id: P00367
gene_symbol: GLUD1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  GLUD1 encodes glutamate dehydrogenase 1, the major, ubiquitously expressed
  mitochondrial-matrix enzyme that catalyzes the reversible oxidative deamination
  of L-glutamate to 2-oxoglutarate (alpha-ketoglutarate) with release of ammonia,
  using NAD(+) or NADP(+) as cofactor (EC 1.4.1.3). It is the central metabolic
  link between amino-acid/nitrogen metabolism and the tricarboxylic acid cycle,
  providing anaplerotic alpha-ketoglutarate and channeling ammonia toward the urea
  cycle. The mature enzyme (after cleavage of an N-terminal mitochondrial transit
  peptide) assembles into a homohexamer whose activity is tightly allosterically
  regulated: it is activated by ADP and L-leucine and inhibited by GTP and ATP,
  and it is inactivated by SIRT4-mediated ADP-ribosylation. The bulk of the protein
  localizes to the mitochondrial matrix, with a small pool in the endoplasmic
  reticulum and cytoplasm. In pancreatic beta-cells GLUD1 couples amino-acid
  catabolism to insulin secretion, and in the brain it contributes to turnover of
  the neurotransmitter glutamate. Dominant gain-of-function mutations that impair
  GTP inhibition cause the hyperinsulinism-hyperammonemia syndrome (familial
  hyperinsulinemic hypoglycemia type 6).
alternative_products:
- name: '1'
  id: P00367-1
- name: '2'
  id: P00367-2
  sequence_note: VSP_056244
- name: '3'
  id: P00367-3
  sequence_note: VSP_056523, VSP_056524
existing_annotations:
- term:
    id: GO:0004352
    label: L-glutamate dehydrogenase (NAD+) activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (PAN-GO) inference of the NAD(+)-dependent glutamate
      dehydrogenase activity. This is the well-established catalytic activity of
      GLUD1 and is directly supported by human experimental data. Because GLUD1
      is a genuine dual-cofactor enzyme using both NAD(+) and NADP(+), the umbrella
      term GO:0004353 [NAD(P)+] is the most representative core function; the
      NAD(+)-specific term is accurate as a component of that activity.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/GLUD1/GLUD1-uniprot.txt
      supporting_text: "Mitochondrial glutamate dehydrogenase that catalyzes the"
- term:
    id: GO:0006538
    label: L-glutamate catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic inference that GLUD1 participates in glutamate catabolism. This
      is the core biological process the enzyme executes (oxidative deamination of
      glutamate) and is experimentally supported in human.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:6121377
      supporting_text: "Decreased glutamate"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic inference of mitochondrial localization. Correct; the enzyme is
      predominantly mitochondrial. The more specific and experimentally supported
      location is the mitochondrial matrix (GO:0005759), so this general term is
      retained as accurate but non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: file:human/GLUD1/GLUD1-uniprot.txt
      supporting_text: "translocates into the mitochondria, only a small amount of the protein"
- term:
    id: GO:0004352
    label: L-glutamate dehydrogenase (NAD+) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated (ARBA/RHEA) assignment of NAD(+)-dependent glutamate dehydrogenase
      activity, consistent with EC 1.4.1.3 and the RHEA:15133 reaction listed in
      UniProt. Accurate and experimentally corroborated.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/GLUD1/GLUD1-uniprot.txt
      supporting_text: "Reaction=L-glutamate + NAD(+) + H2O = 2-oxoglutarate"
- term:
    id: GO:0004353
    label: L-glutamate dehydrogenase [NAD(P)+] activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000003
  qualifier: enables
  review:
    summary: >-
      EC-mapping (EC 1.4.1.3) assignment of the dual-cofactor [NAD(P)+] glutamate
      dehydrogenase activity. This is the single most representative molecular
      function of GLUD1, which uses both NAD(+) and NADP(+); it is experimentally
      supported and designated core.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:11254391
      supporting_text: "only animal GDH utilizes"
- term:
    id: GO:0004354
    label: L-glutamate dehydrogenase (NADP+) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: >-
      Automated (RHEA:11612) assignment of NADP(+)-dependent glutamate dehydrogenase
      activity. GLUD1 genuinely uses NADP(+) as well as NAD(+); the NADP(+) reaction
      is experimentally documented (PMID:11032875) and listed in UniProt.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/GLUD1/GLUD1-uniprot.txt
      supporting_text: "Reaction=L-glutamate + NADP(+) + H2O = 2-oxoglutarate"
- term:
    id: GO:0005525
    label: GTP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: >-
      ARBA electronic assignment of GTP binding. GTP is the major allosteric
      inhibitor of GLUD1 and binds a defined regulatory site; this is supported by
      an experimental IDA annotation (PMID:11032875) and by GTP-binding residues in
      UniProt. Kept as an accurate regulatory-ligand binding function (non-core).
