id: O94925
gene_symbol: GLS
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  GLS (kidney-type glutaminase, also known as GLS1) is a mitochondrial,
  phosphate-activated glutaminase (EC 3.5.1.2) that catalyzes the hydrolytic
  deamidation of L-glutamine to L-glutamate plus ammonia, the first and
  committed step of glutaminolysis. The gene produces two catalytically active
  splice isoforms, KGA (isoform 1) and the shorter GAC/glutaminase C (isoform 3),
  and a catalytically inactive muscle isoform GAM (isoform 2). The enzyme is
  synthesized as a ~74-kDa cytosolic precursor that is imported into mitochondria
  and processed by the mitochondrial-processing peptidase into mature 68- and
  65-kDa chains that reside in the mitochondrial matrix. It assembles into
  homotetramers (dimers of dimers), and phosphate-driven tetramerization is
  coupled to catalytic activation; C-terminal ankyrin repeats modulate higher-order
  assembly. The glutamate produced feeds the TCA cycle (via glutamate
  dehydrogenase and transaminases to alpha-ketoglutarate) for energy and
  anaplerosis. GLS is central to renal ammoniagenesis and acid-base homeostasis,
  to the brain glutamate/glutamine cycle that supplies neurotransmitter glutamate,
  and to the elevated glutamine metabolism of many proliferating cancers, where it
  is an actively pursued drug target (allosteric inhibitors such as BPTES and
  CB-839/telaglenastat). Loss-of-function GLS variants cause severe neonatal
  developmental and epileptic encephalopathy and a global developmental
  delay/ataxia syndrome, whereas a gain-of-function variant causes cataract with
  glutamate excess and profound developmental delay.
alternative_products:
- name: 1 (KGA {ECO:0000303|PubMed:22228304,)
  id: O94925-1
- name: 2 (GAM)
  id: O94925-2
  sequence_note: VSP_001765, VSP_001766
- name: 3 (Glutaminase C {ECO:0000303|PubMed:22228304}, GAC)
  id: O94925-3
  sequence_note: VSP_001767
existing_annotations:
- term:
    id: GO:0004359
    label: glutaminase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetically-inferred glutaminase activity. This is the well-established
      core molecular function of GLS, confirmed directly by multiple experimental
      structural-enzymology studies and by the UniProt catalytic-activity annotation
      (EC 3.5.1.2, L-glutamine + H2O = L-glutamate + NH4+).
    action: ACCEPT
    supported_by:
    - reference_id: file:human/GLS/GLS-uniprot.txt
      supporting_text: "Reaction=L-glutamine + H2O = L-glutamate + NH4(+);"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic inference that GLS is active in the mitochondrion. Correct: the
      mature enzyme is a mitochondrial (matrix) protein. Accepted as a core location.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:22228304
      supporting_text: "GAC is distinctly mitochondrial"
- term:
    id: GO:0006543
    label: L-glutamine catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetically-inferred involvement in glutamine catabolism. This is the
      core biological process for GLS (glutaminolysis begins with glutamine
      hydrolysis). Accepted; also supported directly by IDA (PMID:22049910).
    action: ACCEPT
- term:
    id: GO:0004359
    label: glutaminase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic assertion of glutaminase activity (multiple IEA methods, incl.
      RHEA/EC/InterPro). Correct and redundant with the experimental annotations of
      the same term. Accepted as core MF.
    action: ACCEPT
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UniProt SubCell mapping to mitochondrion. Correct core location; redundant with
      experimental mitochondrial annotations.
    action: ACCEPT
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Electronic assertion of mitochondrial matrix localization. Consistent with the
      mature 68-/65-kDa chains being matrix proteins per UniProt. This is the specific
      compartment within the mitochondrion; accepted.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/GLS/GLS-uniprot.txt
      supporting_text: "Mitochondrion matrix {ECO:0000250|UniProtKB:P13264}."
