GCDH

UniProt ID: Q92947
Organism: Homo sapiens
Review Status: INITIALIZED
📝 Provide Detailed Feedback

Gene Description

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.

Existing Annotations Review

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.
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 		MARK AS OVER ANNOTATED
Summary: Family-level binding term. GCDH binds glutaryl-CoA, a dicarboxylic acyl-CoA (glutaryl-CoA / 5-carboxypentanoyl-CoA), rather than a simple fatty-acyl-CoA; the term is imprecise for this enzyme.
Reason: The substrate of GCDH is glutaryl-CoA, a dicarboxylyl-CoA, not a fatty-acyl-CoA. While GCDH does bind an acyl-CoA thioester, 'fatty-acyl-CoA binding' is a family-level inference propagated from lipid-oxidizing acyl-CoA dehydrogenases and does not accurately describe the physiological ligand.
Propagation Review
Root cause: TERM SCOPING PROBLEM
Failure modes: GRANULARITY MISMATCH
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:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase
IBA
GO_REF:0000033 		MARK AS OVER ANNOTATED
Summary: GCDH does not participate in fatty acid beta-oxidation; it acts in amino-acid (L-lysine/L-hydroxylysine/L-tryptophan) catabolism. This is a family-level over-propagation from lipid-oxidizing acyl-CoA dehydrogenases.
Reason: GCDH is a glutaryl-CoA dehydrogenase acting in the lysine/tryptophan degradative pathway, not in fatty acid beta-oxidation. Although GCDH shares the ETF-linked electron-transfer chemistry of beta-oxidation dehydrogenases, its substrate and pathway are amino-acid catabolic. The IBA term is inherited from lipid-metabolizing relatives and mischaracterizes GCDH's biological process.
Propagation Review
Root cause: PROPAGATION BAD
Failure modes: FUNCTIONAL DIVERGENCE
Supporting Evidence:
file:human/GCDH/GCDH-uniprot.txt
Amino-acid metabolism; lysine degradation.
GO:0046949 fatty-acyl-CoA biosynthetic process
IBA
GO_REF:0000033 		MARK AS OVER ANNOTATED
Summary: Incorrect biological process. GCDH is catabolic (it decarboxylates glutaryl-CoA to crotonyl-CoA), not biosynthetic, and it does not produce a fatty-acyl-CoA.
Reason: The reaction catalysed by GCDH is oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA plus CO2, a catabolic step in amino-acid degradation. The product crotonyl-CoA is a short-chain enoyl-CoA intermediate, not a biosynthetic fatty-acyl-CoA end product. This family-level phylogenetic term is misleading for GCDH; flagged rather than removed to defer to the phylogenetic reviewer.
Propagation Review
Root cause: PROPAGATION BAD
Failure modes: FUNCTIONAL DIVERGENCE ROLE CONFLATION
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
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.
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.
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 		MARK AS OVER ANNOTATED
Summary: Electronic ortholog-transfer of the family-level 'fatty-acyl-CoA binding' term. As with the IBA version, GCDH binds glutaryl-CoA (a dicarboxylyl-CoA), not a fatty-acyl-CoA.
Reason: The physiological ligand is glutaryl-CoA, not a fatty-acyl-CoA. The term is a family-level inference that imprecisely describes the CoA-thioester substrate specificity of GCDH.
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: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 		REMOVE
Summary: Incorrect biological process. GCDH acts in amino-acid catabolism, not fatty acid oxidation; this is an electronic ortholog-transfer of a family-level term to the wrong branch.
Reason: GCDH degrades glutaryl-CoA arising from lysine/tryptophan catabolism, not fatty acids. UniProt explicitly places GCDH in lysine and tryptophan degradation pathways, with no role in fatty acid oxidation. This IEA term is a demonstrably wrong inference propagated from lipid-oxidizing acyl-CoA dehydrogenase relatives.
Supporting Evidence:
file:human/GCDH/GCDH-uniprot.txt
Amino-acid metabolism; lysine degradation.
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 		REMOVE
Summary: Incorrect biological process, here from electronic ortholog transfer. GCDH is catabolic and does not synthesise a fatty-acyl-CoA.
Reason: The GCDH-catalysed reaction is a catabolic oxidative decarboxylation producing crotonyl-CoA and CO2, not a biosynthetic process, and crotonyl-CoA is not a fatty-acyl-CoA biosynthetic product. This electronic inference is on the wrong branch for GCDH and contradicts the enzyme's known catabolic direction.
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: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: The high-confidence mitochondrial proteome dataset includes GCDH, corroborating mitochondrial localization; consistent with all curated and experimental evidence.
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... 		MARK AS OVER ANNOTATED
Summary: This annotation derives from a study of METTL20/ETFβ methylation in which GCDH is used only as one of two test dehydrogenases donating electrons to ETFβ. GCDH acts in amino-acid catabolism, not fatty acid beta-oxidation; the biological-process term is a mischaracterization.
Reason: The cited paper shows that methylation of ETFβ reduces its ability to receive electrons from MCAD and GCDH, i.e. it establishes that GCDH is an ETF-linked dehydrogenase; it does not place GCDH in fatty acid beta-oxidation. GCDH's substrate (glutaryl-CoA) arises from lysine/tryptophan catabolism, not fatty acids, so the process term is over-annotated. Marked rather than removed because the underlying experimental observation (ETF electron transfer) is genuine.
Supporting Evidence:
PMID:25416781
methylation reduced the ability of ETFβ to receive electrons from the dehydrogenases MCAD and GCDH
file:human/GCDH/GCDH-uniprot.txt
Amino-acid metabolism; lysine degradation.
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

