Glutaryl-CoA dehydrogenase (GCDH; EC 1.3.8.6) is a FAD-dependent enzyme of the acyl-CoA dehydrogenase family that resides in the mitochondrial matrix as a homotetramer. It catalyses the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO2, transferring the abstracted electrons via its FAD cofactor to the electron-transfer flavoprotein (ETF), which relays them to ETF-ubiquinone oxidoreductase and the respiratory chain. GCDH acts in the degradative pathways of L-lysine, L-hydroxylysine and L-tryptophan. It is synthesised as a precursor with an N-terminal mitochondrial transit peptide that is cleaved on import. Loss of GCDH activity causes the autosomal recessive disorder glutaric aciduria type 1 (GA1), characterised by accumulation of glutaric and 3-hydroxyglutaric acids, striatal (basal ganglia) degeneration, macrocephaly, dystonia and encephalopathic crises. In glioblastoma stem cells, a nuclear pool associates with CBP and supplies crotonyl-CoA for histone crotonylation; CBP catalyses the histone acyl transfer.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004361 glutaryl-CoA dehydrogenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function of GCDH, correctly captured at the appropriate level of specificity by phylogenetic inference across the acyl-CoA dehydrogenase family orthologue set. Reason: This is the well-established enzymatic activity of GCDH (EC 1.3.8.6), directly demonstrated for the human enzyme and consistent with the phylogenetic assignment. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN005130278 SUPPORTS TRANSFER Verified ancestor of Q92947 leaf PTN002533783 in PTHR42807. Reaction/cofactor or substrate-product evidence agrees with inheritance. Supporting Evidence: file:human/GCDH/GCDH-uniprot.txt Catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L- |
| GO:0000062 fatty-acyl-CoA binding | IBA GO_REF:0000033 | ACCEPT | Summary: Accept fatty-acyl-CoA binding. GCDH binds its glutaryl-CoA substrate and releases crotonyl-CoA from the active site; crotonyl-CoA is a monounsaturated fatty-acyl-CoA. Reason: The previous exclusion of dicarboxylic substrates and short-chain enoyl products was chemically incorrect. Live ChEBI classifies crotonoyl-CoA (CHEBI:15473) under fatty acyl-CoA (CHEBI:37554); glutaryl-CoA(5-) (CHEBI:57378) also has an omega-carboxy-(fatty acyl)-CoA parent. Product binding is supported by the primary kinetic finding that crotonyl-CoA release limits turnover. This is a broad true capacity, even though glutaryl-CoA dehydrogenase activity is the most informative catalytic annotation. The actual human leaf PTN002533783 descends from IBD PTN005130278; no wrong-branch inference is established. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN005130278 SUPPORTS TRANSFER Verified ancestor of Q92947 leaf PTN002533783 in PTHR42807. Reaction/cofactor or substrate-product evidence agrees with inheritance. Supporting Evidence: PMID:17176108 of crotonyl-CoA product because the chemical steps and reoxidation of reduced |
| GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase | IBA GO_REF:0000033 | UNDECIDED | Summary: Unresolved placement in the iterative fatty-acid beta-oxidation pathway. Reason: GCDH clearly oxidizes glutaryl-CoA with ETF and generates crotonyl-CoA. Predominant amino-acid catabolism does not exclude another substrate or a broader chemical process. Current ChEBI even classifies glutaryl-CoA(5-) under an omega-carboxy fatty-acyl-CoA class. GO:0033539 describes iterative beta-oxidation beginning with fatty-acid activation, a more specific claim than isolated dehydrogenation/decarboxylation. The cached PMID:25416781 text omits Methods/Results; independently indexed Figure 5 identifies glutaryl-CoA for GCDH and octanoyl-CoA for MCAD. This confirms the assay distinction without proving all other GCDH capacities absent. The rat substrate study PMID:21974953 is abstract-only and requires full-table assessment. A focused adjudication addresses broad oxidation and the beta-oxidation process separately. The actual beta-oxidation IBD is PTN005130278, grounded on the target human experimental annotation itself; this is legitimate evidence, not circular propagation or demonstrated wrong-paralog placement. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN005130278 UNRESOLVED Verified ancestor of Q92947 leaf PTN002533783 in PTHR42807. The human experimental beta-oxidation source grounds this IBD; process scope remains unresolved, not a demonstrated phylogenetic placement failure. Supporting Evidence: PMID:25416781 methylation reduced the ability of ETFΞ² to receive electrons from the dehydrogenases MCAD and GCDH |
