id: Q99259
gene_symbol: GAD1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Glutamate decarboxylase 1 (GAD67; 67 kDa glutamic acid decarboxylase)
  is a pyridoxal-5'-phosphate (PLP)-dependent decarboxylase (EC 4.1.1.15) that catalyzes
  the conversion of L-glutamate to gamma-aminobutyric acid (GABA) plus CO2, thereby
  producing the major inhibitory neurotransmitter of the central nervous system. It
  is the principal constitutively active GABA-synthesizing enzyme responsible for
  basal GABA production, whereas the paralog GAD2 (GAD65) is the synaptic-vesicle-associated
  isoform that is transiently activated on demand. The enzyme is a homodimer that
  covalently binds PLP at an active-site lysine and belongs to the group II decarboxylase
  family. GAD67 is a soluble cytosolic protein expressed predominantly in GABAergic
  neurons of the brain, with additional expression in some non-neural tissues. Bi-allelic
  loss-of-function variants cause an autosomal recessive developmental and epileptic
  encephalopathy, and hypomorphic missense variation has been associated with spastic
  cerebral palsy / spastic paraplegia phenotypes, consistent with its essential role
  in inhibitory neurotransmission.
alternative_products:
- name: 1 (GAD67)
  id: Q99259-1
- name: '2'
  id: Q99259-2
  sequence_note: Not described
- name: 3 (GAD25 {ECO:0000303|PubMed:10671565})
  id: Q99259-3
  sequence_note: VSP_009123, VSP_009124
- name: '4'
  id: Q99259-4
  sequence_note: VSP_054473, VSP_054474
existing_annotations:
- term:
    id: GO:0009449
    label: GABA biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (IBA) annotation to GABA biosynthetic process. This is the
      core biological process of GAD1/GAD67 - synthesis of the inhibitory neurotransmitter
      GABA by decarboxylation of L-glutamate.
    action: ACCEPT
    reason: GAD67 is the principal constitutive GABA-synthesizing enzyme; this process
      annotation is directly supported by structural/biochemical work and by the UniProt
      FUNCTION statement, and is consistent across orthologs used for the IBA inference.
    supported_by:
    - reference_id: PMID:17384644
      supporting_text: GAD67 is constitutively active and is responsible for basal
        GABA production.
    - reference_id: file:human/GAD1/GAD1-uniprot.txt
      supporting_text: 'Catalyzes the synthesis of the inhibitory neurotransmitter'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic (IBA) annotation placing GAD1 activity in the cytoplasm.
      GAD67 is a soluble cytosolic enzyme, so this localization is correct, though
      the more specific term cytosol (GO:0005829) better captures the compartment.
    action: ACCEPT
    reason: GAD67 lacks the N-terminal membrane-targeting modifications of GAD65 and
      acts as a soluble cytosolic enzyme; cytoplasm is a correct (if general) location.
      Cytosol is used as the specific location in core_functions.
    supported_by:
    - reference_id: file:human/GAD1/GAD1-uniprot.txt
      supporting_text: 'Belongs to the group II decarboxylase family'
- term:
    id: GO:0004351
    label: glutamate decarboxylase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (IBA) annotation to glutamate decarboxylase activity (EC
      4.1.1.15), the core molecular function of GAD1/GAD67.
    action: ACCEPT
    reason: This is the defining catalytic activity of GAD67 and is independently supported
      by experimental (IDA) annotations from crystallographic and biochemical studies.
    supported_by:
    - reference_id: file:human/GAD1/GAD1-uniprot.txt
      supporting_text: 'L-glutamate + H(+) = 4-aminobutanoate + CO2'
- term:
    id: GO:0048786
    label: presynaptic active zone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic (IBA) annotation localizing GAD to the presynaptic active
      zone. This localization applies chiefly to synaptic GABA synthesis and is more
      characteristic of the vesicle-associated paralog GAD65; GAD67 is predominantly
      a soluble cytosolic enzyme responsible for basal GABA production.
    action: KEEP_AS_NON_CORE
    reason: GAD67 can be present at synaptic terminals in GABAergic neurons and contribute
      to the presynaptic GABA pool, but its core activity is cytosolic basal GABA production
      rather than active-zone-restricted synthesis; retained as a non-core localization.
    supported_by:
    - reference_id: PMID:17384644
      supporting_text: GAD67 is constitutively active and is responsible for basal
        GABA production.
