brain lysine catabolism.","method":"Stable isotope-labeled L-lysine tracing in Gcdh-/- mice, purified brain peroxisome fractions, enzyme activity assays","journal":"Journal of inherited metabolic disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isotope tracing and subcellular fractionation in Gcdh-/- mice with functional enzyme assays, single lab","pmids":["25214427"],"is_preprint":false},{"year":2016,"finding":"GCDH protein is localized to mitochondria and is expressed in a tissue- and cell-type-specific pattern. In rat embryos, GCDH is predominantly expressed in neurons of the central and peripheral nervous system. In adult rats, strong expression is found in liver, neurons of multiple brain regions, renal proximal tubules, intestinal mucosa, and peripheral nerves.","method":"Immunofluorescence microscopy with cell-type-specific markers in embryonic and adult rat tissues","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunolocalization with cell-type markers across multiple tissues and developmental stages, single lab","pmids":["27984186"],"is_preprint":false},{"year":2020,"finding":"The GCDH p.Val400Met variant is expressed as a non-functional apo (FAD-free) form that is predominantly monomeric rather than tetrameric. Exogenous FAD drives structural reorganization of the mutant enzyme with concomitant functional recovery, improved thermostability, and resistance to trypsin digestion, establishing FAD as essential for GCDH folding, oligomerization, and catalytic activity.","method":"Recombinant expression of human GCDH-p.Val400Met, biochemical activity assays, size-exclusion chromatography, thermal stability assays, trypsin digestion, FAD supplementation experiments","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with multiple orthogonal biophysical and biochemical methods (activity, oligomerization, stability, proteolysis), single lab","pmids":["32992790"],"is_preprint":false},{"year":2025,"finding":"GCDH is acetylated at lysine 438 by acetyltransferase P300 and deacetylated by HDAC1. K438 acetylation is critical for GCDH's tumor-suppressive function in HCC. GCDH overexpression elevates mitochondrial ROS and reduces oxidative phosphorylation, triggering ATR/Chk1-mediated DNA damage repair dysfunction and autophagy.","method":"Western blot, overexpression/knockdown in HCC cells, ROS measurement, OXPHOS assay, ATR/Chk1 signaling analysis, P300/HDAC1 co-immunoprecipitation/identification","journal":"Research (Washington, D.C.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cellular assays establishing PTM writer (P300) and eraser (HDAC1) and downstream signaling, single lab","pmids":["40896397"],"is_preprint":false},{"year":2025,"finding":"GCDH, together with DHTKD1, modulates intracellular glutaryl-CoA levels, which in turn regulate AKT1 glutarylation at conserved lysines K179 and K289. Glutarylation at K179 disrupts the K179-E198 salt bridge and AKT1-ATP interactions; K289 glutarylation perturbs ATP coordination and reduces PDK1-mediated phosphorylation, collectively inactivating AKT1. SIRT5 acts as the deglutarylase reversing this modification. GCDH overexpression suppresses AKT1 glutarylation and promotes oncogenic signaling.","method":"Mass spectrometry for glutarylation site mapping, mutagenesis of K179 and K289, in vitro AKT1 kinase assays, PDK1 phosphorylation assays, SIRT5 deglutarylation assay, cell proliferation and tumor growth assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro with site-specific mutagenesis, structural rationale for mechanism, multiple orthogonal functional assays establishing GCDH-glutaryl-CoA-AKT1 glutarylation axis","pmids":["42207644"],"is_preprint":false},{"year":2025,"finding":"GCDH controls histone crotonylation: GCDH silencing reduces global H3K27 crotonylation and specifically reduces H3K27 crotonylation at the GLS1 promoter, suppressing GLS1 transcription and glutaminolysis. Overexpression of wild-type GCDH, but not a catalytically inactive mutant, partially restores glutamate production and ATP, demonstrating that the effect depends on GCDH enzymatic activity.","method":"siRNA knockdown, ChIP for H3K27cr, luciferase reporter assays, Western blot, catalytically inactive mutant overexpression, metabolite quantification, xenograft mouse model","journal":"Cancer management and research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, catalytic mutant rescue, and multiple metabolic readouts, single lab","pmids":["41438501"],"is_preprint":false},{"year":2025,"finding":"YEATS2 maintains high promoter H3K27 crotonylation levels by recruiting crotonyltransferase p300 to the SPARC promoter; this H3K27cr mark addition is also dependent on GCDH as the crotonyl-CoA-producing enzyme, linking GCDH's enzymatic production of crotonyl-CoA to epigenetic regulation of EMT-promoting genes in head and neck cancer.","method":"ChIP, co-immunoprecipitation, luciferase reporter assays, GCDH knockdown, histone modification mass spectrometry","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and Co-IP showing GCDH-dependent H3K27cr at specific gene promoters, single lab","pmids":["40810390"],"is_preprint":false},{"year":2024,"finding":"Systemic neonatal delivery of AAV9-GCDH restores GCDH expression and enzyme activity in liver and striatum of