| GO:0046949 fatty-acyl-CoA biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Accept fatty-acyl-CoA biosynthesis: GCDH directly produces crotonyl-CoA by oxidative decarboxylation of glutaryl-CoA. Reason: GO:0046949 covers formation of a fatty-acyl-CoA and does not require fatty-acid chain elongation or an exclusively anabolic pathway. Crotonoyl-CoA is a fatty acyl-CoA in ChEBI. A step in lysine degradation can simultaneously synthesize this metabolite; the two pathway descriptions are compatible. Human glioblastoma stem-cell experiments directly establish a GCDH-dependent crotonyl-CoA pool, including nuclear substrate supply to CBP. GCDH performs the chemical production step, while CBP performs histone crotonyl transfer; no new histone-modification assertion is made. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN005130278 SUPPORTS TRANSFER Verified ancestor of Q92947 leaf PTN002533783 in PTHR42807. Reaction/cofactor or substrate-product evidence agrees with inheritance. Supporting Evidence: PMID:37198486 Crotonyl-CoA produced from glutaryl-CoA by GCDH was utilized by CBP |
| GO:0050660 flavin adenine dinucleotide binding | IBA GO_REF:0000033 | ACCEPT | Summary: GCDH is a flavoprotein that uses a non-covalently bound FAD cofactor as the primary electron acceptor during glutaryl-CoA dehydrogenation. FAD binding is well documented biochemically and structurally. Reason: FAD is the obligate cofactor of GCDH; crystal structures resolve FAD bound in the active site and multiple FAD-binding residues are annotated. Correct at the right level of specificity. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN005130278 SUPPORTS TRANSFER Verified ancestor of Q92947 leaf PTN002533783 in PTHR42807. Reaction/cofactor or substrate-product evidence agrees with inheritance. Supporting Evidence: file:human/GCDH/GCDH-uniprot.txt Name=FAD; Xref=ChEBI:CHEBI:57692; |
| GO:0003995 acyl-CoA dehydrogenase activity | IEA GO_REF:0000120 | MODIFY | Summary: Correct family-level molecular function but less specific than the demonstrated glutaryl-CoA dehydrogenase activity (GO:0004361), which is the precise activity of this enzyme. Reason: GCDH is a specific acyl-CoA dehydrogenase whose demonstrated activity is glutaryl-CoA dehydrogenase activity. The broad parent term should be replaced by the specific child term for which there is direct experimental evidence. Proposed replacements: glutaryl-CoA dehydrogenase activity Supporting Evidence: file:human/GCDH/GCDH-uniprot.txt RecName: Full=Glutaryl-CoA dehydrogenase, mitochondrial; |
| GO:0004361 glutaryl-CoA dehydrogenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Core molecular function of GCDH, here inferred electronically from RHEA/EC and orthologue mapping. Consistent with direct experimental evidence. Reason: The electronic mapping (RHEA:13389, EC:1.3.8.6, orthologues) correctly assigns the demonstrated glutaryl-CoA dehydrogenase activity. Supporting Evidence: file:human/GCDH/GCDH-uniprot.txt EC=1.3.8.6; |
| GO:0005739 mitochondrion | IEA GO_REF:0000117 | ACCEPT | Summary: GCDH is a nuclear-encoded mitochondrial protein with a cleavable N-terminal transit peptide; mitochondrial localization is well established. Reason: Correct, though less specific than the mitochondrial matrix localization. Consistent with the transit peptide, the mature-chain import, and experimental localization data. Supporting Evidence: file:human/GCDH/GCDH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix. |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000120 | ACCEPT | Summary: GCDH acts in the mitochondrial matrix, where it participates in amino-acid catabolism and donates electrons to the matrix-facing ETF. This is the precise subcellular location. Reason: UniProt records the mitochondrion matrix location and Reactome places the reaction in the matrix; consistent with the soluble matrix acyl-CoA dehydrogenase biochemistry. Supporting Evidence: file:human/GCDH/GCDH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix. |