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: file:human/GLUD1/GLUD1-uniprot.txt
      supporting_text: "Inhibited by GTP and ATP"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UniProt subcellular-location keyword mapping to mitochondrion. Correct and
      redundant with the experimental IDA mitochondrion annotations; retained as
      accurate but non-core relative to mitochondrial matrix.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: file:human/GLUD1/GLUD1-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion"
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UniProt subcellular-location keyword mapping to endoplasmic reticulum. This
      reflects a genuine but minor extramitochondrial pool of GLUD1; it is not the
      core site of function.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:19448744
      supporting_text: "part of the protein localizes to the endoplasmic reticulum"
- term:
    id: GO:0006520
    label: amino acid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO assignment of a very general amino-acid metabolic process. GLUD1
      indeed acts in amino-acid (glutamate) metabolism, but the specific, better
      term is L-glutamate catabolic process (GO:0006538), which is already annotated
      experimentally. This general term should be replaced by the specific one.
    action: MODIFY
    proposed_replacement_terms:
    - id: GO:0006538
      label: L-glutamate catabolic process
    supported_by:
    - reference_id: file:human/GLUD1/GLUD1-uniprot.txt
      supporting_text: "catalyzes the"
- term:
    id: GO:0006538
    label: L-glutamate catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA electronic assignment of glutamate catabolism, redundant with the
      experimental IDA/IBA annotations to the same term. Accurate core process.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:11903050
      supporting_text: "catalyses the reversible oxidative deamination of l-glutamate to 2-oxoglutarate in the mitochondrial matrix"
- term:
    id: GO:0016491
    label: oxidoreductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO high-level oxidoreductase activity. Correct but far too general;
      the specific catalytic function is L-glutamate dehydrogenase [NAD(P)+] activity
      (GO:0004353), which is annotated experimentally. Replace with the specific term.
    action: MODIFY
    proposed_replacement_terms:
    - id: GO:0004353
      label: L-glutamate dehydrogenase [NAD(P)+] activity
    supported_by:
    - reference_id: PMID:11254391
      supporting_text: "oxidative"
- term:
    id: GO:0016639
    label: oxidoreductase activity, acting on the CH-NH2 group of donors, NAD or NADP
      as acceptor
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO assignment of the parent class of amino-acid dehydrogenase
      activity. Accurate but a generalization of the specific glutamate
      dehydrogenase [NAD(P)+] activity (GO:0004353). Replace with the specific term.
    action: MODIFY
    proposed_replacement_terms:
    - id: GO:0004353
      label: L-glutamate dehydrogenase [NAD(P)+] activity
    supported_by:
    - reference_id: PMID:11254391
      supporting_text: "deamination of l-glutamate to 2-oxoglutarate"
- term:
    id: GO:0043531
    label: ADP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: >-
      ARBA electronic assignment of ADP binding, redundant with the experimental
      IDA ADP-binding annotation (PMID:12742085). ADP is the principal allosteric
      activator of GLUD1 and binds a defined site; this is a core regulatory-ligand
      binding function.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/GLUD1/GLUD1-uniprot.txt
      supporting_text: "Activated by ADP"
- term:
    id: GO:0070728
    label: L-leucine binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: >-
      ARBA electronic assignment of L-leucine binding, redundant with the
      experimental IDA annotation (PMID:12742085). L-leucine is a physiological
      allosteric activator of GLUD1; accurate regulatory function (non-core).
