GCDH is a mitochondrial matrix flavoprotein that oxidatively decarboxylates glutaryl-CoA to crotonyl-CoA, coupling this reaction to electron-transfer flavoprotein reduction. This reaction connects the degradation of lysine, hydroxylysine and tryptophan to downstream carbon metabolism while directly producing a fatty-acyl-CoA. The active enzyme is a FAD-containing homotetramer. Human GCDH also turns over hexanoyl-CoA and glutaramyl-CoA in vitro without decarboxylating them. A nuclear pool in human glioma stem-like cells supports lysine-derived crotonyl-CoA availability and CBP-mediated histone crotonylation; the acyl-transfer step is performed by CBP. The displayed precursor contains 438 residues, and an alternatively spliced 428-residue short product is reported to be stable but inactive.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000062 fatty-acyl-CoA binding | IBA GO_REF:0000033 | ACCEPT | Summary: The inherited fatty-acyl-CoA-binding claim is consistent with the actual substrate/product chemistry. Reason: The exact 438-residue target descends from the fatty-acyl-CoA-binding IBD at AN3/PTN005130278. GCDH interacts with glutaryl-CoA and releases crotonyl-CoA; the inspected chemical ontology places these species within fatty-acyl-CoA-related classes. The kinetic study identifies product release as turnover-limiting. This is substrate/product recognition intrinsic to its enzyme role, not an inferred fatty-acid beta-oxidation program. The rat donor assertion is preserved without claiming its original binding assay was newly inspected. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN005130278 SUPPORTS TRANSFER Literal PTHR42807 AN3 IBD and target AN28/PTN002533783 descent are verified against the tree, full target sequence and original IBD records. The direct substrate/product or cofactor evidence agrees with inherited function; donor count is not used as a strength score. |
| GO:0000062 fatty-acyl-CoA binding | IEA GO_REF:0000107 | ACCEPT | Summary: Rat-ortholog transfer of fatty-acyl-CoA binding fits independent target chemistry. Reason: The incoming rat A0A8I5ZN89/ENSRNOP00000079491 identity is verified in the official record. Its curated binding assertion is consistent with human substrate turnover and crotonyl-CoA release. The accepted binding class does not depend on claiming that all fatty-acyl substrates are physiologically used or that the rat original assay was inspected. |
| GO:0003995 acyl-CoA dehydrogenase activity | IEA GO_REF:0000002 | MODIFY | Summary: The established physiological activity is more specifically described as glutaryl-CoA dehydrogenase. Reason: The InterPro-derived enzyme class is biologically correct, and GO:0004361 is a verified is_a child. Refine to the established glutaryl-CoA reaction rather than using broad class retention to imply another physiological function. PMID:11024031 explicitly reports human hexanoyl-CoA and glutaramyl-CoA turnover in vitro; that positive breadth is preserved, but its abstract alone establishes neither physiological utilization nor fatty-acid beta-oxidation. The specific replacement does not assert absolute exclusion of alternative substrates. Proposed replacements: glutaryl-CoA dehydrogenase activity Supporting Evidence: PMID:11024031 The steady-state kinetic constants of alternative substrates, hexanoyl-CoA and glutaramyl-CoA, which are not decarboxylated, are modestly affected by the mutations. UniProtKB:Q92947 |
| GO:0004361 glutaryl-CoA dehydrogenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: The actual PAINT lineage supports inherited glutaryl-CoA dehydrogenase activity. Reason: The target AN28/PTN002533783 lies below the literal GO:0004361 assertion at AN3/PTN005130278 in PTHR42807. All incoming mouse, rat and human sources match the retained IBD donor set; the human self-donor is legitimate direct grounding. Human recombinant enzyme evidence agrees with the node placement, with no retained target-path negative record. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN005130278 SUPPORTS TRANSFER Literal PTHR42807 AN3 IBD and target AN28/PTN002533783 descent are verified against the tree, full target sequence and original IBD records. The direct substrate/product or cofactor evidence agrees with inherited function; donor count is not used as a strength score. |
| GO:0004361 glutaryl-CoA dehydrogenase activity | IDA PMID:8541831 Cloning of glutaryl-CoA dehydrogenase cDNA, and expression o... | ACCEPT | Summary: The cited human expression study directly demonstrates the enzyme activity. Reason: The authentic abstract explicitly describes human wild-type cDNA expression and purification from E. coli and compares a nearly inactive patient mutant. It supports the named reaction independently of disease association alone. Full original Methods and the historical construct sequence were not inspected; the alternative-splicing result and curated modern Short mapping are kept separate from this unsuffixed original activity claim. Supporting Evidence: |