| GO:0016627 oxidoreductase activity, acting on the CH-CH group of donors | IEA GO_REF:0000002 | ACCEPT | Summary: Correct broad parent molecular-function term describing the CH-CH dehydrogenation chemistry (introducing the C2-C3 double bond of crotonyl-CoA). Less specific than glutaryl-CoA dehydrogenase activity. Reason: GCDH catalyses dehydrogenation across the CH-CH bond of the CoA-thioester substrate; this InterPro-based broad term is accurate. Broad IEA parent is acceptable to retain alongside the specific activity. Supporting Evidence: file:human/GCDH/GCDH-uniprot.txt Catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L- |
| GO:0050660 flavin adenine dinucleotide binding | IEA GO_REF:0000120 | ACCEPT | Summary: GCDH binds FAD as its cofactor; duplicate of the IBA FAD-binding annotation, here from electronic inference. Reason: FAD is the obligate cofactor; the electronic assignment is correct. Supporting Evidence: file:human/GCDH/GCDH-uniprot.txt Name=FAD; Xref=ChEBI:CHEBI:57692; |
| GO:0000062 fatty-acyl-CoA binding | IEA GO_REF:0000107 | ACCEPT | Summary: Accept fatty-acyl-CoA binding. GCDH binds its glutaryl-CoA substrate and releases crotonyl-CoA from the active site; crotonyl-CoA is a monounsaturated fatty-acyl-CoA. Reason: The previous exclusion of dicarboxylic substrates and short-chain enoyl products was chemically incorrect. Live ChEBI classifies crotonoyl-CoA (CHEBI:15473) under fatty acyl-CoA (CHEBI:37554); glutaryl-CoA(5-) (CHEBI:57378) also has an omega-carboxy-(fatty acyl)-CoA parent. Product binding is supported by the primary kinetic finding that crotonyl-CoA release limits turnover. This is a broad true capacity, even though glutaryl-CoA dehydrogenase activity is the most informative catalytic annotation. The actual human leaf PTN002533783 descends from IBD PTN005130278; no wrong-branch inference is established. Supporting Evidence: PMID:17176108 of crotonyl-CoA product because the chemical steps and reoxidation of reduced |
| GO:0006637 acyl-CoA metabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: Broad but accurate biological-process term. GCDH metabolises glutaryl-CoA, which is an acyl-CoA thioester. Reason: GCDH consumes an acyl-CoA (glutaryl-CoA) and generates an acyl-CoA (crotonyl-CoA); the broad term is correct, though the more informative process is amino-acid/lysine catabolism. Supporting Evidence: file:human/GCDH/GCDH-uniprot.txt Catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L- |
| GO:0009063 amino acid catabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: Accurate broad parent term. GCDH functions in the catabolism of L-lysine, L-hydroxylysine and L-tryptophan. Reason: GCDH is a bona fide amino-acid catabolic enzyme; this broad term is correct and complements the more specific L-lysine catabolic process annotation. Supporting Evidence: file:human/GCDH/GCDH-uniprot.txt in the degradative pathway of L-lysine, L- |
| GO:0019395 fatty acid oxidation | IEA GO_REF:0000107 | UNDECIDED | Summary: Unresolved scope of fatty-acid oxidation for glutaryl-CoA oxidation and any additional substrates. Reason: GCDH clearly oxidizes glutaryl-CoA with ETF and generates crotonyl-CoA. Predominant amino-acid catabolism does not exclude another substrate or a broader chemical process. Current ChEBI even classifies glutaryl-CoA(5-) under an omega-carboxy fatty-acyl-CoA class. GO:0033539 describes iterative beta-oxidation beginning with fatty-acid activation, a more specific claim than isolated dehydrogenation/decarboxylation. The cached PMID:25416781 text omits Methods/Results; independently indexed Figure 5 identifies glutaryl-CoA for GCDH and octanoyl-CoA for MCAD. This confirms the assay distinction without proving all other GCDH capacities absent. The rat substrate study PMID:21974953 is abstract-only and requires full-table assessment. A focused adjudication addresses broad oxidation and the beta-oxidation process separately. The actual beta-oxidation IBD is PTN005130278, grounded on the target human experimental annotation itself; this is legitimate evidence, not circular propagation or demonstrated wrong-paralog placement. Supporting Evidence: PMID:25416781 methylation reduced the ability of ETFΞ² to receive electrons from the dehydrogenases MCAD and GCDH |