Core Functions

FAD-dependent glutaryl-CoA dehydrogenase catalysing the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO2 in the mitochondrial matrix, feeding electrons to the electron-transfer flavoprotein

Molecular Function:
glutaryl-CoA dehydrogenase activity
Directly Involved In:
L-lysine catabolic process
Cellular Locations:
mitochondrial matrix
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-
  • PMID:8541831
    We have cloned, sequenced, and expressed cDNAs encoding wild type human

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:25416781
Human METTL20 is a mitochondrial lysine methyltransferase that targets the β subunit of electron transfer flavoprotein (ETFβ) and modulates its activity.
  • Methylation of ETFβ by METTL20 reduces the ability of ETFβ to receive electrons from GCDH (and MCAD), establishing that GCDH is an ETF-linked dehydrogenase that donates electrons to the electron-transfer flavoprotein.
    "methylation reduced the ability of ETFβ to receive electrons from the dehydrogenases MCAD and GCDH"
PMID:34800366
Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
  • GCDH is a component of the high-confidence human mitochondrial proteome, consistent with its mitochondrial-matrix localization.
PMID:37198486
Lysine catabolism reprograms tumour immunity through histone crotonylation.
  • GCDH is the crotonyl-CoA-producing enzyme of the lysine catabolic pathway; its depletion abolishes lysine-induced histone crotonylation.
    "GCDH depletion abolished increased Kcr induced by L-lysine supplementation"
  • A minor nuclear pool of GCDH (>20% of total) partners with CBP to promote histone lysine crotonylation, while the majority co-localizes with the mitochondrial marker COX IV.
    "GCDH most frequently co-localized with the mitochondrial marker COX IV, but >20% of total GCDH localized to nuclei in GSCs"
PMID:8541831
Cloning of glutaryl-CoA dehydrogenase cDNA, and expression of wild type and mutant enzymes in Escherichia coli.
  • Human GCDH cDNA was cloned and expressed with glutaryl-CoA dehydrogenase activity and kinetic constants similar to the purified porcine enzyme; a disease mutant had <1% activity and the alternatively spliced short isoform is inactive.
    "Purified expressed human glutaryl-CoA"
Reactome:R-HSA-71046
glutaryl-CoA + FAD => crotonyl-CoA + FADH2 + CO2
  • GCDH catalyses glutaryl-CoA + FAD to crotonyl-CoA + FADH2 + CO2 in the mitochondrial matrix as a homotetramer lacking the 44-residue transit peptide.
    "The active enzyme is a tetramer of GCDH polypeptides lacking a 44-residue aminoterminal mitochondrial targeting sequence."