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UniProt SubCell mapping to cytosol. This reflects the ~74-kDa cytosolic
      precursor of isoform 1 before mitochondrial import, not a steady-state site of
      catalysis. Real but transient/non-core; keep as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: file:human/GLS/GLS-uniprot.txt
      supporting_text: "Cytoplasm, cytosol"
- term:
    id: GO:0006520
    label: amino acid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA electronic annotation to the very general parent 'amino acid metabolic
      process'. Not wrong, but far less informative than the specific L-glutamine
      catabolic / L-glutamate biosynthetic terms that are directly supported. Keep as
      a non-core general grouping term.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0006541
    label: L-glutamine metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO electronic annotation to 'L-glutamine metabolic process', the parent
      of the specific catabolic term. Correct but general; the specific child
      GO:0006543 (L-glutamine catabolic process) is the appropriate core term and is
      already annotated. Generalize/keep as non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0006543
    label: L-glutamine catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl-Compara electronic transfer of glutamine catabolic process. Correct core
      BP; redundant with IBA and IDA annotations of the same term.
    action: ACCEPT
- term:
    id: GO:0051289
    label: protein homotetramerization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic transfer of protein homotetramerization. GLS does form homotetramers
      (dimers of dimers), so this captures a real quaternary-structure property rather
      than the enzyme's pathway function. Keep as non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0097054
    label: L-glutamate biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic transfer of L-glutamate biosynthetic process. This is the product
      side of the glutaminase reaction and is a legitimate core BP; redundant with the
      IDA (PMID:22049910) and TAS (PMID:21757002) annotations of the same term.
    action: ACCEPT
- term:
    id: GO:0062133
    label: negative regulation of L-glutamine biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:16899818
  qualifier: involved_in
  review:
    summary: >-
      Derived from the ATCAY/Caytaxin study (PMID:16899818). That paper shows that
      Caytaxin (ATCAY) binds and inhibits KGA and thereby lowers glutamate; it does
      not show that GLS itself negatively regulates glutamine biosynthesis. GLS
      degrades glutamine (catabolism) rather than regulating its synthesis, so this
      process term is a poor fit for GLS's own function. As an experimental IDA it is
      retained but flagged as an over-annotation.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:16899818
      supporting_text: "It also reduced the steady-state \nlevels of glutamate by inhibiting KGA enzyme activity."
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      HPA immunofluorescence localization to mitochondrion. Consistent with all other
      evidence; accepted as core location.
    action: ACCEPT
- term:
    id: GO:0004359
    label: glutaminase activity
  evidence_type: EXP
  original_reference_id: PMID:22538822
  qualifier: enables
  review:
    summary: >-
      Experimental glutaminase activity from the KGA structure/enzymology study
      (crystal structures with glutamate/glutamine substrate, catalytic-activity
      assays, active-site mutagenesis). Directly establishes the core molecular
      function. Accepted.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:22538822
      supporting_text: "human kidney-type glutaminase isoform (KGA) is becoming an \nattractive target"
- term:
    id: GO:0004359
    label: glutaminase activity
  evidence_type: EXP
  original_reference_id: PMID:24451979
  qualifier: enables
  review:
    summary: >-
      Experimental glutaminase activity confirmed by the cKGA active-site inhibition
      study: glutaminase assays plus active-site mutagenesis (Ser286, Lys289, Tyr249,
      Tyr466) that reduce activity. Directly supports the core MF. Accepted.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:24451979
      supporting_text: "Glutaminase controls the first step in the glutaminolysis pathway by converting glutamine (Gln) to glutamate (Glu)"
- term:
    id: GO:0004359
    label: glutaminase activity
  evidence_type: EXP
  original_reference_id: PMID:26988803
  qualifier: enables
  review:
    summary: >-
      Experimental glutaminase activity from the glutaminase-inhibitor design study,
      which assayed catalytic activity and solved KGA/GAC structures. Supports the
      core MF. Accepted.
    action: ACCEPT
- term:
    id: GO:0004359
    label: glutaminase activity
  evidence_type: EXP
  original_reference_id: PMID:28526749
  qualifier: enables
  review:
    summary: >-
      Experimental glutaminase activity from the glutaminase evolution/structure study
      (full-length KGA crystal structure with catalytic-activity determination).