| GO:0004361 glutaryl-CoA dehydrogenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The combined rule, ortholog, Rhea and EC mapping names the established GCDH reaction. Reason: RHEA:13389 and EC 1.3.8.6 describe oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA with electron-transfer flavoprotein. Direct human expression and purified-enzyme studies support this activity independently of the ARBA and rodent annotations. Preserve every incoming supporting entity; the activity is not assigned to a particular modern natural product by the unsuffixed row. |
| GO:0005634 nucleus | IDA PMID:37198486 Lysine catabolism reprograms tumour immunity through histone... | KEEP AS NON CORE | Summary: A nuclear GCDH pool is demonstrated in the studied glioma stem-cell context. Reason: Selected original microscopy and fractionation text reports a nuclear pool in human GSCs and human tumor sections alongside mitochondrial localization. Nuclear association with CBP and engineered localization constructs support this context, but do not establish constitutive nuclear localization in every cell or a natural short-product assignment. Preserve the direct observation outside the general mitochondrial catabolic core. Supporting Evidence: |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: The authentic high-throughput target record supports mitochondrial localization. Reason: The original supplementary Table S1A protein group 8892 contains Q92947 and Q92947-2. HEK293T subtractive/spatial profiling and HeLa TOMM40-knockdown importomics place it in high-confidence mitochondrial classes. The protein group is soluble, but its matrix column is inherited annotation rather than a separate matrix assay, and grouped accessions do not establish isoform-specific peptides. Its beta-oxidation functional category is not an independent metabolic-flux result. Supporting Evidence: |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: The HPA mitochondrial assertion agrees with independent target-specific localization evidence. Reason: The original GO_REF:0000052 IDA assertion is retained. Independent human protein-group mitochondrial profiling, human cellular localization and precursor import studies support the same organelle. No new claim to inspect the original HPA image or distinguish natural products is made. The root-organelle annotation remains intact under the organelle policy. |
| GO:0005739 mitochondrion | IDA PMID:37198486 Lysine catabolism reprograms tumour immunity through histone... | ACCEPT | Summary: Human GSC experiments detect a mitochondrial pool as well as a nuclear pool. Reason: Selected original localization text reports substantial GCDH overlap with the mitochondrial marker COXIV in the tested human GSCs. The additional nuclear fraction does not negate mitochondrial localization. Engineered truncation and localization-signal constructs are distinguished from natural products, and the whole mitochondrion term is retained rather than automatically narrowed. Supporting Evidence: |
| GO:0005739 mitochondrion | TAS PMID:8541831 Cloning of glutaryl-CoA dehydrogenase cDNA, and expression o... | ACCEPT | Summary: The cited human cloning study reports mitochondrial import and processing. Reason: The authentic abstract explicitly states that the primary translation product is translocated into mitochondria and processed. This supports the original TAS organelle assertion. The inspected abstract does not provide an isoform-resolved import comparison, and the official predicted transit-peptide coordinates are not presented as a newly measured cleavage site. Supporting Evidence: |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic mitochondrial-matrix assignment matches the conserved catabolic enzyme setting. Reason: The official human SL-0170 assignment, incoming mouse/ARBA evidence and exact human Reactome chain support a matrix enzyme. The broader mitochondrial proteomics result is corroboration at organelle level, not an independent matrix-localization experiment. The matrix claim and separate parent-organelle rows are both retained. Supporting Evidence: UniProtKB:Q92947 UniProtKB:Q60759 Reactome:R-HSA-71046 |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-71046 | ACCEPT | Summary: The actual Reactome catalyst chain places human GCDH in the mitochondrial matrix. Reason: R-HSA-71046 links catalyst 71044 to GCDH tetramer 71040, whose component 71039 is human Q92947 chain 45β438 through reference 55484. The component explicitly carries matrix GO:0005759. This target-specific participant chain supports the localization rather than borrowing an unrelated pathway compartment; the modeled mature chain is distinct from a natural short isoform. Supporting Evidence: Reactome:R-HSA-71046 |
| GO:0006637 acyl-CoA metabolic process | IEA GO_REF:0000107 | TOO GENERAL | Summary: The broad acyl-CoA claim is already entailed by a retained, more specific process. Reason: Acyl-CoA metabolism is true but adds no distinct process information beyond the retained GO:0046949 fatty-acyl-CoA biosynthesis assertions. That term is a verified is_a descendant through GO:0071616 and independently through GO:0035337. GCDH directly forms crotonyl-CoA; formation of this catabolic intermediate remains supported. TOO_GENERAL records this redundancy without disputing the biosynthetic child or inferring fatty-acid oxidation. |