Gcdh-/- mice, protects against high-lysine diet lethality, reduces accumulation of glutaric acid, 3-hydroxyglutaric acid, and glutarylcarnitine in tissues, and ameliorates striatal neuropathology (neuronal dysfunction, gliosis, myelination defects) as assessed by MRI.","method":"AAV9 gene delivery in Gcdh-/- mouse model, enzyme activity assays, metabolite quantification, MRI, histopathology","journal":"Molecular therapy. Methods & clinical development","confidence":"High","confidence_rationale":"Tier 2 / Strong — gene replacement with multiple functional readouts (enzyme activity, metabolites, neuropathology, MRI, survival), demonstrating GCDH is the causal enzyme for GA-I phenotype","pmids":["38983872"],"is_preprint":false},{"year":2020,"finding":"In Gcdh-/- mice, systemic inflammation induced by lipopolysaccharide (LPS) causes selective oxidative stress (elevated MDA, decreased GSH and antioxidant enzyme activities) in cerebral cortex and striatum but not in hippocampus, liver, or heart, demonstrating region-specific vulnerability of these brain structures in GCDH deficiency. High lysine diet combined with LPS exacerbated these effects and increased S100B and NF-κB in brain.","method":"LPS intraperitoneal injection in Gcdh-/- and WT mice on low/high lysine diet, tissue-specific measurement of MDA, GSH, GPx, GR, SOD, S100B, and NF-κB protein","journal":"Neurotoxicity research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — controlled knockout mouse experiment with tissue-specific biochemical readouts, single lab","pmids":["33001399"],"is_preprint":false},{"year":2014,"finding":"Gcdh-/- mice show overexpression of NMDA receptor subunits (NR2A, NR2B), AMPA (GluR2), and kainate (GluR6) receptor subunits, as well as glutamate transporters GLAST and GLT1, preferentially in striatum and cerebral cortex, with changes both at mRNA and protein level. High lysine intake further amplifies these changes, suggesting that accumulation of GCDH-deficiency metabolites drives glutamate receptor/transporter dysregulation in vulnerable brain regions.","method":"mRNA expression analysis, protein expression (Western blot) of glutamate receptors and transporters in Gcdh-/- vs WT mice at ages 7, 30, and 60 days, with and without high-lysine diet","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse with age- and diet-dependent analysis at both mRNA and protein level, single lab","pmids":["24594605"],"is_preprint":false}],"current_model":"GCDH (glutaryl-CoA dehydrogenase) is a mitochondrial FAD-dependent enzyme that functions as a homotetramer to catalyze a key step in L-lysine, L-hydroxylysine, and L-tryptophan catabolism; it controls intracellular glutaryl-CoA and crotonyl-CoA levels, thereby regulating protein glutarylation (including of NRF2 and AKT1) and histone crotonylation (H3K27cr), linking lysine metabolism to epigenetic gene regulation and oncogenic signaling; its acetylation at K438 by P300 (reversed by HDAC1) modulates its tumor-suppressive activity, and loss of GCDH enzymatic activity in humans (due to diverse GCDH mutations that impair catalysis, FAD binding, stability, or tetramerization) causes accumulation of neurotoxic glutaric acid and 3-hydroxyglutaric acid, selective striatal and cortical injury, and the neurometabolic disease glutaric aciduria type I."},"narrative":{"mechanistic_narrative":"GCDH is a mitochondrial FAD-dependent enzyme that catalyzes a downstream step in L-lysine catabolism, generating substrates such that its loss causes accumulation of neurotoxic glutaric and 3-hydroxyglutaric acid [PMID:28545977, PMID:25214427]. It assembles as a homotetramer, and FAD binding is essential for its folding, oligomerization, thermostability, and catalytic activity; FAD-free variants remain monomeric and non-functional [PMID:18775954, PMID:32992790]. Disease-causing missense mutations inactivate the enzyme by impairing catalysis, tetrameric assembly, or by accelerating intramitochondrial degradation, and gene replacement in Gcdh-/- mice restores enzyme activity and metabolite levels while protecting against striatal neuropathology, establishing GCDH as the causal enzyme of glutaric aciduria type I [PMID:18775954, PMID:38983872]. Beyond its catabolic role, GCDH controls intracellular glutaryl-CoA and crotonyl-CoA pools and thereby governs two distinct post-translational/epigenetic programs: it regulates protein glutarylation of substrates including NRF2 and AKT1—modifications reversed by SIRT5 that alter NRF2 stability/transcriptional output and inactivate AKT1 kinase signaling—and it supplies crotonyl-CoA for histone H3K27 crotonylation at target gene promoters such as GLS1 and SPARC, linking lysine metabolism to oncogenic signaling and gene regulation [PMID:36050469, PMID:42207644, PMID:41438501, PMID:40810390]. GCDH activity is itself tuned by acetylation at K438 by P300 and deacetylation by HDAC1, which modulates its tumor-suppressive function [PMID:40896397]. In the brain, GCDH deficiency produces region-selective vulnerability of cortex and striatum, marked by oxidative stress and dysregulation of glutamate receptors and transporters [PMID:33001399, PMID:24594605].","teleology":[{"year":2008,"claim":"Established that GCDH functions as a homotetramer and defined how disease mutations abrogate activity through