📚 Additional Documentation

Notes

(GCDH-notes.md)

GCDH (Q92947) review notes

Deep research (GCDH-deep-research-falcon.md) did NOT appear within the 8-minute poll window,
so this review is grounded in the UniProt record (GCDH-uniprot.txt), the seeded GOA
(GCDH-goa.tsv), the cached Reactome entry, and cached publications. No deep-research file
was fabricated.

Verified core biology

  • GCDH is the mitochondrial-matrix, FAD-dependent glutaryl-CoA dehydrogenase (EC 1.3.8.6),
    a member of the acyl-CoA dehydrogenase family. It catalyses the oxidative decarboxylation
    of glutaryl-CoA to crotonyl-CoA + CO2    , transferring electrons via FAD to the
    electron-transfer flavoprotein (ETF → ETFDH → respiratory chain).
    [file:UniProt 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."]
  • Acts in the degradative pathway of L-lysine, L-hydroxylysine and L-tryptophan metabolism.
    UniProt PATHWAY: lysine degradation; tryptophan metabolism.
  • Homotetramer, mitochondrion matrix. Precursor with a 44-residue N-terminal mitochondrial
    transit peptide cleaved on import (mature chain 45-438). [UniProt SUBUNIT/SUBCELLULAR LOCATION;
    Reactome R-HSA-71046]
  • Isoform Short (Q92947-2) is inactive (alternative C-terminus replacing the FAD/substrate
    C-terminal helix region). [PMID:8541831 abstract; UniProt]
  • Deficiency causes glutaric aciduria type 1 (GA1, MIM:231670) — progressive dystonia/
    athetosis, striatal (basal ganglia) degeneration, macrocephaly, encephalopathic crises.
    Extensive GA1 missense variant catalogue in UniProt.

Evidence for specific annotations

  • GO:0004361 glutaryl-CoA dehydrogenase activity (IDA PMID:8541831, IBA, IEA): core MF.
    Cloned/expressed human enzyme with kinetic constants; disease mutant <1% activity. ACCEPT.
  • GO:0050660 FAD binding (IBA/IEA): cofactor is FAD; multiple FAD-binding residues in
    UniProt features; crystal structures 1SIQ etc. with FAD. ACCEPT.
  • GO:0005759 mitochondrial matrix (TAS Reactome, IEA): matrix localization. ACCEPT.
  • GO:0005739 mitochondrion (IDA PMID:37198486, IDA HPA, HTP PMID:34800366, TAS): ACCEPT.
  • GO:0019477 L-lysine catabolic process (IMP PMID:37198486, IEA): core BP.
    PMID:37198486 shows GCDH is the crotonyl-CoA-producing enzyme in lysine catabolism; GCDH
    depletion abolishes lysine-induced crotonylation. ACCEPT.
  • GO:0005634 nucleus (IDA PMID:37198486): a moonlighting/context-specific pool.
    "GCDH most frequently co-localized with the mitochondrial marker COX IV, but >20% of total
    GCDH localized to nuclei in GSCs" — nuclear GCDH-CBP complex crotonylates histones. This is a
    cancer-cell (glioblastoma stem cell) context, not the canonical mitochondrial-matrix function.
    KEEP_AS_NON_CORE.
  • GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase (IDA PMID:25416781, IBA):
    MISLEADING for GCDH. GCDH acts in amino-acid (lysine/Trp) catabolism, NOT fatty-acid
    beta-oxidation. PMID:25416781 (METTL20/ETFβ) only uses GCDH as an ETFβ electron-acceptor test
    case ("reduced its ability to receive electrons from the medium chain acyl-CoA dehydrogenase
    and the glutaryl-CoA dehydrogenase"); it does not assay GCDH in fatty-acid beta-oxidation.
    This is family-level over-propagation. MARK_AS_OVER_ANNOTATED (IDA; do not REMOVE experimental)
    and REMOVE for the IBA (electronic phylo inference on a clearly wrong branch for GCDH).
  • GO:0000062 fatty-acyl-CoA binding (IBA/IEA): GCDH binds glutaryl-CoA (a dicarboxylyl-CoA),
    not a fatty-acyl-CoA. Family-level term; loosely defensible as CoA-thioester binding but
    imprecise. MARK_AS_OVER_ANNOTATED.
  • GO:0046949 fatty-acyl-CoA biosynthetic process (IBA/IEA): WRONG — GCDH is catabolic
    (produces crotonyl-CoA by decarboxylation) and does not biosynthesise fatty-acyl-CoA. The
    product crotonyl-CoA is a short-chain enoyl-CoA, not a fatty-acyl-CoA, and the direction is
    catabolic. REMOVE the IEA; MARK_AS_OVER_ANNOTATED the IBA (defer to phylo review, but flag).
  • GO:0003995 acyl-CoA dehydrogenase activity (IEA): parent/family MF, correct but less
    precise than GO:0004361. MODIFY → GO:0004361.
  • GO:0016627 oxidoreductase activity, acting on the CH-CH group of donors (IEA InterPro):
    correct broad parent of the dehydrogenase activity. ACCEPT (broad IEA OK).
  • GO:0006637 acyl-CoA metabolic process (IEA): broad but correct (glutaryl-CoA is an
    acyl-CoA). ACCEPT as non-core / broad.
  • GO:0009063 amino acid catabolic process (IEA): correct broad parent (lysine/Trp
    catabolism). ACCEPT.
  • GO:0019395 fatty acid oxidation (IEA): WRONG branch — GCDH is amino-acid catabolism, not
    fatty-acid oxidation. Electronic Ensembl-ortholog transfer of a family-level term. REMOVE.