      Supports the core MF. Accepted.
    action: ACCEPT
- term:
    id: GO:0004359
    label: glutaminase activity
  evidence_type: EXP
  original_reference_id: PMID:29317493
  qualifier: enables
  review:
    summary: >-
      Experimental glutaminase activity from the GAC allosteric-inhibitor study, which
      measured enzymatic activity of recombinant GAC. Supports the core MF. Accepted.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:29317493
      supporting_text: "glutaminase C \n(GAC), which catalyzes the first step in glutamine metabolism"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Sequence-similarity transfer of mitochondrial localization from the rat ortholog
      (P13264). Correct core location; redundant with experimental evidence.
    action: ACCEPT
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: EXP
  original_reference_id: PMID:22228304
  qualifier: located_in
  review:
    summary: >-
      Experimental demonstration that GAC is mitochondrial (subcellular-localization
      analysis). Directly supports the core mitochondrial localization. Accepted.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:22228304
      supporting_text: "GAC is distinctly mitochondrial"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Sequence-similarity transfer of mitochondrial matrix localization from the rat
      ortholog. Consistent with the mature matrix-resident chains; accepted as the
      specific compartment.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/GLS/GLS-uniprot.txt
      supporting_text: "Mitochondrion matrix {ECO:0000250|UniProtKB:P13264}."
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70609
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable assertion placing the glutaminase reaction in the
      mitochondrial matrix. Consistent with UniProt; accepted as the specific
      compartment of catalysis.
    action: ACCEPT
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput mitochondrial proteomics detection of GLS. Consistent with the
      established mitochondrial localization; accepted (corroborating, non-core relative
      to the direct localization studies).
    action: ACCEPT
- term:
    id: GO:0090461
    label: intracellular glutamate homeostasis
  evidence_type: IMP
  original_reference_id: PMID:30239721
  qualifier: involved_in
  review:
    summary: >-
      Supported by the gain-of-function Ser482Cys study: hyperactive GLS raises
      glutamate and lowers glutamine in patient cells, and inhibiting GLS reverses the
      phenotype, directly implicating GLS in setting intracellular glutamate levels.
      Accepted as a physiological process downstream of the core catalytic function.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:30239721
      supporting_text: "increased glutamate and decreased glutamine \nconcentrations were measured in urine and fibroblasts"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16899818
  qualifier: enables
  review:
    summary: >-
      IPI capturing the direct interaction with ATCAY/Caytaxin (Q86WG3), a
      brain-specific regulator that relocalizes GLS and inhibits its activity. The
      interaction is real and biologically meaningful, but bare 'protein binding' is
      uninformative as a molecular function. Retained as evidence of the ATCAY
      interaction but flagged as over-annotation; the regulatory biology is captured in
      the notes.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:16899818
      supporting_text: "binding studies showed that they interact with each other \ndirectly"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:16899818
  qualifier: located_in
  review:
    summary: >-
      Direct localization of KGA to mitochondria (baseline, before ATCAY-induced
      relocalization to neurite terminals). Supports the core mitochondrial location.
      Accepted.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:16899818
      supporting_text: "relocalised \nKGA from the mitochondria to neurite terminals"
- term:
    id: GO:0004359
    label: glutaminase activity
  evidence_type: IDA
  original_reference_id: PMID:22049910
  qualifier: enables
  review:
    summary: >-
      Direct assay of glutaminase activity on full-length human GLS/GAC (kinetics; KM
      for glutamine reported in UniProt). Definitive support for the core molecular
      function. Accepted.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:22049910
      supporting_text: "Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and \nammonia."
- term:
    id: GO:0006543
    label: L-glutamine catabolic process
  evidence_type: IDA
  original_reference_id: PMID:22049910
  qualifier: involved_in
  review:
    summary: >-
      Direct evidence that GLS catalyzes the committed catabolic step for glutamine
      (glutamine -> glutamate + ammonia). Core biological process. Accepted.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:22049910
      supporting_text: "Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and \nammonia."