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:11032875
      supporting_text: "L-leucine, at 1.0 mM:, enhanced the activity of the nerve tissue-specific"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: >-
      Generic protein binding from a high-throughput affinity-purification
      interactome (BioPlex). The term is uninformative about GLUD1 molecular
      function; the recorded partners (GLUD2 paralog, KLHL22) are captured elsewhere.
      Flagged as over-annotated per curation policy for bare protein binding IPIs.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      Generic protein binding from a large-scale interactome (BioPlex 3.0).
      Uninformative molecular-function term; flagged as over-annotated.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:37788672
  qualifier: enables
  review:
    summary: >-
      Protein binding from the cryo-EM structure of the KLHL22 E3 ligase bound to
      the GDH1 hexamer. Although this is a biologically meaningful interaction
      (KLHL22/CUL3 ubiquitinates GDH1), the bare protein binding term is
      uninformative; the specific relationship is documented in the notes and the
      KLHL22 interaction is retained in UniProt. Flagged as over-annotated.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:37788672
      supporting_text: "ligase mediated the polyubiquitination of GDH1 in vitro"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: >-
      Generic protein binding from a multimodal cell-map/interactome study.
      Uninformative molecular-function term; flagged as over-annotated.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Immunofluorescence (HPA) localization to mitochondrion. Correct; consistent
      with the predominant mitochondrial localization. Retained as accurate but
      non-core relative to mitochondrial matrix.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0004352
    label: L-glutamate dehydrogenase (NAD+) activity
  evidence_type: EXP
  original_reference_id: PMID:11254391
  qualifier: enables
  review:
    summary: >-
      Experimental characterization of GDH catalytic activity and purine regulation
      from crystallographic/kinetic studies (bovine GDH structures; human HHS mutant
      kinetics). Supports the NAD(+)-dependent glutamate dehydrogenase activity of
      GLUD1. Core catalytic function.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:11254391
      supporting_text: "deamination of l-glutamate to 2-oxoglutarate"
- term:
    id: GO:0004352
    label: L-glutamate dehydrogenase (NAD+) activity
  evidence_type: EXP
  original_reference_id: PMID:16023112
  qualifier: enables
  review:
    summary: >-
      Experimental measurement of purified human GDH activity and its inhibition by
      ADP-ribosylation. Confirms the NAD(+)-dependent glutamate dehydrogenase
      activity of GLUD1. Core catalytic function.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:16023112
      supporting_text: "hGDH isozymes were inhibited by up to 75%"
- term:
    id: GO:0004352
    label: L-glutamate dehydrogenase (NAD+) activity
  evidence_type: EXP
  original_reference_id: PMID:16959573
  qualifier: enables
  review:
    summary: >-
      Experimental demonstration that GDH activity is regulated (downregulated by
      SIRT4-mediated ADP-ribosylation). Supports the NAD(+)-dependent glutamate
      dehydrogenase activity. Core catalytic function.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:16959573
      supporting_text: "downregulate glutamate dehydrogenase (GDH) activity"
- term:
    id: GO:0004354
    label: L-glutamate dehydrogenase (NADP+) activity
  evidence_type: EXP
  original_reference_id: PMID:11032875
  qualifier: enables
  review:
    summary: >-
      Experimental kinetic characterization of recombinant human GLUD1-derived GDH,
      which functions with NADP(+) as well as NAD(+). Supports the NADP(+)-dependent
      activity, part of the dual-cofactor core function.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:11032875
      supporting_text: "Nonactivated GLUD1 GDH was markedly inhibited"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput mitochondrial-proteome detection. Consistent with the
      established mitochondrial localization; accurate but non-core relative to
      mitochondrial matrix.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:11903050
  qualifier: enables
  review:
    summary: >-
      Self-interaction annotation. GLUD1 assembles into a homohexamer (a trimer of