catalytic, assembly, and stability defects.","evidence":"Mammalian expression of missense mutants with cross-linking, pulse-chase, enzyme assays, and molecular modeling","pmids":["18775954"],"confidence":"High","gaps":["No high-resolution structure of the tetramer","Identity of the heterologous proteins forming the 97/130/200 kDa complexes not determined"]},{"year":2014,"claim":"Mapped GCDH's substrate-generating pathway in brain, showing L-pipecolate is the major lysine degradation route and situating GCDH downstream of peroxisomal/pipecolate steps.","evidence":"Stable isotope L-lysine tracing in Gcdh-/- mice with purified brain peroxisome fractions and enzyme assays","pmids":["25214427"],"confidence":"Medium","gaps":["Single-lab tracing","Does not quantify flux contribution to neurotoxic metabolite accumulation"]},{"year":2014,"claim":"Linked GCDH-deficiency metabolites to glutamatergic excitotoxicity by showing region-selective upregulation of glutamate receptors and transporters.","evidence":"mRNA and protein expression analysis in Gcdh-/- vs WT mice across ages and lysine diets","pmids":["24594605"],"confidence":"Medium","gaps":["Correlative expression changes","Direct causal link between specific metabolite and receptor dysregulation not isolated"]},{"year":2016,"claim":"Defined GCDH's mitochondrial localization and tissue/cell-type expression pattern, emphasizing neuronal and hepatic expression.","evidence":"Immunofluorescence with cell-type markers in embryonic and adult rat tissues","pmids":["27984186"],"confidence":"Medium","gaps":["Descriptive localization","No functional consequence tied to expression pattern"]},{"year":2017,"claim":"Revealed a DHTKD1-independent route generating glutaryl-CoA, refining the placement of GCDH in lysine degradation.","evidence":"Dhtkd1-/-/Gcdh-/- double knockout mice with quantitative metabolite measurement","pmids":["28545977"],"confidence":"High","gaps":["Identity of the alternative glutaryl-CoA-producing enzyme not established"]},{"year":2020,"claim":"Established FAD as essential for GCDH folding, oligomerization, and catalysis using a clinical variant that is FAD-free and monomeric.","evidence":"Recombinant GCDH-p.Val400Met with SEC, thermostability, proteolysis, and FAD supplementation assays","pmids":["32992790"],"confidence":"High","gaps":["Generalization to other variants not tested","Structural basis of FAD-driven reorganization not resolved"]},{"year":2020,"claim":"Demonstrated region-specific oxidative stress vulnerability of cortex and striatum in GCDH deficiency under inflammatory challenge.","evidence":"LPS challenge in Gcdh-/- mice with tissue-specific oxidative stress and inflammatory marker measurement","pmids":["33001399"],"confidence":"Medium","gaps":["Mechanism of regional selectivity unknown","Single-lab study"]},{"year":2022,"claim":"Showed GCDH controls protein glutarylation, with knockdown driving NRF2 glutarylation, stabilization, and a transcriptional death program in melanoma.","evidence":"siRNA/inducible KO, glutarylation mass spectrometry, transcriptional reporters, DHTKD1 epistasis, xenografts","pmids":["36050469"],"confidence":"High","gaps":["Direct demonstration that glutaryl-CoA non-enzymatically modifies NRF2 in vivo limited","Generalizability beyond melanoma"]},{"year":2024,"claim":"Established GCDH as the causal enzyme of glutaric aciduria type I by gene-replacement rescue of metabolic and neuropathological phenotypes.","evidence":"Neonatal systemic AAV9-GCDH delivery in Gcdh-/- mice with enzyme, metabolite, MRI, and histology readouts","pmids":["38983872"],"confidence":"High","gaps":["Long-term durability and human translation not addressed","Does not resolve mechanism of selective striatal injury"]},{"year":2025,"claim":"Defined a GCDH–glutaryl-CoA–AKT1 axis in which glutarylation at K179/K289 inactivates AKT1, reversed by SIRT5, connecting GCDH to oncogenic kinase signaling.","evidence":"Glutarylation site mapping, K179/K289 mutagenesis, in vitro AKT1 kinase and PDK1 assays, SIRT5 deglutarylation, growth assays","pmids":["42207644"],"confidence":"High","gaps":["In vivo relevance of AKT1 glutarylation in tumors not fully delineated"]},{"year":2025,"claim":"Showed GCDH activity is regulated by reversible K438 acetylation (P300 writer, HDAC1 eraser) controlling its tumor-suppressive function in HCC via ROS/OXPHOS and ATR/Chk1 signaling.","evidence":"Overexpression/knockdown in HCC cells, ROS/OXPHOS assays, ATR/Chk1 analysis, P300/HDAC1 Co-IP","pmids":["40896397"],"confidence":"Medium","gaps":["Single lab","Mechanistic link between K438 acetylation and catalytic activity not biochemically reconstituted"]},{"year":2025,"claim":"Established GCDH as the crotonyl-CoA source for histone H3K27 crotonylation, coupling its enzymatic activity to epigenetic control of metabolic and EMT genes.","evidence":"siRNA knockdown, ChIP for H3K27cr, luciferase reporters, catalytic-mutant rescue, Co-IP with YEATS2/p300, xenografts","pmids":["41438501","40810390"],"confidence":"Medium","gaps":["Quantitative contribution of GCDH to total cellular crotonyl-CoA not measured","Single-lab studies per cancer type"]},{"year":null,"claim":"How GCDH balances its catabolic, glutarylation, and crotonylation-supplying roles and what determines the selective