- term:
    id: GO:0051289
    label: protein homotetramerization
  evidence_type: IDA
  original_reference_id: PMID:22049910
  qualifier: involved_in
  review:
    summary: >-
      Direct structural evidence for the GAC homotetramer (full-length crystal
      structure; BPTES binds at the tetramer interface). This is a genuine
      quaternary-structure property that underlies phosphate activation, but it is not
      the enzyme's core pathway function. Keep as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:22049910
      supporting_text: "Two BPTES molecules bind at an interface region of the GAC \ntetramer"
- term:
    id: GO:0097054
    label: L-glutamate biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:22049910
  qualifier: involved_in
  review:
    summary: >-
      Direct evidence that GLS produces L-glutamate from glutamine. This is the product
      side of the glutaminase reaction and is a legitimate core BP (glutamate
      biosynthesis via glutamine hydrolysis). Accepted.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:22049910
      supporting_text: "Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and \nammonia."
- term:
    id: GO:0097054
    label: L-glutamate biosynthetic process
  evidence_type: TAS
  original_reference_id: PMID:21757002
  qualifier: involved_in
  review:
    summary: >-
      Traceable assertion (FXR/hepatic glutamine-glutamate metabolism review context)
      that glutaminase generates glutamate. Consistent with the core function; the
      cited paper is about FXR regulation of hepatic glutamine/glutamate metabolism and
      only contextually establishes GLS's role. Accepted as corroborating (non-core
      relative to the direct enzymology).
    action: ACCEPT
- term:
    id: GO:0004359
    label: glutaminase activity
  evidence_type: NAS
  original_reference_id: PMID:10719215
  qualifier: enables
  review:
    summary: >-
      Non-traceable/author-stated glutaminase activity from the human brain
      glutaminase cDNA cloning paper (recombinant enzyme was active). Correct core MF;
      redundant with the experimental annotations.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:10719215
      supporting_text: "express high levels of properly processed \nand active glutaminase"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: NAS
  original_reference_id: PMID:10719215
  qualifier: located_in
  review:
    summary: >-
      Author-stated mitochondrial localization inferred from the N-terminal
      mitochondrial targeting signal in the human brain glutaminase cDNA. Correct core
      location; redundant with direct evidence.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:10719215
      supporting_text: "N-terminal mitochondrial targeting signal"
- term:
    id: GO:0006543
    label: L-glutamine catabolic process
  evidence_type: NAS
  original_reference_id: PMID:10719215
  qualifier: involved_in
  review:
    summary: >-
      Author-stated involvement in glutamine metabolism (the cloned enzyme catalyzes a
      key reaction in glutamine metabolism and neurotransmitter synthesis). Core BP;
      redundant with the IBA/IDA annotations.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:10719215
      supporting_text: "a key reaction in the metabolism of glutamine and the synthesis of \nimportant excitatory and inhibitory neurotransmitters"
- term:
    id: GO:0004359
    label: glutaminase activity
  evidence_type: NAS
  original_reference_id: PMID:11015561
  qualifier: enables
  review:
    summary: >-
      Author-stated glutaminase activity from the isoform-cloning paper (hKGA/hGAC are
      active kidney-type glutaminases; hGAC has high glutaminase activity in breast
      cancer cells). Correct core MF; redundant with experimental annotations.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:11015561
      supporting_text: "a high rate \nof glutamine utilization and glutaminase activity"
core_functions:
- description: >-
    Hydrolyzes L-glutamine to L-glutamate and ammonia in the mitochondrial matrix
    (glutaminase activity, EC 3.5.1.2), the first, committed step of glutaminolysis
    that supplies glutamate for TCA-cycle anaplerosis, renal ammoniagenesis, and the
    neuronal glutamate/glutamine cycle.
  molecular_function:
    id: GO:0004359
    label: glutaminase activity
  directly_involved_in:
  - id: GO:0006543
    label: L-glutamine catabolic process
  - id: GO:0097054
    label: L-glutamate biosynthetic process
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: file:human/GLS/GLS-uniprot.txt
    supporting_text: "Reaction=L-glutamine + H2O = L-glutamate + NH4(+);"
  - reference_id: PMID:22049910
    supporting_text: "Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and \nammonia."
  - reference_id: PMID:24451979
    supporting_text: "Glutaminase controls the first step in the glutaminolysis pathway by converting glutamine (Gln) to glutamate (Glu)"
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  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: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:10719215
  title: Isolation, characterization and expression of a human brain mitochondrial
    glutaminase cDNA.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Cloning of the human brain mitochondrial glutaminase cDNA; recombinant enzyme is
      active and carries an N-terminal mitochondrial targeting signal. Abstract-only in
      cache; supports glutaminase activity and mitochondrial localization.