      dimers), so a homo-oligomerization/self-association activity is real, though
      homodimerization is a slightly imprecise description of the hexameric
      assembly. The self-association is intrinsic to enzyme assembly rather than a
      standalone signaling function, so it is kept as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: file:human/GLUD1/GLUD1-uniprot.txt
      supporting_text: "Homohexamer (By similarity)"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:19448744
  qualifier: located_in
  review:
    summary: >-
      Experimental (confocal colocalization with a mitochondrial marker) localization
      to mitochondrion. Directly supports the predominant mitochondrial localization
      of GLUD1. Retained as accurate but non-core relative to the matrix term.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:19448744
      supporting_text: "colocalized with the mitochondrial marker DsRed2-Mito"
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:19448744
  qualifier: located_in
  review:
    summary: >-
      Experimental colocalization showing a minor pool of GLUD1 in the endoplasmic
      reticulum in addition to mitochondria. Real but minor; not the core site of
      function.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:19448744
      supporting_text: "part of the protein localizes to the endoplasmic reticulum"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5688276
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author localization to the mitochondrial matrix (in the
      context of SIRT4 transferring ADP-ribose to GLUD). This is the specific,
      correct site of the active enzyme. Core location.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:11903050
      supporting_text: "in the mitochondrial matrix"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5688289
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author localization to the mitochondrial matrix (SIRT3
      deacetylation reaction context). Correct core location of the enzyme.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:11903050
      supporting_text: "in the mitochondrial matrix"
- term:
    id: GO:0021762
    label: substantia nigra development
  evidence_type: HEP
  original_reference_id: PMID:22926577
  qualifier: involved_in
  review:
    summary: >-
      Derived from a quantitative proteomics survey of human substantia nigra in
      neurodegenerative disease (expression-pattern HEP evidence). Mere detection or
      differential abundance in a brain region does not establish a role in
      substantia nigra development; this is an over-annotation of GLUD1 function.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0006541
    label: L-glutamine metabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence-similarity transfer of a role in glutamine metabolism. GLUD1 does not
      act directly on glutamine, but it is central to glutamine anaplerosis by
      producing alpha-ketoglutarate downstream of glutaminase; this places it within
      the glutamine metabolic network. Kept as accurate but non-core (indirect).
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: file:human/GLUD1/GLUD1-uniprot.txt
      supporting_text: "glutamine anaplerosis by producing alpha-ketoglutarate, an important"
- term:
    id: GO:0072350
    label: tricarboxylic acid metabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence-similarity transfer of a role in TCA-cycle intermediate metabolism.
      Accurate: GLUD1 supplies alpha-ketoglutarate, a key TCA intermediate, linking
      it to the tricarboxylic acid metabolic process (anaplerosis). Core-adjacent
      process reflecting the enzyme principal metabolic role.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/GLUD1/GLUD1-uniprot.txt
      supporting_text: "intermediate in the tricarboxylic acid cycle"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70589
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author localization to the mitochondrial matrix, annotated
      on the reverse GDH reaction (alpha-ketoglutarate + NH4+ + NAD(P)H -> glutamate).
      Correct core location.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:11903050
      supporting_text: "in the mitochondrial matrix"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70600
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author localization to the mitochondrial matrix, annotated
      on the forward GDH reaction (glutamate + NAD(P)+ -> alpha-ketoglutarate).