- term:
    id: GO:0004351
    label: glutamate decarboxylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic (ARBA) annotation to glutamate decarboxylase activity mapped
      via EC 4.1.1.15 / RHEA:17785. Redundant with the experimental and IBA annotations
      to the same term.
    action: ACCEPT
    reason: Correct core molecular function; the EC/RHEA-based electronic mapping agrees
      with the experimentally established activity.
    supported_by:
    - reference_id: file:human/GAD1/GAD1-uniprot.txt
      supporting_text: 'L-glutamate + H(+) = 4-aminobutanoate + CO2'
- term:
    id: GO:0016830
    label: carbon-carbon lyase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-derived (IEA) annotation to carbon-carbon lyase activity, a broad
      parent of the specific glutamate decarboxylase activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: Not incorrect - glutamate decarboxylase activity IS a carbon-carbon lyase
      activity - but this parent term is far less informative than the specific EC
      4.1.1.15 activity, which is captured by the more specific glutamate decarboxylase
      activity annotation.
    supported_by:
    - reference_id: file:human/GAD1/GAD1-uniprot.txt
      supporting_text: 'L-glutamate + H(+) = 4-aminobutanoate + CO2'
- term:
    id: GO:0016831
    label: carboxy-lyase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-derived (IEA) annotation to carboxy-lyase activity, the immediate
      lyase parent of glutamate decarboxylase activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: Correct as a parent (decarboxylases are carboxy-lyases) but uninformative
      relative to the specific glutamate decarboxylase activity term already annotated.
    supported_by:
    - reference_id: file:human/GAD1/GAD1-uniprot.txt
      supporting_text: 'L-glutamate + H(+) = 4-aminobutanoate + CO2'
- term:
    id: GO:0030170
    label: pyridoxal phosphate binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-derived (IEA) annotation to pyridoxal phosphate binding. PLP
      is the essential catalytic cofactor of GAD67, covalently bound as a Schiff base
      at the active-site lysine (Lys405).
    action: ACCEPT
    reason: PLP binding is a genuine, core cofactor-binding function required for glutamate
      decarboxylase catalysis; independently supported by the crystal structure and
      UniProt COFACTOR/MOD_RES annotations.
    supported_by:
    - reference_id: file:human/GAD1/GAD1-uniprot.txt
      supporting_text: 'Name=pyridoxal 5'
    - reference_id: PMID:17384644
      supporting_text: glutamic acid decarboxylase (GAD65 and
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: Bare protein binding (IPI) from a proteome-scale yeast two-hybrid interactome
      screen (CCSB-HI1). Uninformative as to GAD1's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic protein binding term conveys no specific functional information
      and derives from a high-throughput binary interactome screen rather than a curated
      functional interaction; per curation guidelines the bare term is over-annotated.
      Retained (not removed) as it records a real experimental interaction.
    supported_by:
    - reference_id: PMID:16189514
      supporting_text: an initial version of a proteome-scale map of
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17474147
  qualifier: enables
  review:
    summary: Bare protein binding (IPI) from an SH3-domain peptide-array (PATS) systematic
      interaction screen.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic protein binding derived from a high-throughput SH3
      domain-ligand screen; no specific functional MF is conveyed. Retained as a recorded
      interaction rather than removed.
    supported_by:
    - reference_id: PMID:17474147
      supporting_text: Systematic identification of SH3 domain-mediated human protein-protein
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21516116
  qualifier: enables
  review:
    summary: Bare protein binding (IPI) from a next-generation-sequencing-based (Stitch-seq)
      high-throughput Y2H interactome dataset.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic, uninformative protein binding from a proteome-scale interactome-mapping
      method; provides no specific molecular function. Kept as a recorded interaction.
    supported_by:
    - reference_id: PMID:21516116
      supporting_text: massively parallel interactome-mapping pipeline, Stitch-seq
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Bare protein binding (IPI) from a proteome-scale human binary interactome
      map (HI-II-14).