- id: PMID:11015561
  title: Cloning and analysis of unique human glutaminase isoforms generated by tissue-specific
    alternative splicing.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Defines the human KGA, GAC and GAM splice isoforms and their tissue expression;
      GAC is the high-glutaminase-activity isoform in breast cancer cells. GAM (isoform
      2) lacks catalytic activity per UniProt.
- id: PMID:16899818
  title: Brain-specific BNIP-2-homology protein Caytaxin relocalises glutaminase to
    neurite terminals and reduces glutamate levels.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes the direct ATCAY (Caytaxin, Q86WG3)-KGA interaction and shows ATCAY
      inhibits KGA activity and lowers glutamate. Supports the protein-binding IPI and
      the mitochondrial IDA; the derived GO:0062133 process term describes ATCAY's
      regulatory effect rather than a GLS function (flagged as over-annotation).
- id: PMID:21757002
  title: The nuclear receptor FXR regulates hepatic transport and metabolism of glutamine
    and glutamate.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Primarily about FXR regulation of hepatic glutamine/glutamate metabolism; only
      contextually supports glutaminase producing glutamate. Basis for a TAS annotation
      of L-glutamate biosynthetic process.
- id: PMID:22049910
  title: Full-length human glutaminase in complex with an allosteric inhibitor.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      First full-length human GAC crystal structure with kinetic assays; directly
      supports glutaminase activity, glutamine catabolism/glutamate biosynthesis, and
      the homotetramer.
- id: PMID:22228304
  title: Mitochondrial localization and structure-based phosphate activation mechanism
    of Glutaminase C with implications for cancer metabolism.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Demonstrates GAC is mitochondrial and describes the phosphate/tetramerization
      activation mechanism relevant to cancer metabolism. Supports the mitochondrial
      localization annotation.
- id: PMID:22538822
  title: Structural basis for the allosteric inhibitory mechanism of human kidney-type
    glutaminase (KGA) and its regulation by Raf-Mek-Erk signaling in cancer cell metabolism.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      KGA crystal structures with glutamate/glutamine, catalytic-activity assays,
      active-site mutagenesis, and RAF1/MAP2K2 interaction; supports the EXP glutaminase
      activity annotation and the homotetramer/regulation biology.
- id: PMID:24451979
  title: Structural basis for the active site inhibition mechanism of human kidney-type
    glutaminase (KGA).
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text available; cKGA:DON structure and active-site mutagenesis (Ser286,
      Lys289, Tyr249, Tyr466) confirm catalytic residues and glutaminase activity.
- id: PMID:26988803
  title: Design and evaluation of novel glutaminase inhibitors.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Glutaminase-inhibitor design study with KGA/GAC structures and activity assays;
      supports the EXP glutaminase activity annotation.
- id: PMID:28526749
  title: The origin and evolution of human glutaminases and their atypical C-terminal
    ankyrin repeats.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full-length KGA structure and evolutionary/ANK-repeat analysis; determines
      catalytic activity and subunit structure. Supports the EXP glutaminase activity
      annotation and the homotetramer/filament biology.
- id: PMID:29317493
  title: Characterization of the interactions of potent allosteric inhibitors with
    glutaminase C, a key enzyme in cancer cell glutamine metabolism.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      GAC allosteric-inhibitor (UPGL00004/CB-839/BPTES) structural and enzymatic
      characterization; supports the EXP glutaminase activity annotation.
- id: PMID:30239721
  title: GLS hyperactivity causes glutamate excess, infantile cataract and profound
    developmental delay.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Gain-of-function Ser482Cys GLS variant (CASGID) causing glutamate excess;
      functional basis for the intracellular glutamate homeostasis IMP 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-throughput mitochondrial proteome study; corroborates GLS mitochondrial
      localization (HTP evidence).
- id: Reactome:R-HSA-70609
  title: glutamine + H2O => glutamate + NH4+ (GLS)
  findings: []