| GO:0009063 amino acid catabolic process | IEA GO_REF:0000107 | MODIFY | Summary: Refine amino-acid catabolism to the supported lysine and tryptophan pathways. Reason: The human record places the glutaryl-CoA reaction in lysine, hydroxylysine and tryptophan degradation. GO:0019477 and GO:0006569 are verified is_a descendants of amino acid catabolic process; the lysine term is already present elsewhere. Both specific pathways are retained, with hydroxylysine metabolism explicit in the biological description rather than assigned an unverified additional term. GCDH catalyzes the shared step itself. Proposed replacements: L-lysine catabolic process L-tryptophan catabolic process Supporting Evidence: UniProtKB:Q92947 UniProtKB:Q60759 Reactome:R-HSA-71064 |
| GO:0016627 oxidoreductase activity, acting on the CH-CH group of donors | IEA GO_REF:0000002 | MODIFY | Summary: A specific glutaryl-CoA dehydrogenase term better describes this broad oxidoreductase annotation. Reason: The domain-based CH-CH oxidoreductase category includes the measured glutaryl-CoA reaction. Official is_a paths connect GO:0004361 through GO:0003995 and GO:0052890 to GO:0016627. The supported specific activity is therefore a valid refinement. Alternative-substrate capacity reported in the human abstract is retained as biochemical scope, without converting it into an additional physiological pathway. Proposed replacements: glutaryl-CoA dehydrogenase activity |
| GO:0019395 fatty acid oxidation | IEA GO_REF:0000107 | UNDECIDED | Summary: The physiological extent of the rat-derived fatty-acid-oxidation assertion remains unresolved. Reason: The rat donor and its curated oxidation assertion are verified, but the detailed PMID:21974953 assay remains inaccessible. Human alternative-substrate turnover does not by itself establish physiological fatty-acid oxidation. The broader term covers electron removal from fatty acids, whereas GO:0033539 specifies an iterative beta-oxidation pathway; overreach for that child does not decide every route covered by the parent. The two newly assessed dicarboxylic-acid studies leave a plausible substrate-source route unresolved rather than establish direct human GCDH participation. Retain source-specific uncertainty without asserting inactivity or treating an amino-acid classification as an exclusive substrate boundary. |
| GO:0019477 L-lysine catabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic lysine-catabolism support agrees with the performed enzymatic step. Reason: The ARBA and mouse-derived annotation matches the established human glutaryl-CoA conversion and the actual Reactome lysine-catabolism event. Human GSC perturbation and metabolite experiments additionally connect GCDH to lysine-derived crotonyl-CoA. The conclusion rests on catalytic participation, not on tumor or neurological phenotypes alone. |
| GO:0019477 L-lysine catabolic process | IMP PMID:37198486 Lysine catabolism reprograms tumour immunity through histone... | ACCEPT | Summary: Human cell experiments support GCDH participation in lysine-derived crotonyl-CoA production. Reason: Selected original Results and Methods describe patient-derived human GSCs, independent knockdowns and acyl-CoA measurements. GCDH-dependent changes in the lysine pathway agree with its independently established catalytic step. The study distinguishes GCDH generation of the acyl donor from CBP-mediated histone acylation; it does not make GCDH a histone transferase. Supporting Evidence: PMID:37198486 Crotonyl-CoA produced from glutaryl-CoA by GCDH was utilized by CBP |
| GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: The inherited beta-oxidation process exceeds the resolved experimental scope. Reason: The verified IBD is grounded in the target experiment reassessed in the reference note. The original Introduction classifies GCDH with amino-acid oxidation, and its actual human glutaryl-CoA assay does not establish the iterative pathway specified by this term. Descent and target self-grounding remain valid. This is process-scope overreach, not circularity, target-specific loss or exclusion of every possible dicarboxylic-acid route. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN005130278 SOURCE WEAK OR INFERRED The literal AN3/PTN005130278 placement and target descent are verified. Experimental grounding is genuine but insufficient for this complete process claim; the classification concerns term scope, not an inferred assay or circular target self-support. |
| GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase | IDA PMID:25416781 Human METTL20 is a mitochondrial lysine methyltransferase th... | MARK AS OVER ANNOTATED | Summary: The actual human GCDH assay supports its reaction but not the full beta-oxidation process. Reason: The newly inspected protocol verifies human GCDH with its amino-acid-derived substrate. The measured electron-transfer reaction supports catalysis but not the iterative fatty-acid pathway required by this term. This is process overreach, not a wrong-protein claim or a global negative activity result. 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: GCDH directly forms a fatty-acyl-CoA product within amino-acid catabolism. Reason: The actual IBD at AN3/PTN005130278 descends to the verified human sequence. Crotonyl-CoA is a fatty-acyl-CoA by the inspected chemical ontology, and GCDH itself generates it through oxidative decarboxylation. A biosynthetic product-forming step can occur within a degradative amino-acid pathway; that context is not a contradiction. This assertion does not imply de novo long-chain fatty-acid synthesis or a complete beta-oxidation cycle. The current ontology includes amino-acid catabolic-intermediate biosynthesis among this termβs children, so a catabolic setting does not exclude direct product formation. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN005130278 SUPPORTS TRANSFER Literal PTHR42807 AN3 IBD and target AN28/PTN002533783 descent are verified against the tree, full target sequence and original IBD records. The direct substrate/product or cofactor evidence agrees with inherited function; donor count is not used as a strength score. |
| GO:0046949 fatty-acyl-CoA biosynthetic process | IEA GO_REF:0000107 | ACCEPT | Summary: The rat-derived product-biosynthesis claim is consistent with direct target chemistry. Reason: The verified rat record and human catalytic reaction both identify crotonyl-CoA formation. The GO term covers formation of a fatty-acyl-CoA, and the product fits that chemical class. Retaining this claim does not transfer every rat lipid-metabolism function or treat catabolism and product biosynthesis as mutually exclusive. The current ontology includes amino-acid catabolic-intermediate biosynthesis among this termβs children, so a catabolic setting does not exclude direct product formation. Supporting Evidence: UniProtKB:A0A8I5ZN89 UniProtKB:Q92947 Reactome:R-HSA-71046 |
| GO:0050660 flavin adenine dinucleotide binding | IBA GO_REF:0000033 | ACCEPT | Summary: FAD binding is a conserved part of the GCDH catalytic mechanism. Reason: The exact target descends from the FAD-binding IBD at AN3/PTN005130278. The inspected kinetic abstract describes one noncovalently bound FAD per monomer, while the official human record independently identifies this cofactor. This supports the inherited binding assertion without a false claim that species or construct details were established from that abstract alone. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN005130278 SUPPORTS TRANSFER Literal PTHR42807 AN3 IBD and target AN28/PTN002533783 descent are verified against the tree, full target sequence and original IBD records. The direct substrate/product or cofactor evidence agrees with inherited function; donor count is not used as a strength score. |
| GO:0050660 flavin adenine dinucleotide binding | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic FAD-binding assertion agrees with the cofactor-dependent enzyme. Reason: The incoming InterPro and rat-ortholog evidence is corroborated by the official human FAD annotation and kinetic description of a bound flavin. FAD is the enzyme cofactor; electron-transfer flavoprotein accepts reducing equivalents. Neither molecule is treated as an interchangeable substrate or a second catalytic activity. |
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Download this section (compressed HTML)Q: Does GCDH contribute measurably to oxidation of fatty-acid-derived dicarboxylates under physiological conditions, and can that contribution be separated from amino-acid-derived glutaryl-CoA turnover and from upstream peroxisomal chain shortening?
Q: Which natural GCDH product or processed species supplies the nuclear pool observed in human glioma stem-like cells, and how broadly does that pool occur outside the tested tumor context?
Q: What structural or assembly defect explains the short natural productβs reported inactivity, and does it retain FAD or interact with the active long product under physiological expression conditions?
Experiment: Use isotope-resolved flux measurements in matched GCDH-deficient and rescued cells to distinguish glutaryl-CoA oxidation from hexanoyl-CoA oxidation, while measuring relevant acyl-CoA pools and electron-transfer dependencies.
Type: Physiological substrate-flux discrimination
Experiment: Compare sequence-verified long and short natural products using glutaryl-CoA turnover, FAD occupancy, oligomeric-state and mitochondrial-import assays; distinguish intact precursors from explicitly mapped processed forms.
Type: Product-resolved enzymology and import
Experiment: Identify nuclear GCDH proteoforms in glioma stem-like and nonmalignant cells, and test their contribution to crotonyl-CoA availability separately from CBP-catalyzed transfer to histones.
Type: Compartment-specific proteoform and metabolic analysis
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