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic protein binding from a systematic binary interactome
      screen; no specific MF conveyed. Retained rather than removed as it records genuine
      high-throughput interaction data.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: a systematic map of ?14,000 high-quality human
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26871637
  qualifier: enables
  review:
    summary: Bare protein binding (IPI) from an isoform-resolved interactome study of
      alternatively spliced ORFs.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding from a high-throughput isoform interaction-profiling
      study; not an informative molecular function term. Kept as recorded interaction
      evidence.
    supported_by:
    - reference_id: PMID:26871637
      supporting_text: Widespread Expansion of Protein Interaction Capabilities by
        Alternative
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: Bare protein binding (IPI) from a large-scale study of interaction disruption
      by human genetic variants (Y2H/PCA).
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic protein binding from a high-throughput variant-interactome
      screen; conveys no specific molecular function. Retained as a recorded interaction.
    supported_by:
    - reference_id: PMID:31515488
      supporting_text: Extensive disruption of protein interactions by genetic variants
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Bare protein binding (IPI) from the HuRI human reference binary interactome
      map.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic, uninformative protein binding from an all-by-all proteome-wide binary
      interactome screen; no specific MF is conveyed. Kept as a recorded interaction
      rather than removed.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: reference interactome map of human binary protein interactions,
        or 'HuRI'
- term:
    id: GO:0006540
    label: GABA shunt
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Electronic (Ensembl ortholog-transfer) annotation to the GABA shunt, the
      metabolic bypass in which glutamate is decarboxylated to GABA and GABA is subsequently
      transaminated and oxidized back into the TCA cycle. GAD1 catalyzes the entry
      (decarboxylation) step.
    action: KEEP_AS_NON_CORE
    reason: GAD1 genuinely participates in the GABA shunt as the glutamate-decarboxylation
      step, but the shunt as a whole is a multi-enzyme metabolic process; the gene's
      core process is more precisely GABA biosynthesis. Retained as a non-core metabolic-context
      process.
    supported_by:
    - reference_id: file:human/GAD1/GAD1-uniprot.txt
      supporting_text: 'L-glutamate + H(+) = 4-aminobutanoate + CO2'
- term:
    id: GO:0009449
    label: GABA biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Electronic (ARBA) annotation to GABA biosynthetic process, duplicating
      the IBA annotation to the same core biological process.
    action: ACCEPT
    reason: Correct core process; the ARBA electronic mapping agrees with the phylogenetic
      and experimental evidence for GABA synthesis.
    supported_by:
    - reference_id: PMID:17384644
      supporting_text: GAD67 is constitutively active and is responsible for basal
        GABA production.
- term:
    id: GO:0006540
    label: GABA shunt
  evidence_type: IDA
  original_reference_id: PMID:17384644
  qualifier: involved_in
  review:
    summary: Experimental (IDA) annotation to the GABA shunt based on the structural/biochemical
      characterization of GAD67 catalyzing L-glutamate decarboxylation to GABA, the
      committed entry step of the shunt.
    action: KEEP_AS_NON_CORE
    reason: Directly supported by experimental characterization of the decarboxylation
      step, but the shunt is a multi-enzyme metabolic process; GAD1's own core process
      is GABA biosynthesis. Deferring to the curator's experimental annotation, kept
      as non-core metabolic context.