striatal/cortical neurotoxicity in GA-I remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating FAD binding, tetramerization, and PTM regulation","Mechanism of regional brain vulnerability undefined","Alternative glutaryl-CoA source enzyme unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,5,8]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[8,9]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[8,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,10]}],"complexes":[],"partners":["DHTKD1","P300","HDAC1","SIRT5","NRF2","AKT1","YEATS2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92947","full_name":"Glutaryl-CoA dehydrogenase, mitochondrial","aliases":[],"length_aa":438,"mass_kda":48.1,"function":"Catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-hydroxylysine, and L-tryptophan metabolism. It uses electron transfer flavoprotein as its electron acceptor. Isoform Short is inactive","subcellular_location":"Mitochondrion matrix","url":"https://www.uniprot.org/uniprotkb/Q92947/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GCDH","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GCDH","total_profiled":1310},"omim":[{"mim_id":"615256","title":"ELECTRON TRANSFER FLAVOPROTEIN BETA-SUBUNIT LYSINE METHYLTRANSFERASE; ETFBKMT","url":"https://www.omim.org/entry/615256"},{"mim_id":"614984","title":"DEHYDROGENASE E1 AND TRANSKETOLASE DOMAINS-CONTAINING PROTEIN 1; DHTKD1","url":"https://www.omim.org/entry/614984"},{"mim_id":"608801","title":"GLUTARYL-CoA DEHYDROGENASE; GCDH","url":"https://www.omim.org/entry/608801"},{"mim_id":"604773","title":"ACYL-CoA DEHYDROGENASE FAMILY, MEMBER 8; ACAD8","url":"https://www.omim.org/entry/604773"},{"mim_id":"231670","title":"GLUTARIC ACIDEMIA I; GA1","url":"https://www.omim.org/entry/231670"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":86.6}],"url":"https://www.proteinatlas.org/search/GCDH"},"hgnc":{"alias_symbol":["ACAD5","GCD"],"prev_symbol":[]},"alphafold":{"accession":"Q92947","domains":[{"cath_id":"1.10.540.10","chopping":"55-174","consensus_level":"medium","plddt":98.603,"start":55,"end":174},{"cath_id":"2.40.110.10","chopping":"175-281","consensus_level":"medium","plddt":97.6304,"start":175,"end":281},{"cath_id":"1.20.140.10","chopping":"283-428","consensus_level":"medium","plddt":98.3376,"start":283,"end":428}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92947","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92947-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92947-F1-predicted_aligned_error_v6.png","plddt_mean":92.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GCDH","jax_strain_url":"https://www.jax.org/strain/search?query=GCDH"},"sequence":{"accession":"Q92947","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92947.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92947/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92947"}},"corpus_meta":[{"pmid":"17724338","id":"PMC_17724338","title":"Contribution of the receptor guanylyl cyclase GC-D to chemosensory function in the olfactory epithelium.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17724338","citation_count":164,"is_preprint":false},{"pmid":"12417526","id":"PMC_12417526","title":"A novel gene, Pog, is necessary for primordial germ cell proliferation in the mouse and underlies the germ cell deficient mutation, gcd.","date":"2002","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12417526","citation_count":105,"is_preprint":false},{"pmid":"1924340","id":"PMC_1924340","title":"Germ-cell deficient (gcd), an insertional mutation manifested as infertility in transgenic mice.","date":"1991","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/1924340","citation_count":84,"is_preprint":false},{"pmid":"3540603","id":"PMC_3540603","title":"Multiple GCD genes required for repression of GCN4, a transcriptional activator of amino acid biosynthetic genes in Saccharomyces cerevisiae.","date":"1986","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/3540603","citation_count":79,"is_preprint":false},{"pmid":"28545977","id":"PMC_28545977","title":"Elevated glutaric acid levels in Dhtkd1-/Gcdh- double knockout mice challenge our current understanding of lysine metabolism.","date":"2017","source":"Biochimica et biophysica acta. 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Dexamethasone(GCD)Therapy with Rituximab].","date":"2023","source":"Gan to kagaku ryoho. Cancer & chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/38056881","citation_count":0,"is_preprint":false},{"pmid":"38924972","id":"PMC_38924972","title":"Generation of hiPSC lines from four glutaric aciduria type I (GA1) patients carrying pathogenic biallelic variants in GCDH.","date":"2024","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/38924972","citation_count":0,"is_preprint":false},{"pmid":"42207644","id":"PMC_42207644","title":"AKT1 glutarylation regulated by GCDH and SIRT5 suppresses oncogenic signaling.","date":"2026","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/42207644","citation_count":0,"is_preprint":false},{"pmid":"34964964","id":"PMC_34964964","title":"[Analysis of GCDH gene variant in a child with Glutaric aciduria type I].","date":"2022","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/34964964","citation_count":0,"is_preprint":false},{"pmid":"28781846","id":"PMC_28781846","title":"Excessive