| GO:0019477 L-lysine catabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: Core biological process of GCDH. Glutaryl-CoA is the key intermediate of the saccharopine (lysine degradation) pathway, and GCDH catalyses its dehydrogenation/decarboxylation. Reason: L-lysine catabolism is a central physiological role of GCDH, supported by the UniProt lysine-degradation pathway assignment and by experimental evidence that GCDH is the crotonyl-CoA-producing enzyme in lysine catabolism. Supporting Evidence: file:human/GCDH/GCDH-uniprot.txt Amino-acid metabolism; lysine degradation. |
| GO:0046949 fatty-acyl-CoA biosynthetic process | IEA GO_REF:0000107 | ACCEPT | Summary: Accept fatty-acyl-CoA biosynthesis: GCDH directly produces crotonyl-CoA by oxidative decarboxylation of glutaryl-CoA. Reason: GO:0046949 covers formation of a fatty-acyl-CoA and does not require fatty-acid chain elongation or an exclusively anabolic pathway. Crotonoyl-CoA is a fatty acyl-CoA in ChEBI. A step in lysine degradation can simultaneously synthesize this metabolite; the two pathway descriptions are compatible. Human glioblastoma stem-cell experiments directly establish a GCDH-dependent crotonyl-CoA pool, including nuclear substrate supply to CBP. GCDH performs the chemical production step, while CBP performs histone crotonyl transfer; no new histone-modification assertion is made. Supporting Evidence: PMID:37198486 Crotonyl-CoA produced from glutaryl-CoA by GCDH was utilized by CBP |
| GO:0005634 nucleus | IDA PMID:37198486 Lysine catabolism reprograms tumour immunity through histone... | KEEP AS NON CORE | Summary: A context-specific (moonlighting) nuclear pool of GCDH was demonstrated in glioblastoma stem cells, where nuclear GCDH partners with the crotonyltransferase CBP to generate a local crotonyl-CoA supply for histone lysine crotonylation. This is not the canonical mitochondrial-matrix metabolic function. Reason: The IDA is valid (experimental co-localization and nuclear-fraction immunoprecipitation), but the nuclear localization is a specialized, cancer-cell-context function distinct from GCDH's core role as a mitochondrial-matrix amino-acid catabolic enzyme. Retain as a non-core moonlighting localization. Supporting Evidence: PMID:37198486 GCDH most frequently co-localized with the mitochondrial marker COX IV, but >20% of total GCDH localized to nuclei in GSCs PMID:37198486 GCDH interacts with the crotonyltransferase CBP to promote histone |
| GO:0005739 mitochondrion | IDA PMID:37198486 Lysine catabolism reprograms tumour immunity through histone... | ACCEPT | Summary: Direct co-localization with the mitochondrial marker COX IV confirms the predominant mitochondrial localization of GCDH, consistent with its role as a matrix acyl-CoA dehydrogenase. Reason: GCDH most frequently co-localized with the mitochondrial marker COX IV, confirming the canonical mitochondrial localization by direct assay. Supporting Evidence: PMID:37198486 GCDH most frequently co-localized with the mitochondrial marker COX IV, but >20% of total GCDH localized to nuclei in GSCs |
| GO:0019477 L-lysine catabolic process | IMP PMID:37198486 Lysine catabolism reprograms tumour immunity through histone... | ACCEPT | Summary: Genetic depletion of GCDH abolishes the lysine-driven increase in crotonyl-CoA and histone crotonylation, providing mutational-phenotype evidence that GCDH functions in L-lysine catabolism (the crotonyl-CoA-producing branch). Reason: GCDH was identified as the crotonyl-CoA-producing enzyme of the lysine catabolic pathway, and GCDH depletion abolished lysine-induced crotonylation, directly supporting involvement in L-lysine catabolism. Supporting Evidence: PMID:37198486 GCDH depletion abolished increased Kcr induced by L-lysine supplementation PMID:37198486 (crotonyl-CoA)-producing enzyme glutaryl-CoA dehydrogenase (GCDH) with |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence-based (HPA) evidence of mitochondrial localization, consistent with all other localization data. Reason: Corroborates the well-established mitochondrial localization of GCDH. Supporting Evidence: file:human/GCDH/GCDH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput mitochondrial proteomics identifies GCDH as a component of the human mitochondrial proteome, consistent with its established localization. Reason: Retain the GOA-curated mitochondrial proteomics assignment, independently corroborated by human GCDH import and COX IV colocalization. The target supplementary proteomics identification was not independently re-counted in this session. Supporting Evidence: file:human/GCDH/GCDH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix. |
| GO:0004361 glutaryl-CoA dehydrogenase activity | IDA PMID:8541831 Cloning of glutaryl-CoA dehydrogenase cDNA, and expression o... | ACCEPT | Summary: Direct experimental demonstration of glutaryl-CoA dehydrogenase activity for the cloned and expressed human enzyme, with kinetic constants matching purified porcine enzyme; a disease mutant retained <1% activity. Reason: This is the defining, experimentally demonstrated catalytic activity of GCDH. The human cDNA was cloned, expressed in E. coli, and shown to have glutaryl-CoA dehydrogenase activity with kinetic constants similar to the purified enzyme. Supporting Evidence: PMID:8541831 kinetic constants similar to those of the previously purified PMID:8541831 We have cloned, sequenced, and expressed cDNAs encoding wild type human |
| GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase | IDA PMID:25416781 Human METTL20 is a mitochondrial lysine methyltransferase th... | UNDECIDED | Summary: Unresolved placement in the iterative fatty-acid beta-oxidation pathway. Reason: GCDH clearly oxidizes glutaryl-CoA with ETF and generates crotonyl-CoA. Predominant amino-acid catabolism does not exclude another substrate or a broader chemical process. Current ChEBI even classifies glutaryl-CoA(5-) under an omega-carboxy fatty-acyl-CoA class. GO:0033539 describes iterative beta-oxidation beginning with fatty-acid activation, a more specific claim than isolated dehydrogenation/decarboxylation. The cached PMID:25416781 text omits Methods/Results; independently indexed Figure 5 identifies glutaryl-CoA for GCDH and octanoyl-CoA for MCAD. This confirms the assay distinction without proving all other GCDH capacities absent. The rat substrate study PMID:21974953 is abstract-only and requires full-table assessment. A focused adjudication addresses broad oxidation and the beta-oxidation process separately. The actual beta-oxidation IBD is PTN005130278, grounded on the target human experimental annotation itself; this is legitimate evidence, not circular propagation or demonstrated wrong-paralog placement. Supporting Evidence: PMID:25416781 methylation reduced the ability of ETFΞ² to receive electrons from the dehydrogenases MCAD and GCDH |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-71046 | ACCEPT | Summary: Reactome places the glutaryl-CoA dehydrogenase reaction in the mitochondrial matrix, catalysed by the GCDH homotetramer lacking its transit peptide. This is the precise, correct subcellular location. Reason: The traceable Reactome assertion agrees with UniProt (Mitochondrion matrix) and with the soluble-matrix biochemistry of GCDH. Supporting Evidence: Reactome:R-HSA-71046 The active enzyme is a tetramer of GCDH polypeptides lacking a 44-residue aminoterminal mitochondrial targeting sequence. |
| GO:0005739 mitochondrion | TAS PMID:8541831 Cloning of glutaryl-CoA dehydrogenase cDNA, and expression o... | ACCEPT | Summary: The GCDH primary translation product is translocated into mitochondria and processed like other nuclear-encoded mitochondrial proteins, supporting mitochondrial localization. Reason: The cited study reports mitochondrial import and processing of the GCDH precursor, a traceable author statement supporting mitochondrial localization. Supporting Evidence: PMID:8541831 is translocated into mitochondria |
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