    supported_by:
    - reference_id: PMID:17384644
      supporting_text: GAD67 shows a tethered loop covering the active site, providing
        a catalytic
- term:
    id: GO:0004351
    label: glutamate decarboxylase activity
  evidence_type: IDA
  original_reference_id: PMID:17384644
  qualifier: enables
  review:
    summary: Experimental (IDA) annotation to glutamate decarboxylase activity from
      crystallographic and kinetic characterization of human GAD67, the definitive
      molecular function of the gene.
    action: ACCEPT
    reason: This is the gold-standard experimental support for the core catalytic function;
      the structure shows a tethered catalytic loop sustaining constitutive GABA production.
    supported_by:
    - reference_id: PMID:17384644
      supporting_text: GAD67 is constitutively active and is responsible for basal
        GABA production.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IDA
  original_reference_id: PMID:17384644
  qualifier: enables
  review:
    summary: Experimental (IDA) annotation to identical protein binding, reflecting
      the fact that catalytically active GAD67 is a homodimer, as established by the
      crystal structure.
    action: ACCEPT
    reason: Homodimerization is a structurally verified, functionally relevant property
      of GAD67 (the active enzyme is a homodimer); identical protein binding is the
      appropriate specific MF term.
    supported_by:
    - reference_id: file:human/GAD1/GAD1-uniprot.txt
      supporting_text: 'Homodimer.'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-888589
  qualifier: located_in
  review:
    summary: Reactome (TAS) localization to the plasma membrane, derived from a GABA-release-at-the-synapse
      pathway context. GAD67 is a soluble cytosolic enzyme and does not itself reside
      in the plasma membrane.
    action: MARK_AS_OVER_ANNOTATED
    reason: This localization reflects the pathway/reaction context (synaptic GABA release)
      rather than the intrinsic subcellular location of GAD67, which is cytosolic.
      Unlike the palmitoylated paralog GAD65, GAD67 has no membrane-targeting features.
    supported_by:
    - reference_id: file:human/GAD1/GAD1-uniprot.txt
      supporting_text: 'Belongs to the group II decarboxylase family'
- term:
    id: GO:0061202
    label: clathrin-sculpted gamma-aminobutyric acid transport vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-888572
  qualifier: located_in
  review:
    summary: Reactome (TAS) localization to the clathrin-sculpted GABA transport vesicle
      membrane, a GABA-synthesis/vesicle-loading pathway context. GAD67 is a soluble
      cytosolic enzyme rather than an integral/peripheral vesicle-membrane protein.
    action: MARK_AS_OVER_ANNOTATED
    reason: Pathway-context localization; the membrane association is characteristic
      of the palmitoylated GAD65 isoform, whereas GAD67 acts in the cytosol. Overstates
      GAD67's own subcellular location.
    supported_by:
    - reference_id: file:human/GAD1/GAD1-uniprot.txt
      supporting_text: 'Belongs to the group II decarboxylase family'
- term:
    id: GO:0061202
    label: clathrin-sculpted gamma-aminobutyric acid transport vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-888577
  qualifier: located_in
  review:
    summary: Reactome (TAS) localization to the clathrin-sculpted GABA transport vesicle
      membrane (duplicate pathway-context annotation, from the GAD2 GABA-synthesis
      reaction). GAD67 is cytosolic.
    action: MARK_AS_OVER_ANNOTATED
    reason: Same pathway-context over-localization as the other GO:0061202 annotations;
      this reaction is actually the GAD2 (GAD65) synthesis step. GAD67 itself is soluble
      cytosolic.
    supported_by:
    - reference_id: file:human/GAD1/GAD1-uniprot.txt
      supporting_text: 'Belongs to the group II decarboxylase family'
- term:
    id: GO:0061202
    label: clathrin-sculpted gamma-aminobutyric acid transport vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-888589
  qualifier: located_in
  review:
    summary: Reactome (TAS) localization to the clathrin-sculpted GABA transport vesicle
      membrane (duplicate pathway-context annotation, from the GABA-release reaction).