homozygosity identified by chromosomal microarray at a known GCDH mutation locus correlates with brain MRI abnormalities in an infant with glutaric aciduria.","date":"2017","source":"Clinical case reports","url":"https://pubmed.ncbi.nlm.nih.gov/28781846","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.24.25322813","title":"Randomized Double Blind Inpatient Study of a Gluten-Free Diet in Persons with Schizophrenia","date":"2025-02-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.24.25322813","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":30266,"output_tokens":3932,"usd":0.074889,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11684,"output_tokens":3732,"usd":0.07586,"stage2_stop_reason":"end_turn"},"total_usd":0.150749,"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\": 2008,\n      \"finding\": \"GCDH forms homotetramers and also interacts with distinct heterologous polypeptides to form novel 97, 130, and 200 kDa GCDH complexes. Disease-causing missense mutations (p.Arg138Gly, p.Met263Val, p.Arg402Trp, p.Glu414Lys) render the enzyme enzymatically inactive (except p.Met263Val which retains 10% activity). p.Arg402Trp undergoes rapid intramitochondrial degradation. p.Met263Val and p.Arg402Trp strongly impair homotetrameric assembly. Molecular modeling suggests Met263 is at the surface contact interface with interacting proteins.\",\n      \"method\": \"Mammalian cell expression, western blot, pulse-chase analysis, cross-linking, biochemical enzyme activity assays, molecular modeling\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (activity assay, cross-linking, pulse-chase, modeling) in a single rigorous study establishing oligomerization, stability, and catalytic mechanism\",\n      \"pmids\": [\"18775954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GCDH acts downstream of DHTKD1 in the L-lysine degradation pathway. Genetic inhibition of DHTKD1 (upstream of GCDH) in Dhtkd1-/-/Gcdh-/- double knockout mice did not rescue the GA-I phenotype or prevent accumulation of glutaric acid in brain and liver, indicating that a DHTKD1-independent mechanism generates glutaryl-CoA substrates for GCDH.\",\n      \"method\": \"Gcdh-/- and Dhtkd1-/- mouse models, Dhtkd1-/-/Gcdh-/- double knockout, biochemical metabolite measurement (GA, 3-OHGA, glutarylcarnitine) in brain and liver\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via double-knockout mouse with quantitative metabolite readouts, reveals a previously unknown lysine-to-glutaryl-CoA route\",\n      \"pmids\": [\"28545977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GCDH controls protein glutarylation (a post-translational modification); its knockdown induces NRF2 glutarylation, increasing NRF2 stability and DNA-binding activity, which transcriptionally upregulates ATF4, ATF3, DDIT3, and CHAC1, resulting in melanoma cell death. Inhibition of the upstream lysine catabolism enzyme DHTKD1 blocks GCDH-knockdown-induced cell death, confirming pathway placement. In vivo, inducible GCDH inactivation inhibits melanoma tumor growth.\",\n      \"method\": \"siRNA knockdown, in vivo inducible inactivation (mouse xenograft), glutarylation mass spectrometry, transcriptional reporter assays, DHTKD1 epistasis rescue experiments\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KD, KO, in vivo, mass spec, epistasis) establishing GCDH's role in controlling NRF2 glutarylation and downstream apoptotic signaling\",\n      \"pmids\": [\"36050469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In the murine brain, L-pipecolate is the major L-lysine degradation product, generated predominantly via α-deamination along the pipecolate pathway. L-pipecolate oxidation was detectable only in brain peroxisomes (not mitochondria), and L-pipecolate oxidase activity was low, situating GCDH's substrates downstream of these pathways in brain lysine catabolism.\",\n      \"method\": \"Stable isotope-labeled L-lysine tracing in Gcdh-/- mice, purified brain peroxisome fractions, enzyme activity assays\",\n      \"journal\": \"Journal of inherited metabolic disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isotope tracing and subcellular fractionation in Gcdh-/- mice with functional enzyme assays, single lab\",\n      \"pmids\": [\"25214427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GCDH protein is localized to mitochondria and is expressed in a tissue- and cell-type-specific pattern. In rat embryos, GCDH is predominantly expressed in neurons of the central and peripheral nervous system. In adult rats, strong expression is found in liver, neurons of multiple brain regions, renal proximal tubules, intestinal mucosa, and peripheral nerves.\",\n      \"method\": \"Immunofluorescence microscopy with cell-type-specific markers in embryonic and adult rat tissues\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunolocalization with cell-type markers across multiple tissues and developmental stages, single lab\",\n      \"pmids\": [\"27984186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The GCDH p.Val400Met variant is expressed as a non-functional apo (FAD-free) form that is predominantly monomeric rather than tetrameric. Exogenous FAD drives structural reorganization of the mutant enzyme with concomitant functional recovery, improved thermostability, and resistance to trypsin digestion, establishing FAD as essential for GCDH folding, oligomerization, and catalytic activity.