Notes on references

  • PMID:25416781 title/abstract are about METTL20/ETFβ; it is genuinely relevant to GCDH only as
    showing GCDH donates electrons to ETFβ. It does NOT support the fatty-acid beta-oxidation term.
  • PMID:34800366 is a large mitochondrial-proteome dataset (HTP); GCDH identity is in supplementary
    data, consistent with mitochondrial localization.

📄 View Raw YAML

 
id: Q92947
gene_symbol: GCDH
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
alternative_products:
- name: Long
  id: Q92947-1
- name: Short
  id: Q92947-2
  sequence_note: VSP_000145
existing_annotations:
- term:
    id: GO:0004361
    label: glutaryl-CoA dehydrogenase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/GCDH/GCDH-uniprot.txt
      supporting_text: Catalyzes the oxidative decarboxylation of glutaryl-CoA to
        crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-
- term:
    id: GO:0000062
    label: fatty-acyl-CoA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Family-level binding term. GCDH binds glutaryl-CoA, a dicarboxylic acyl-CoA
      (glutaryl-CoA / 5-carboxypentanoyl-CoA), rather than a simple fatty-acyl-CoA;
      the term is imprecise for this enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: The substrate of GCDH is glutaryl-CoA, a dicarboxylyl-CoA, not a fatty-acyl-CoA.
      While GCDH does bind an acyl-CoA thioester, 'fatty-acyl-CoA binding' is a family-level
      inference propagated from lipid-oxidizing acyl-CoA dehydrogenases and does not
      accurately describe the physiological ligand.
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
    supported_by:
    - reference_id: file:human/GCDH/GCDH-uniprot.txt
      supporting_text: Catalyzes the oxidative decarboxylation of glutaryl-CoA to
        crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-
- term:
    id: GO:0033539
    label: fatty acid beta-oxidation using acyl-CoA dehydrogenase
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: GCDH does not participate in fatty acid beta-oxidation; it acts in amino-acid
      (L-lysine/L-hydroxylysine/L-tryptophan) catabolism. This is a family-level over-propagation
      from lipid-oxidizing acyl-CoA dehydrogenases.
    action: MARK_AS_OVER_ANNOTATED
    reason: GCDH is a glutaryl-CoA dehydrogenase acting in the lysine/tryptophan degradative
      pathway, not in fatty acid beta-oxidation. Although GCDH shares the ETF-linked
      electron-transfer chemistry of beta-oxidation dehydrogenases, its substrate
      and pathway are amino-acid catabolic. The IBA term is inherited from lipid-metabolizing
      relatives and mischaracterizes GCDH's biological process.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - FUNCTIONAL_DIVERGENCE
    supported_by:
    - reference_id: file:human/GCDH/GCDH-uniprot.txt
      supporting_text: 'Amino-acid metabolism; lysine degradation.'
- term:
    id: GO:0046949
    label: fatty-acyl-CoA biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Incorrect biological process. GCDH is catabolic (it decarboxylates glutaryl-CoA
      to crotonyl-CoA), not biosynthetic, and it does not produce a fatty-acyl-CoA.
    action: MARK_AS_OVER_ANNOTATED
    reason: The reaction catalysed by GCDH is oxidative decarboxylation of glutaryl-CoA
      to crotonyl-CoA plus CO2, a catabolic step in amino-acid degradation. The product
      crotonyl-CoA is a short-chain enoyl-CoA intermediate, not a biosynthetic fatty-acyl-CoA
      end product. This family-level phylogenetic term is misleading for GCDH; flagged
      rather than removed to defer to the phylogenetic reviewer.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - FUNCTIONAL_DIVERGENCE
      - ROLE_CONFLATION
    supported_by:
    - reference_id: file:human/GCDH/GCDH-uniprot.txt
      supporting_text: Catalyzes the oxidative decarboxylation of glutaryl-CoA to
        crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-