      GAD67 is cytosolic.
    action: MARK_AS_OVER_ANNOTATED
    reason: Duplicate pathway-context over-localization; GAD67 does not itself reside
      in the vesicle membrane.
    supported_by:
    - reference_id: file:human/GAD1/GAD1-uniprot.txt
      supporting_text: 'Belongs to the group II decarboxylase family'
- term:
    id: GO:0061202
    label: clathrin-sculpted gamma-aminobutyric acid transport vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-917744
  qualifier: located_in
  review:
    summary: Reactome (TAS) localization to the clathrin-sculpted GABA transport vesicle
      membrane (duplicate pathway-context annotation, from the vesicle docking/priming
      reaction). GAD67 is cytosolic.
    action: MARK_AS_OVER_ANNOTATED
    reason: Duplicate pathway-context over-localization; not an intrinsic location of
      soluble cytosolic GAD67.
    supported_by:
    - reference_id: file:human/GAD1/GAD1-uniprot.txt
      supporting_text: 'Belongs to the group II decarboxylase family'
- term:
    id: GO:0004351
    label: glutamate decarboxylase activity
  evidence_type: IDA
  original_reference_id: PMID:10671565
  qualifier: enables
  review:
    summary: Experimental (IDA) annotation to glutamate decarboxylase activity. This
      study establishes GAD67 enzymatic activity while characterizing a non-neural
      splice variant (GAD25/isoform 3) that lacks decarboxylase activity.
    action: ACCEPT
    reason: Supports the core catalytic activity of full-length GAD67; the paper explicitly
      contrasts active GAD67 with the enzymatically inactive GAD25 isoform.
    supported_by:
    - reference_id: PMID:10671565
      supporting_text: This transcript directs the synthesis of a protein without GAD
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10671565
  qualifier: enables
  review:
    summary: Bare protein binding (IPI) associated with the GAD25/GAD67 splice-variant
      study (interactant UniProtKB:Q05329). Uninformative generic MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic protein binding term conveys no specific molecular function;
      per curation guidelines it is over-annotated. Retained as a recorded interaction
      rather than removed, deferring to the curator's IPI.
    supported_by:
    - reference_id: PMID:10671565
      supporting_text: a third form of
- term:
    id: GO:0006538
    label: L-glutamate catabolic process
  evidence_type: TAS
  original_reference_id: PMID:10671565
  qualifier: involved_in
  review:
    summary: Author-statement (TAS) annotation to L-glutamate catabolic process. GAD67
      consumes L-glutamate as substrate in the decarboxylation to GABA, so glutamate
      is catabolized in this reaction.
    action: ACCEPT
    reason: Correct broader biological process - decarboxylation of L-glutamate is a
      glutamate catabolic step; complements the GABA biosynthetic process annotation
      by describing the fate of the substrate.
    supported_by:
    - reference_id: file:human/GAD1/GAD1-uniprot.txt
      supporting_text: 'L-glutamate + H(+) = 4-aminobutanoate + CO2'
- term:
    id: GO:0012506
    label: vesicle membrane
  evidence_type: NAS
  original_reference_id: PMID:10671565
  qualifier: located_in
  review:
    summary: Non-traceable author statement (NAS) localizing GAD to the vesicle membrane.
      GAD67 is a soluble cytosolic enzyme; membrane/vesicle association is a property
      of the palmitoylated GAD65 isoform rather than GAD67.
    action: MARK_AS_OVER_ANNOTATED
    reason: NAS localization that overstates GAD67's subcellular location; GAD67 has
      no membrane-anchoring modifications and acts in the cytosol. Kept (not removed)
      but flagged as an over-annotation of the intrinsic location.
    supported_by:
    - reference_id: file:human/GAD1/GAD1-uniprot.txt
      supporting_text: 'Belongs to the group II decarboxylase family'
- term:
    id: GO:0006540
    label: GABA shunt
  evidence_type: TAS
  original_reference_id: PMID:1549570
  qualifier: involved_in
  review:
    summary: Author-statement (TAS) annotation to the GABA shunt from the cDNA-cloning
      paper that established the two human GAD genes and their enzymatic activity.