      Correct core location.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:11903050
      supporting_text: "in the mitochondrial matrix"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9838081
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author localization to the mitochondrial matrix (LONP1
      degradation of matrix proteins context). Correct core location.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:11903050
      supporting_text: "in the mitochondrial matrix"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9838093
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author localization to the mitochondrial matrix (LONP1
      binding of matrix proteins context). Correct core location.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:11903050
      supporting_text: "in the mitochondrial matrix"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16959573
  qualifier: enables
  review:
    summary: >-
      Protein binding annotation with SIRT4 (Q9Y6E7) as partner. The biologically
      meaningful relationship is that SIRT4 ADP-ribosylates and inhibits GLUD1; the
      bare protein binding term is uninformative about the GLUD1 molecular function.
      Flagged as over-annotated per policy.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:16959573
      supporting_text: "SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate"
- term:
    id: GO:0070728
    label: L-leucine binding
  evidence_type: IDA
  original_reference_id: PMID:12742085
  qualifier: enables
  review:
    summary: >-
      Experimental (structure-function/mutagenesis) evidence for L-leucine binding,
      the physiological allosteric activator site. Accurate regulatory-ligand binding
      function; kept as non-core relative to catalysis.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:11032875
      supporting_text: "L-leucine, at 1.0 mM:, enhanced the activity of the nerve tissue-specific"
- term:
    id: GO:0005525
    label: GTP binding
  evidence_type: IDA
  original_reference_id: PMID:11032875
  qualifier: enables
  review:
    summary: >-
      Experimental evidence for GTP binding, the major allosteric inhibitor of
      GLUD1 (nonactivated enzyme inhibited by GTP with IC50 ~0.2 microM). Accurate
      regulatory-ligand binding function; central to physiology and disease
      (loss of GTP inhibition causes HHF6) but kept as non-core relative to catalysis.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:11032875
      supporting_text: "Nonactivated GLUD1 GDH was markedly inhibited"
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:18688271
  qualifier: located_in
  review:
    summary: >-
      Experimental localization showing GLUD1 in the cytoplasm in addition to
      mitochondria (in contrast to the mitochondria-specific GLUD2). This is a
      genuine but minor extramitochondrial pool; not the core site of function.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:18688271
      supporting_text: "GLUD1 localizes to the mitochondria as well as the cytoplasm"
- term:
    id: GO:0043531
    label: ADP binding
  evidence_type: IDA
  original_reference_id: PMID:12742085
  qualifier: enables
  review:
    summary: >-
      Experimental (structure-function) evidence for ADP binding, the principal
      allosteric activator site of GLUD1. ADP binding is core to the activated
      physiological state of the enzyme.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/GLUD1/GLUD1-uniprot.txt
      supporting_text: "Activated by ADP"
- term:
    id: GO:0097054
    label: L-glutamate biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:11032875
  qualifier: involved_in
  review:
    summary: >-
      The GDH reaction is reversible, and in the reductive amination direction
      (alpha-ketoglutarate + NH4+ + NAD(P)H -> glutamate) GLUD1 can synthesize
      glutamate. Reactome models this reverse reaction (R-HSA-70589). Real capacity,
      but the physiologically dominant/core direction is oxidative deamination
      (catabolic); glutamate biosynthesis is kept as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: file:human/GLUD1/GLUD1-uniprot.txt
      supporting_text: "Reaction=L-glutamate + NAD(+) + H2O = 2-oxoglutarate"
- term:
    id: GO:0004352
    label: L-glutamate dehydrogenase (NAD+) activity
  evidence_type: IDA
  original_reference_id: PMID:11903050
  qualifier: enables
  review:
    summary: >-
      Direct experimental characterization of purified recombinant human GDH
      (wild-type and allosteric-regulatory mutants), confirming NAD(+)-dependent
      glutamate dehydrogenase activity. Core catalytic function.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:11903050