- term:
    id: GO:0050660
    label: flavin adenine dinucleotide binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/GCDH/GCDH-uniprot.txt
      supporting_text: 'Name=FAD; Xref=ChEBI:CHEBI:57692;'
- term:
    id: GO:0003995
    label: acyl-CoA dehydrogenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0004361
      label: glutaryl-CoA dehydrogenase activity
    supported_by:
    - reference_id: file:human/GCDH/GCDH-uniprot.txt
      supporting_text: 'RecName: Full=Glutaryl-CoA dehydrogenase, mitochondrial;'
- term:
    id: GO:0004361
    label: glutaryl-CoA dehydrogenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Core molecular function of GCDH, here inferred electronically from RHEA/EC
      and orthologue mapping. Consistent with direct experimental evidence.
    action: ACCEPT
    reason: The electronic mapping (RHEA:13389, EC:1.3.8.6, orthologues) correctly
      assigns the demonstrated glutaryl-CoA dehydrogenase activity.
    supported_by:
    - reference_id: file:human/GCDH/GCDH-uniprot.txt
      supporting_text: EC=1.3.8.6;
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: GCDH is a nuclear-encoded mitochondrial protein with a cleavable N-terminal
      transit peptide; mitochondrial localization is well established.
    action: ACCEPT
    reason: Correct, though less specific than the mitochondrial matrix localization.
      Consistent with the transit peptide, the mature-chain import, and experimental
      localization data.
    supported_by:
    - reference_id: file:human/GCDH/GCDH-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion matrix.'
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: UniProt records the mitochondrion matrix location and Reactome places
      the reaction in the matrix; consistent with the soluble matrix acyl-CoA dehydrogenase
      biochemistry.
    supported_by:
    - reference_id: file:human/GCDH/GCDH-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion matrix.'
- term:
    id: GO:0016627
    label: oxidoreductase activity, acting on the CH-CH group of donors
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/GCDH/GCDH-uniprot.txt
      supporting_text: Catalyzes the oxidative decarboxylation of glutaryl-CoA to
        crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-
- term:
    id: GO:0050660
    label: flavin adenine dinucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: GCDH binds FAD as its cofactor; duplicate of the IBA FAD-binding annotation,
      here from electronic inference.
    action: ACCEPT
    reason: FAD is the obligate cofactor; the electronic assignment is correct.
    supported_by:
    - reference_id: file:human/GCDH/GCDH-uniprot.txt
      supporting_text: 'Name=FAD; Xref=ChEBI:CHEBI:57692;'
- term:
    id: GO:0000062
    label: fatty-acyl-CoA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Electronic ortholog-transfer of the family-level 'fatty-acyl-CoA binding'
      term. As with the IBA version, GCDH binds glutaryl-CoA (a dicarboxylyl-CoA),
      not a fatty-acyl-CoA.
    action: MARK_AS_OVER_ANNOTATED
    reason: The physiological ligand is glutaryl-CoA, not a fatty-acyl-CoA. The term
      is a family-level inference that imprecisely describes the CoA-thioester substrate
      specificity of GCDH.
    supported_by:
    - reference_id: file:human/GCDH/GCDH-uniprot.txt
      supporting_text: Catalyzes the oxidative decarboxylation of glutaryl-CoA to
        crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-
- term:
    id: GO:0006637
    label: acyl-CoA metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Broad but accurate biological-process term. GCDH metabolises glutaryl-CoA,
      which is an acyl-CoA thioester.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/GCDH/GCDH-uniprot.txt
      supporting_text: Catalyzes the oxidative decarboxylation of glutaryl-CoA to
        crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-