    action: KEEP_AS_NON_CORE
    reason: GAD1 catalyzes the entry step of the GABA shunt; retained as a non-core
      metabolic-context process (core process is GABA biosynthesis). The cited paper
      confirms both GADs encode enzymatically active decarboxylases.
    supported_by:
    - reference_id: PMID:1549570
      supporting_text: Both cDNAs direct the synthesis of enzymatically active GADs
        in
- term:
    id: GO:0007268
    label: chemical synaptic transmission
  evidence_type: TAS
  original_reference_id: PMID:8954991
  qualifier: involved_in
  review:
    summary: Author-statement (TAS) annotation to chemical synaptic transmission. GAD67
      contributes to inhibitory neurotransmission indirectly by supplying GABA; the
      cited GAD65-knockout study shows GAD67 maintains brain GABA levels and its loss
      relates to seizure susceptibility.
    action: KEEP_AS_NON_CORE
    reason: Synaptic transmission is a downstream physiological consequence of GAD1's
      GABA-synthesizing activity rather than its own molecular action; kept as a non-core
      process annotation.
    supported_by:
    - reference_id: PMID:8954991
      supporting_text: levels of mRNA and protein were largely unchanged by the GAD65
        mutation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Proposed specific cytosolic localization for GAD67. GAD67 is a soluble
      cytosolic enzyme lacking the membrane-targeting modifications of GAD65; cytosol
      is the compartment where its constitutive GABA synthesis occurs, refining the
      existing cytoplasm (GO:0005737) IBA annotation.
    action: NEW
    reason: Added to record the specific cytosolic location used in core_functions;
      it refines the existing cytoplasm IBA annotation to the compartment in which
      soluble GAD67 acts.
    supported_by:
    - reference_id: file:human/GAD1/GAD1-uniprot.txt
      supporting_text: 'Belongs to the group II decarboxylase family'
core_functions:
- description: Pyridoxal-5'-phosphate-dependent decarboxylation of L-glutamate to gamma-aminobutyric
    acid (GABA) plus CO2 in the cytosol, providing constitutive (basal) synthesis of
    the major inhibitory neurotransmitter GABA. GAD67 uses PLP covalently bound at
    an active-site lysine and functions as a homodimer.
  molecular_function:
    id: GO:0004351
    label: glutamate decarboxylase activity
  directly_involved_in:
  - id: GO:0009449
    label: GABA biosynthetic process
  - id: GO:0006538
    label: L-glutamate catabolic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:17384644
    supporting_text: GAD67 is constitutively active and is responsible for basal GABA
      production.
  - reference_id: file:human/GAD1/GAD1-uniprot.txt
    supporting_text: 'L-glutamate + H(+) = 4-aminobutanoate + CO2'
- description: Binding of the cofactor pyridoxal 5'-phosphate (PLP), which is essential
    for the decarboxylase catalytic mechanism; PLP forms a Schiff base with the active-site
    lysine (Lys405) of GAD67.
  molecular_function:
    id: GO:0030170
    label: pyridoxal phosphate binding
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/GAD1/GAD1-uniprot.txt
    supporting_text: 'Name=pyridoxal 5'
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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10671565
  title: Alternative splicing of GAD67 results in the synthesis of a third form of
    glutamic-acid decarboxylase in human islets and other non-neural tissues.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. Establishes GAD67 enzymatic activity and describes
      the enzymatically inactive GAD25 splice variant (isoform 3) in non-neural tissues.
      Source of IDA for glutamate decarboxylase activity and TAS for L-glutamate catabolic
      process. Abstract-only cache.