      supporting_text: "catalyses the reversible oxidative deamination of l-glutamate to 2-oxoglutarate in the mitochondrial matrix"
- term:
    id: GO:0004353
    label: L-glutamate dehydrogenase [NAD(P)+] activity
  evidence_type: IDA
  original_reference_id: PMID:11032875
  qualifier: enables
  review:
    summary: >-
      Direct experimental evidence for the dual-cofactor [NAD(P)+] glutamate
      dehydrogenase activity of human GLUD1-derived GDH. This is the single most
      representative molecular function of the gene. Core catalytic function.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:11254391
      supporting_text: "only animal GDH utilizes"
- term:
    id: GO:0006538
    label: L-glutamate catabolic process
  evidence_type: IDA
  original_reference_id: PMID:11032875
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental support for GLUD1 role in glutamate catabolism (oxidative
      deamination). Core biological process.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:11903050
      supporting_text: "catalyses the reversible oxidative deamination of l-glutamate to 2-oxoglutarate in the mitochondrial matrix"
- term:
    id: GO:0032024
    label: positive regulation of insulin secretion
  evidence_type: IMP
  original_reference_id: PMID:11502802
  qualifier: involved_in
  review:
    summary: >-
      Clinical/mutation evidence that GLUD1 activity promotes insulin secretion:
      gain-of-function GLUD1 mutations (loss of GTP inhibition) cause exaggerated
      leucine-stimulated insulin release in the hyperinsulinism/hyperammonemia
      syndrome. This is a genuine, physiologically and clinically important role in
      pancreatic beta-cells, but it is a downstream, tissue-specific function rather
      than the enzyme core catalytic role. Kept as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:11502802
      supporting_text: "syndrome by desensitizing glutamate dehydrogenase to allosteric inhibition by"
- term:
    id: GO:0070403
    label: NAD+ binding
  evidence_type: IDA
  original_reference_id: PMID:12193607
  qualifier: enables
  review:
    summary: >-
      Direct experimental identification of the NAD(+) coenzyme-binding site
      (photoaffinity labeling and mutagenesis of Glu279). NAD(+) binding is intrinsic
      to catalysis; a genuine cofactor-binding function, kept as non-core relative to
      the catalytic activity term it supports.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:12193607
      supporting_text: "Glu(279) plays an important role for efficient binding of NAD(+) to human"
- term:
    id: GO:0004352
    label: L-glutamate dehydrogenase (NAD+) activity
  evidence_type: IDA
  original_reference_id: PMID:15578726
  qualifier: enables
  review:
    summary: >-
      Direct experimental characterization of recombinant human GLUD1-derived GDH
      activity and its regulation. Confirms NAD(+)-dependent glutamate dehydrogenase
      activity. Core catalytic function.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:15578726
      supporting_text: "GTP potently inhibits GLUD1-derived GDH"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:15578726
  qualifier: located_in
  review:
    summary: >-
      Experimental (GFP-fusion imaging) localization of GLUD1 to mitochondria,
      colocalizing with a mitochondrial marker. Supports the predominant
      mitochondrial localization; kept as non-core relative to mitochondrial matrix.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:15578726
      supporting_text: "revealed a GFP fluorescence pattern nearly identical to that of the"
- term:
    id: GO:0006538
    label: L-glutamate catabolic process
  evidence_type: IDA
  original_reference_id: PMID:6121377
  qualifier: involved_in
  review:
    summary: >-
      Human evidence linking GDH deficiency to impaired glutamate catabolism
      (elevated plasma glutamate, reduced alpha-ketoglutarate; decreased glutamate
      catabolism in patients with partial GDH deficiency). Supports the core
      glutamate catabolic process.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:6121377
      supporting_text: "Decreased glutamate"
core_functions:
- description: >-
    L-glutamate dehydrogenase [NAD(P)+] activity: catalyzes the reversible oxidative
    deamination of L-glutamate to 2-oxoglutarate (alpha-ketoglutarate) with release
    of ammonia, using either NAD(+) or NADP(+) as the redox cofactor, in the
    mitochondrial matrix. This is the defining catalytic activity of GLUD1 and the
    central link between amino-acid/nitrogen metabolism and the TCA cycle.