\",\n      \"method\": \"Recombinant expression of human GCDH-p.Val400Met, biochemical activity assays, size-exclusion chromatography, thermal stability assays, trypsin digestion, FAD supplementation experiments\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with multiple orthogonal biophysical and biochemical methods (activity, oligomerization, stability, proteolysis), single lab\",\n      \"pmids\": [\"32992790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GCDH is acetylated at lysine 438 by acetyltransferase P300 and deacetylated by HDAC1. K438 acetylation is critical for GCDH's tumor-suppressive function in HCC. GCDH overexpression elevates mitochondrial ROS and reduces oxidative phosphorylation, triggering ATR/Chk1-mediated DNA damage repair dysfunction and autophagy.\",\n      \"method\": \"Western blot, overexpression/knockdown in HCC cells, ROS measurement, OXPHOS assay, ATR/Chk1 signaling analysis, P300/HDAC1 co-immunoprecipitation/identification\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cellular assays establishing PTM writer (P300) and eraser (HDAC1) and downstream signaling, single lab\",\n      \"pmids\": [\"40896397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GCDH, together with DHTKD1, modulates intracellular glutaryl-CoA levels, which in turn regulate AKT1 glutarylation at conserved lysines K179 and K289. Glutarylation at K179 disrupts the K179-E198 salt bridge and AKT1-ATP interactions; K289 glutarylation perturbs ATP coordination and reduces PDK1-mediated phosphorylation, collectively inactivating AKT1. SIRT5 acts as the deglutarylase reversing this modification. GCDH overexpression suppresses AKT1 glutarylation and promotes oncogenic signaling.\",\n      \"method\": \"Mass spectrometry for glutarylation site mapping, mutagenesis of K179 and K289, in vitro AKT1 kinase assays, PDK1 phosphorylation assays, SIRT5 deglutarylation assay, cell proliferation and tumor growth assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro with site-specific mutagenesis, structural rationale for mechanism, multiple orthogonal functional assays establishing GCDH-glutaryl-CoA-AKT1 glutarylation axis\",\n      \"pmids\": [\"42207644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GCDH controls histone crotonylation: GCDH silencing reduces global H3K27 crotonylation and specifically reduces H3K27 crotonylation at the GLS1 promoter, suppressing GLS1 transcription and glutaminolysis. Overexpression of wild-type GCDH, but not a catalytically inactive mutant, partially restores glutamate production and ATP, demonstrating that the effect depends on GCDH enzymatic activity.\",\n      \"method\": \"siRNA knockdown, ChIP for H3K27cr, luciferase reporter assays, Western blot, catalytically inactive mutant overexpression, metabolite quantification, xenograft mouse model\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, catalytic mutant rescue, and multiple metabolic readouts, single lab\",\n      \"pmids\": [\"41438501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YEATS2 maintains high promoter H3K27 crotonylation levels by recruiting crotonyltransferase p300 to the SPARC promoter; this H3K27cr mark addition is also dependent on GCDH as the crotonyl-CoA-producing enzyme, linking GCDH's enzymatic production of crotonyl-CoA to epigenetic regulation of EMT-promoting genes in head and neck cancer.\",\n      \"method\": \"ChIP, co-immunoprecipitation, luciferase reporter assays, GCDH knockdown, histone modification mass spectrometry\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Co-IP showing GCDH-dependent H3K27cr at specific gene promoters, single lab\",\n      \"pmids\": [\"40810390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Systemic neonatal delivery of AAV9-GCDH restores GCDH expression and enzyme activity in liver and striatum of Gcdh-/- mice, protects against high-lysine diet lethality, reduces accumulation of glutaric acid, 3-hydroxyglutaric acid, and glutarylcarnitine in tissues, and ameliorates striatal neuropathology (neuronal dysfunction, gliosis, myelination defects) as assessed by MRI.\",\n      \"method\": \"AAV9 gene delivery in Gcdh-/- mouse model, enzyme activity assays, metabolite quantification, MRI, histopathology\",\n      \"journal\": \"Molecular therapy. Methods & clinical development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gene replacement with multiple functional readouts (enzyme activity, metabolites, neuropathology, MRI, survival), demonstrating GCDH is the causal enzyme for GA-I phenotype\",\n      \"pmids\": [\"38983872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In Gcdh-/- mice, systemic inflammation induced by lipopolysaccharide (LPS) causes selective oxidative stress (elevated MDA, decreased GSH and antioxidant enzyme activities) in cerebral cortex and striatum but not in hippocampus, liver, or heart, demonstrating region-specific vulnerability of these brain structures in GCDH deficiency. High lysine diet combined with LPS exacerbated these effects and increased S100B and NF-κB in brain.