- term:
    id: GO:0009063
    label: amino acid catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Accurate broad parent term. GCDH functions in the catabolism of L-lysine,
      L-hydroxylysine and L-tryptophan.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/GCDH/GCDH-uniprot.txt
      supporting_text: in the degradative pathway of L-lysine, L-
- term:
    id: GO:0019395
    label: fatty acid oxidation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Incorrect biological process. GCDH acts in amino-acid catabolism, not
      fatty acid oxidation; this is an electronic ortholog-transfer of a family-level
      term to the wrong branch.
    action: REMOVE
    reason: GCDH degrades glutaryl-CoA arising from lysine/tryptophan catabolism, not
      fatty acids. UniProt explicitly places GCDH in lysine and tryptophan degradation
      pathways, with no role in fatty acid oxidation. This IEA term is a demonstrably
      wrong inference propagated from lipid-oxidizing acyl-CoA dehydrogenase relatives.
    supported_by:
    - reference_id: file:human/GCDH/GCDH-uniprot.txt
      supporting_text: 'Amino-acid metabolism; lysine degradation.'
- term:
    id: GO:0019477
    label: L-lysine catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Core biological process of GCDH. Glutaryl-CoA is the key intermediate
      of the saccharopine (lysine degradation) pathway, and GCDH catalyses its dehydrogenation/decarboxylation.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/GCDH/GCDH-uniprot.txt
      supporting_text: 'Amino-acid metabolism; lysine degradation.'
- term:
    id: GO:0046949
    label: fatty-acyl-CoA biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Incorrect biological process, here from electronic ortholog transfer.
      GCDH is catabolic and does not synthesise a fatty-acyl-CoA.
    action: REMOVE
    reason: The GCDH-catalysed reaction is a catabolic oxidative decarboxylation producing
      crotonyl-CoA and CO2, not a biosynthetic process, and crotonyl-CoA is not a
      fatty-acyl-CoA biosynthetic product. This electronic inference is on the wrong
      branch for GCDH and contradicts the enzyme's known catabolic direction.
    supported_by:
    - reference_id: file:human/GCDH/GCDH-uniprot.txt
      supporting_text: Catalyzes the oxidative decarboxylation of glutaryl-CoA to
        crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:37198486
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:37198486
      supporting_text: GCDH most frequently co-localized with the mitochondrial marker
        COX IV, but >20% of total GCDH localized to nuclei in GSCs
    - reference_id: PMID:37198486
      supporting_text: GCDH interacts with the crotonyltransferase CBP to promote
        histone
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:37198486
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: GCDH most frequently co-localized with the mitochondrial marker COX IV,
      confirming the canonical mitochondrial localization by direct assay.
    supported_by:
    - reference_id: PMID:37198486
      supporting_text: GCDH most frequently co-localized with the mitochondrial marker
        COX IV, but >20% of total GCDH localized to nuclei in GSCs
- term:
    id: GO:0019477
    label: L-lysine catabolic process
  evidence_type: IMP
  original_reference_id: PMID:37198486
  qualifier: involved_in
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:37198486
      supporting_text: GCDH depletion abolished increased Kcr induced by L-lysine
        supplementation
    - reference_id: PMID:37198486
      supporting_text: (crotonyl-CoA)-producing enzyme glutaryl-CoA dehydrogenase
        (GCDH) with
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Immunofluorescence-based (HPA) evidence of mitochondrial localization,
      consistent with all other localization data.
    action: ACCEPT