  molecular_function:
    id: GO:0004353
    label: L-glutamate dehydrogenase [NAD(P)+] activity
  directly_involved_in:
  - id: GO:0006538
    label: L-glutamate catabolic process
  - id: GO:0072350
    label: tricarboxylic acid metabolic process
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: PMID:11903050
    supporting_text: "catalyses the reversible oxidative deamination of l-glutamate to 2-oxoglutarate in the mitochondrial matrix"
  - reference_id: PMID:11254391
    supporting_text: "only animal GDH utilizes"
- description: >-
    ADP binding: binds ADP at a defined allosteric site, which activates the enzyme
    (and sensitizes it to L-leucine). ADP binding drives GLUD1 into its catalytically
    active state under conditions of high ADP:ATP ratio, integrating enzyme activity
    with cellular energy charge.
  molecular_function:
    id: GO:0043531
    label: ADP binding
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: file:human/GLUD1/GLUD1-uniprot.txt
    supporting_text: "Activated by ADP"
  - reference_id: PMID:11903050
    supporting_text: "The major allosteric activator and inhibitor are ADP and GTP"
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000003
  title: Gene Ontology annotation based on Enzyme Commission mapping
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  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:11032875
  title: 'Nerve tissue-specific (GLUD2) and housekeeping (GLUD1) human glutamate dehydrogenases
    are regulated by distinct allosteric mechanisms: implications for biologic function.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Primary characterization of human GLUD1-derived GDH: dual-cofactor activity,
      potent GTP inhibition (IC50 ~0.2 microM), and ADP/leucine activation. Directly
      supports the catalytic and allosteric-regulation annotations.
- id: PMID:11254391
  title: Structures of bovine glutamate dehydrogenase complexes elucidate the mechanism
    of purine regulation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Bovine GDH structures (with human HHS-mutant kinetics) establishing the shared
      mechanism of oxidative deamination and dual NAD(H)/NADP(H) usage and the ADP/GTP
      allosteric sites; used by UniProt as experimental evidence for EC 1.4.1.3.
- id: PMID:11502802
  title: Acute insulin responses to leucine in children with the hyperinsulinism/hyperammonemia
    syndrome.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Clinical study of HI/HA (HHF6) patients; establishes the mechanistic link
      between loss of GTP inhibition of GDH and leucine-stimulated insulin secretion.
      Supports the positive-regulation-of-insulin-secretion annotation.
- id: PMID:11903050
  title: Expression, purification and characterization of human glutamate dehydrogenase
    (GDH) allosteric regulatory mutations.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Purified human GDH; states the reversible oxidative deamination reaction in the
      mitochondrial matrix and characterizes ADP/GTP allosteric sites via mutants.
      Anchors the catalytic-activity, location, and ADP-binding annotations.
- id: PMID:12193607
  title: Importance of glutamate 279 for the coenzyme binding of human glutamate dehydrogenase.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Photoaffinity-labeling and mutagenesis identifying Glu279 at the NAD(+)
      coenzyme-binding site of human GDH. Supports the NAD+ binding annotation.
- id: PMID:12742085
  title: Study of structure-function relationships in human glutamate dehydrogenases
    reveals novel molecular mechanisms for the regulation of the nerve tissue-specific
    (GLUD2) isoenzyme.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Structure-function/mutagenesis of human GDH isoenzymes (GLUD1 vs GLUD2) mapping
      allosteric (ADP/leucine/GTP) determinants. Supports ADP- and L-leucine-binding
      annotations.
- id: PMID:15578726
  title: Molecular basis of human glutamate dehydrogenase regulation under changing
    energy demands.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Characterizes GLUD1-derived GDH activity/regulation and confirms mitochondrial
      localization by GFP fusion. Supports the catalytic-activity and mitochondrion
      annotations.