\",\n      \"method\": \"LPS intraperitoneal injection in Gcdh-/- and WT mice on low/high lysine diet, tissue-specific measurement of MDA, GSH, GPx, GR, SOD, S100B, and NF-κB protein\",\n      \"journal\": \"Neurotoxicity research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — controlled knockout mouse experiment with tissue-specific biochemical readouts, single lab\",\n      \"pmids\": [\"33001399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Gcdh-/- mice show overexpression of NMDA receptor subunits (NR2A, NR2B), AMPA (GluR2), and kainate (GluR6) receptor subunits, as well as glutamate transporters GLAST and GLT1, preferentially in striatum and cerebral cortex, with changes both at mRNA and protein level. High lysine intake further amplifies these changes, suggesting that accumulation of GCDH-deficiency metabolites drives glutamate receptor/transporter dysregulation in vulnerable brain regions.\",\n      \"method\": \"mRNA expression analysis, protein expression (Western blot) of glutamate receptors and transporters in Gcdh-/- vs WT mice at ages 7, 30, and 60 days, with and without high-lysine diet\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with age- and diet-dependent analysis at both mRNA and protein level, single lab\",\n      \"pmids\": [\"24594605\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GCDH (glutaryl-CoA dehydrogenase) is a mitochondrial FAD-dependent enzyme that functions as a homotetramer to catalyze a key step in L-lysine, L-hydroxylysine, and L-tryptophan catabolism; it controls intracellular glutaryl-CoA and crotonyl-CoA levels, thereby regulating protein glutarylation (including of NRF2 and AKT1) and histone crotonylation (H3K27cr), linking lysine metabolism to epigenetic gene regulation and oncogenic signaling; its acetylation at K438 by P300 (reversed by HDAC1) modulates its tumor-suppressive activity, and loss of GCDH enzymatic activity in humans (due to diverse GCDH mutations that impair catalysis, FAD binding, stability, or tetramerization) causes accumulation of neurotoxic glutaric acid and 3-hydroxyglutaric acid, selective striatal and cortical injury, and the neurometabolic disease glutaric aciduria type I.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GCDH is a mitochondrial FAD-dependent enzyme that catalyzes a downstream step in L-lysine catabolism, generating substrates such that its loss causes accumulation of neurotoxic glutaric and 3-hydroxyglutaric acid [#1, #3]. It assembles as a homotetramer, and FAD binding is essential for its folding, oligomerization, thermostability, and catalytic activity; FAD-free variants remain monomeric and non-functional [#0, #5]. Disease-causing missense mutations inactivate the enzyme by impairing catalysis, tetrameric assembly, or by accelerating intramitochondrial degradation, and gene replacement in Gcdh-/- mice restores enzyme activity and metabolite levels while protecting against striatal neuropathology, establishing GCDH as the causal enzyme of glutaric aciduria type I [#0, #10]. Beyond its catabolic role, GCDH controls intracellular glutaryl-CoA and crotonyl-CoA pools and thereby governs two distinct post-translational/epigenetic programs: it regulates protein glutarylation of substrates including NRF2 and AKT1—modifications reversed by SIRT5 that alter NRF2 stability/transcriptional output and inactivate AKT1 kinase signaling—and it supplies crotonyl-CoA for histone H3K27 crotonylation at target gene promoters such as GLS1 and SPARC, linking lysine metabolism to oncogenic signaling and gene regulation [#2, #7, #8, #9]. GCDH activity is itself tuned by acetylation at K438 by P300 and deacetylation by HDAC1, which modulates its tumor-suppressive function [#6]. In the brain, GCDH deficiency produces region-selective vulnerability of cortex and striatum, marked by oxidative stress and dysregulation of glutamate receptors and transporters [#11, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that GCDH functions as a homotetramer and defined how disease mutations abrogate activity through catalytic, assembly, and stability defects.\",\n      \"evidence\": \"Mammalian expression of missense mutants with cross-linking, pulse-chase, enzyme assays, and molecular modeling\",\n      \"pmids\": [\"18775954\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of the tetramer\", \"Identity of the heterologous proteins forming the 97/130/200 kDa complexes not determined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapped GCDH's substrate-generating pathway in brain, showing L-pipecolate is the major lysine degradation route and situating GCDH downstream of peroxisomal/pipecolate steps.\",\n      \"evidence\": \"Stable isotope L-lysine tracing in Gcdh-/- mice with purified brain peroxisome fractions and enzyme assays\",\n      \"pmids\": [\"25214427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab tracing\", \"Does not quantify flux contribution to neurotoxic metabolite accumulation\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked GCDH-deficiency metabolites to glutamatergic excitotoxicity by showing region-selective upregulation of glutamate receptors and transporters.