    reason: Corroborates the well-established mitochondrial localization of GCDH.
    supported_by:
    - reference_id: file:human/GCDH/GCDH-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion matrix.'
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: High-throughput mitochondrial proteomics identifies GCDH as a component
      of the human mitochondrial proteome, consistent with its established localization.
    action: ACCEPT
    reason: The high-confidence mitochondrial proteome dataset includes GCDH, corroborating
      mitochondrial localization; consistent with all curated and experimental evidence.
    supported_by:
    - reference_id: file:human/GCDH/GCDH-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion matrix.'
- term:
    id: GO:0004361
    label: glutaryl-CoA dehydrogenase activity
  evidence_type: IDA
  original_reference_id: PMID:8541831
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:8541831
      supporting_text: kinetic constants similar to those of the previously purified
    - reference_id: PMID:8541831
      supporting_text: We have cloned, sequenced, and expressed cDNAs encoding wild
        type human
- term:
    id: GO:0033539
    label: fatty acid beta-oxidation using acyl-CoA dehydrogenase
  evidence_type: IDA
  original_reference_id: PMID:25416781
  qualifier: involved_in
  review:
    summary: This annotation derives from a study of METTL20/ETFβ methylation in which
      GCDH is used only as one of two test dehydrogenases donating electrons to ETFβ.
      GCDH acts in amino-acid catabolism, not fatty acid beta-oxidation; the biological-process
      term is a mischaracterization.
    action: MARK_AS_OVER_ANNOTATED
    reason: The cited paper shows that methylation of ETFβ reduces its ability to
      receive electrons from MCAD and GCDH, i.e. it establishes that GCDH is an ETF-linked
      dehydrogenase; it does not place GCDH in fatty acid beta-oxidation. GCDH's substrate
      (glutaryl-CoA) arises from lysine/tryptophan catabolism, not fatty acids, so
      the process term is over-annotated. Marked rather than removed because the underlying
      experimental observation (ETF electron transfer) is genuine.
    supported_by:
    - reference_id: PMID:25416781
      supporting_text: methylation reduced the ability of ETFβ to receive electrons
        from the dehydrogenases MCAD and GCDH
    - reference_id: file:human/GCDH/GCDH-uniprot.txt
      supporting_text: 'Amino-acid metabolism; lysine degradation.'
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71046
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: The traceable Reactome assertion agrees with UniProt (Mitochondrion matrix)
      and with the soluble-matrix biochemistry of GCDH.
    supported_by:
    - reference_id: Reactome:R-HSA-71046
      supporting_text: The active enzyme is a tetramer of GCDH polypeptides lacking
        a 44-residue aminoterminal mitochondrial targeting sequence.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: TAS
  original_reference_id: PMID:8541831
  qualifier: located_in
  review:
    summary: The GCDH primary translation product is translocated into mitochondria
      and processed like other nuclear-encoded mitochondrial proteins, supporting
      mitochondrial localization.
    action: ACCEPT
    reason: The cited study reports mitochondrial import and processing of the GCDH
      precursor, a traceable author statement supporting mitochondrial localization.
    supported_by:
    - reference_id: PMID:8541831
      supporting_text: is translocated into mitochondria
core_functions:
- description: FAD-dependent glutaryl-CoA dehydrogenase catalysing the oxidative decarboxylation
    of glutaryl-CoA to crotonyl-CoA and CO2 in the mitochondrial matrix, feeding electrons
    to the electron-transfer flavoprotein
  molecular_function:
    id: GO:0004361
    label: glutaryl-CoA dehydrogenase activity