- id: PMID:16023112
  title: Identification of ADP-ribosylation site in human glutamate dehydrogenase
    isozymes.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Measures human GDH activity and its inhibition by ADP-ribosylation; establishes
      one-subunit-per-hexamer stoichiometry and the reactive Cys. Supports catalytic
      activity and the ADP-ribosylation PTM.
- id: PMID:16959573
  title: SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie
    restriction in pancreatic beta cells.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Shows SIRT4 ADP-ribosylates and downregulates GDH, linking GDH activity to
      amino-acid-stimulated insulin secretion in beta-cells. Supports catalytic-activity
      and the SIRT4-interaction/regulation annotations.
- id: PMID:18688271
  title: Mitochondrial targeting adaptation of the hominoid-specific glutamate dehydrogenase
    driven by positive Darwinian selection.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Full-text-available; directly states GLUD1 localizes to both mitochondria and
      cytoplasm (vs mitochondria-specific GLUD2). Supports the cytoplasm annotation.
- id: PMID:19448744
  title: Human GLUD1 and GLUD2 glutamate dehydrogenase localize to mitochondria and
    endoplasmic reticulum.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Experimental subcellular localization: most GDH translocates into mitochondria,
      with a minor ER pool. Supports the mitochondrion and endoplasmic-reticulum
      location annotations.
- id: PMID:22926577
  title: Quantitative proteomic analysis of human substantia nigra in Alzheimer's
    disease, Huntington's disease and Multiple sclerosis.
  findings: []
  reference_review:
    relevance: LOW
    correctness: MISCITED
    review_notes: >-
      Proteomic abundance survey of substantia nigra in neurodegenerative disease.
      Detection/differential abundance does not support a role in substantia nigra
      development; the derived GO annotation is an over-interpretation.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale BioPlex interactome. Correctly cited as source of a high-throughput
      protein-protein interaction, but yields only an uninformative protein-binding
      term for GLUD1.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      BioPlex 3.0 interactome; source of a high-throughput interaction giving only a
      generic protein-binding annotation.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      High-confidence mitochondrial proteome; corroborates mitochondrial localization
      of GLUD1.
- id: PMID:37788672
  title: Cryo-EM structure of the KLHL22 E3 ligase bound to an oligomeric metabolic
    enzyme.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Cryo-EM structure of CUL3(KLHL22)-RBX1 bound to the GDH1 hexamer; KLHL22
      polyubiquitinates GDH1 in vitro. Biologically meaningful KLHL22 interaction, but
      recorded in GOA only as generic protein binding.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Multimodal cell-map/interactome; source of a generic protein-binding annotation.
- id: PMID:6121377
  title: Abnormal glutamate metabolism in an adult-onset degenerative neurological
    disorder.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Human patients with partial GDH deficiency show elevated plasma glutamate and
      reduced alpha-ketoglutarate, indicating decreased glutamate catabolism. Supports
      the L-glutamate catabolic process annotation.
- id: Reactome:R-HSA-5688276
  title: SIRT4 transfers ADPRib to GLUD
  findings: []
- id: Reactome:R-HSA-5688289
  title: SIRT3 deacetylates ACCS2, GLUD, IDH2, SOD2
  findings: []
- id: Reactome:R-HSA-70589
  title: alpha-ketoglutarate + NH4+ + NAD(P)H + H+ <=> glutamate + NAD(P)+ (GLUD1,2)
  findings: []
- id: Reactome:R-HSA-70600
  title: glutamate + NAD(P)+ => alpha-ketoglutarate + NH4+ + NAD(P)H + H+ (GLUD1,2)
  findings: []
- id: Reactome:R-HSA-9838081
  title: LONP1 degrades mitochondrial matrix proteins
  findings: []
- id: Reactome:R-HSA-9838093
  title: LONP1 binds mitochondrial matrix proteins
  findings: []