- id: PMID:1549570
  title: Two human glutamate decarboxylases, 65-kDa GAD and 67-kDa GAD, are each encoded
    by a single gene.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. Cloning of human GAD65 and GAD67 cDNAs; shows both
      encode enzymatically active decarboxylases (EC 4.1.1.15) and maps GAD67 to 2q31.
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. Proteome-scale Y2H interactome (CCSB-HI1); source
      of a bare protein-binding IPI. Not informative about GAD1's specific function.
- id: PMID:17384644
  title: GABA production by glutamic acid decarboxylase is regulated by a dynamic
    catalytic loop.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. Crystal structures of GAD67 and GAD65; establishes
      catalytic activity, PLP cofactor, homodimer, and that GAD67 is constitutively
      active for basal GABA production. Primary experimental support (IDA) for the
      core functions. Abstract-only cache.
- id: PMID:17474147
  title: Systematic identification of SH3 domain-mediated human protein-protein interactions
    by peptide array target screening.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. SH3-domain peptide-array (PATS) systematic screen;
      source of a bare protein-binding IPI. Not informative about GAD1's specific function.
- id: PMID:21516116
  title: Next-generation sequencing to generate interactome datasets.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. Stitch-seq NGS-based high-throughput Y2H interactome;
      source of a bare protein-binding IPI. Not informative about GAD1's specific function.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. Systematic binary interactome map (HI-II-14); source
      of a bare protein-binding IPI. Not informative about GAD1's specific function.
- id: PMID:26871637
  title: Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. Isoform-resolved interactome profiling; source of
      bare protein-binding IPIs. Not informative about GAD1's specific function.
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the
    allele frequency spectrum in human populations.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. Variant-interactome disruption study (Y2H/PCA);
      source of a bare protein-binding IPI. Not informative about GAD1's specific function.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. HuRI all-by-all human binary interactome reference
      map; source of bare protein-binding IPIs. Not informative about GAD1's specific
      function.
- id: PMID:8954991
  title: Mice lacking the 65 kDa isoform of glutamic acid decarboxylase (GAD65) maintain
    normal levels of GAD67 and GABA in their brains but are susceptible to seizures.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified. GAD65-knockout mice retain normal GAD67 and brain
      GABA levels but are seizure-prone, supporting GAD67's role as the constitutive
      GABA-synthesizing enzyme and its link to synaptic (inhibitory) transmission.
- id: Reactome:R-HSA-888572
  title: PXLP-K405-GAD1 decarboxylates L-Glu to form GABA
  findings: []
- id: Reactome:R-HSA-888577
  title: Synthesis of GABA by GAD2
  findings: []
- id: Reactome:R-HSA-888589
  title: Release of GABA at the synapse
  findings: []
- id: Reactome:R-HSA-917744
  title: GABA loaded synaptic vesicle Docking and Priming
  findings: []
- id: file:human/GAD1/GAD1-uniprot.txt
  title: UniProt entry Q99259 (DCE1_HUMAN), Glutamate decarboxylase 1
  findings: []
suggested_questions:
- question: To what extent is GAD67 (versus GAD65) responsible for the pool of GABA
    that supports phasic synaptic inhibition rather than only tonic/basal GABA, and
    does GAD67 have a physiologically meaningful presence at the presynaptic active
    zone in human neurons?
- question: Which of the reported GAD1 disease phenotypes (developmental and epileptic
    encephalopathy vs spastic cerebral palsy / spastic paraplegia) are robustly attributable
    to GAD1 loss of function, given that one cerebral-palsy pedigree was later reattributed
    to HPDL?
suggested_experiments:
- description: Fractionation and imaging of endogenous GAD67 in human GABAergic neurons
    to quantify the cytosolic versus membrane/vesicle-associated pools and directly
    test the Reactome-derived vesicle-membrane localization annotations.
- description: Enzyme kinetics and thermal/holo-apo stability comparison of recombinant
    wild-type GAD67 versus disease-associated variants (e.g. DEE89 alleles) to link
    specific mutations to loss of decarboxylase activity and PLP cofactor binding.