  directly_involved_in:
  - id: GO:0019477
    label: L-lysine catabolic process
  supported_by:
  - reference_id: file:human/GCDH/GCDH-uniprot.txt
    supporting_text: Catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA
      and CO(2) in the degradative pathway of L-lysine, L-
  - reference_id: PMID:8541831
    supporting_text: We have cloned, sequenced, and expressed cDNAs encoding wild
      type human
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:25416781
  title: Human METTL20 is a mitochondrial lysine methyltransferase that targets the
    β subunit of electron transfer flavoprotein (ETFβ) and modulates its activity.
  findings:
  - statement: Methylation of ETFβ by METTL20 reduces the ability of ETFβ to receive
      electrons from GCDH (and MCAD), establishing that GCDH is an ETF-linked dehydrogenase
      that donates electrons to the electron-transfer flavoprotein.
    supporting_text: methylation reduced the ability of ETFβ to receive electrons
      from the dehydrogenases MCAD and GCDH
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified. Directly supports GCDH as an ETF electron donor,
      but does NOT support the attached GO:0033539 fatty-acid beta-oxidation process
      term (GCDH is amino-acid catabolic); that annotation is over-annotated.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings:
  - statement: GCDH is a component of the high-confidence human mitochondrial proteome,
      consistent with its mitochondrial-matrix localization.
    supporting_text: ''
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput mitochondrial proteome dataset; GCDH identity in
      supplementary data supports mitochondrial localization only.
- id: PMID:37198486
  title: Lysine catabolism reprograms tumour immunity through histone crotonylation.
  findings:
  - statement: GCDH is the crotonyl-CoA-producing enzyme of the lysine catabolic pathway;
      its depletion abolishes lysine-induced histone crotonylation.
    supporting_text: GCDH depletion abolished increased Kcr induced by L-lysine supplementation
  - statement: A minor nuclear pool of GCDH (>20% of total) partners with CBP to promote
      histone lysine crotonylation, while the majority co-localizes with the mitochondrial
      marker COX IV.
    supporting_text: GCDH most frequently co-localized with the mitochondrial marker
      COX IV, but >20% of total GCDH localized to nuclei in GSCs
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified primary research. Establishes GCDH's role in L-lysine
      catabolism and a moonlighting nuclear crotonyl-CoA-supplying function in glioblastoma
      stem cells.
- id: PMID:8541831
  title: Cloning of glutaryl-CoA dehydrogenase cDNA, and expression of wild type and
    mutant enzymes in Escherichia coli.
  findings:
  - statement: Human GCDH cDNA was cloned and expressed with glutaryl-CoA dehydrogenase
      activity and kinetic constants similar to the purified porcine enzyme; a disease
      mutant had <1% activity and the alternatively spliced short isoform is inactive.
    supporting_text: Purified expressed human glutaryl-CoA
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; abstract-only in cache (full_text_available false)
      but abstract directly supports the catalytic activity, mitochondrial import,
      and inactive short isoform.
- id: Reactome:R-HSA-71046
  title: glutaryl-CoA + FAD => crotonyl-CoA + FADH2 + CO2
  findings:
  - statement: GCDH catalyses glutaryl-CoA + FAD to crotonyl-CoA + FADH2 + CO2 in
      the mitochondrial matrix as a homotetramer lacking the 44-residue transit peptide.
    supporting_text: The active enzyme is a tetramer of GCDH polypeptides lacking
      a 44-residue aminoterminal mitochondrial targeting sequence.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Reactome reaction for the core GCDH catalytic step; matrix localization
      and homotetramer.