\",\n      \"evidence\": \"mRNA and protein expression analysis in Gcdh-/- vs WT mice across ages and lysine diets\",\n      \"pmids\": [\"24594605\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative expression changes\", \"Direct causal link between specific metabolite and receptor dysregulation not isolated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined GCDH's mitochondrial localization and tissue/cell-type expression pattern, emphasizing neuronal and hepatic expression.\",\n      \"evidence\": \"Immunofluorescence with cell-type markers in embryonic and adult rat tissues\",\n      \"pmids\": [\"27984186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Descriptive localization\", \"No functional consequence tied to expression pattern\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed a DHTKD1-independent route generating glutaryl-CoA, refining the placement of GCDH in lysine degradation.\",\n      \"evidence\": \"Dhtkd1-/-/Gcdh-/- double knockout mice with quantitative metabolite measurement\",\n      \"pmids\": [\"28545977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the alternative glutaryl-CoA-producing enzyme not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established FAD as essential for GCDH folding, oligomerization, and catalysis using a clinical variant that is FAD-free and monomeric.\",\n      \"evidence\": \"Recombinant GCDH-p.Val400Met with SEC, thermostability, proteolysis, and FAD supplementation assays\",\n      \"pmids\": [\"32992790\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generalization to other variants not tested\", \"Structural basis of FAD-driven reorganization not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated region-specific oxidative stress vulnerability of cortex and striatum in GCDH deficiency under inflammatory challenge.\",\n      \"evidence\": \"LPS challenge in Gcdh-/- mice with tissue-specific oxidative stress and inflammatory marker measurement\",\n      \"pmids\": [\"33001399\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of regional selectivity unknown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed GCDH controls protein glutarylation, with knockdown driving NRF2 glutarylation, stabilization, and a transcriptional death program in melanoma.\",\n      \"evidence\": \"siRNA/inducible KO, glutarylation mass spectrometry, transcriptional reporters, DHTKD1 epistasis, xenografts\",\n      \"pmids\": [\"36050469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration that glutaryl-CoA non-enzymatically modifies NRF2 in vivo limited\", \"Generalizability beyond melanoma\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established GCDH as the causal enzyme of glutaric aciduria type I by gene-replacement rescue of metabolic and neuropathological phenotypes.\",\n      \"evidence\": \"Neonatal systemic AAV9-GCDH delivery in Gcdh-/- mice with enzyme, metabolite, MRI, and histology readouts\",\n      \"pmids\": [\"38983872\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term durability and human translation not addressed\", \"Does not resolve mechanism of selective striatal injury\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a GCDH–glutaryl-CoA–AKT1 axis in which glutarylation at K179/K289 inactivates AKT1, reversed by SIRT5, connecting GCDH to oncogenic kinase signaling.\",\n      \"evidence\": \"Glutarylation site mapping, K179/K289 mutagenesis, in vitro AKT1 kinase and PDK1 assays, SIRT5 deglutarylation, growth assays\",\n      \"pmids\": [\"42207644\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of AKT1 glutarylation in tumors not fully delineated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed GCDH activity is regulated by reversible K438 acetylation (P300 writer, HDAC1 eraser) controlling its tumor-suppressive function in HCC via ROS/OXPHOS and ATR/Chk1 signaling.\",\n      \"evidence\": \"Overexpression/knockdown in HCC cells, ROS/OXPHOS assays, ATR/Chk1 analysis, P300/HDAC1 Co-IP\",\n      \"pmids\": [\"40896397\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanistic link between K438 acetylation and catalytic activity not biochemically reconstituted\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established GCDH as the crotonyl-CoA source for histone H3K27 crotonylation, coupling its enzymatic activity to epigenetic control of metabolic and EMT genes.\",\n      \"evidence\": \"siRNA knockdown, ChIP for H3K27cr, luciferase reporters, catalytic-mutant rescue, Co-IP with YEATS2/p300, xenografts\",\n      \"pmids\": [\"41438501\", \"40810390\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution of GCDH to total cellular crotonyl-CoA not measured\", \"Single-lab studies per cancer type\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GCDH balances its catabolic, glutarylation, and crotonylation-supplying roles and what determines the selective striatal/cortical neurotoxicity in GA-I remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating FAD binding, tetramerization, and PTM regulation\", \"Mechanism of regional brain vulnerability undefined\", \"Alternative glutaryl-CoA source enzyme unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 5, 8]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"GO:0050660\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DHTKD1\", \"P300\", \"HDAC1\", \"SIRT5\", \"NRF2\", \"AKT1\", \"YEATS2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}