id: P04075
gene_symbol: ALDOA
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ALDOA encodes fructose-bisphosphate aldolase A, the muscle/red-cell isozyme of the
  ubiquitous class-I fructose-bisphosphate aldolase (three vertebrate isozymes exist:
  A in muscle, B in liver, C in brain). It is a cytosolic homotetramer that uses a
  Schiff-base (active-site lysine) mechanism to catalyze the reversible aldol cleavage
  of beta-D-fructose 1,6-bisphosphate into dihydroxyacetone phosphate (DHAP) and
  D-glyceraldehyde 3-phosphate (EC 4.1.2.13), the fourth step of glycolysis, and the
  reverse aldol condensation in gluconeogenesis. Aldolase A is highly abundant in
  skeletal muscle and erythrocytes. Beyond catalysis it is a well-documented moonlighting
  protein that binds F-actin and other cytoskeletal components (and the actin
  nucleation-promoting factor WASP) via its active-site region, links glycolysis to
  cytoskeletal dynamics, and binds RNA. Loss-of-function variants cause glycogen storage
  disease type XII (aldolase A deficiency), presenting as hereditary nonspherocytic
  hemolytic anemia frequently accompanied by myopathy, exercise intolerance and
  rhabdomyolysis (often triggered by febrile illness).
alternative_products:
- name: '1'
  id: P04075-1
- name: '2'
  id: P04075-2
  sequence_note: VSP_047261
existing_annotations:
- term:
    id: GO:0004332
    label: fructose-bisphosphate aldolase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (PAN-GO) inference of the core catalytic molecular function of
      aldolase A, transferred across the class-I fructose-bisphosphate aldolase family
      (PANTHER PTHR11627). This is correct and central: aldolase A cleaves
      fructose-1,6-bisphosphate to DHAP and glyceraldehyde-3-phosphate (EC 4.1.2.13).
    action: ACCEPT
    reason: >-
      Correct core molecular function, well supported by direct enzymatic and structural
      studies of the human muscle enzyme and consistent across the family.
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "Reaction=beta-D-fructose 1,6-bisphosphate = D-glyceraldehyde 3-"
    - reference_id: PMID:14766013
      supporting_text: >-
        We have identified a new mutation in the FBP (fructose 1,6-bisphosphate)
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic inference that aldolase A acts in the cytosol. Glycolysis/gluconeogenesis
      occur in the cytosol and aldolase A is a soluble cytoplasmic enzyme.
    action: ACCEPT
    reason: >-
      Correct primary subcellular location for the catalytic activity; consistent with
      the cytoplasmic classification in UniProt and with Reactome cytosol annotations.
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "glycolysis and gluconeogenesis (PubMed:14766013). In addition, also"
- term:
    id: GO:0006096
    label: glycolytic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic inference that aldolase A participates in glycolysis. This is the
      canonical biological process for aldolase A (the fourth glycolytic step).
    action: ACCEPT
    reason: >-
      Correct core biological process, supported by direct study of the human enzyme and
      the deficiency phenotype.
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "glycolysis and gluconeogenesis (PubMed:14766013). In addition, also"
- term:
    id: GO:0030388
    label: fructose 1,6-bisphosphate metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic inference; fructose-1,6-bisphosphate is the direct substrate of
      aldolase A, so this metabolic process term is appropriate at the substrate level.
    action: ACCEPT
    reason: >-
      Accurately captures the substrate-level metabolic process (F1,6BP is consumed in
      glycolysis and produced in gluconeogenesis by this enzyme).
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "Reaction=beta-D-fructose 1,6-bisphosphate = D-glyceraldehyde 3-"
- term:
    id: GO:0004332
    label: fructose-bisphosphate aldolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic assignment of the core catalytic activity from InterPro FBA_I signature,
      RHEA:14729 and EC 4.1.2.13. Redundant with experimental/IBA annotations of the same
      function.
    action: ACCEPT
    reason: >-
      Correct core molecular function; the EC/RHEA/InterPro mapping matches the
      experimentally established reaction.
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "ChEBI:CHEBI:32966, ChEBI:CHEBI:57642, ChEBI:CHEBI:59776; EC=4.1.2.13;"
- term:
    id: GO:0006000
    label: fructose metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA electronic inference of involvement in fructose metabolism. Aldolase A acts on
      fructose-1,6-bisphosphate (a fructose derivative); this is broader/context term
      rather than the core glycolytic role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Not incorrect, but general relative to the specific F1,6BP/glycolytic role; kept as
      non-core context. (Unlike the liver isozyme ALDOB, aldolase A is not the principal
      dietary fructolysis enzyme.)
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "Reaction=beta-D-fructose 1,6-bisphosphate = D-glyceraldehyde 3-"
- term:
    id: GO:0006096
    label: glycolytic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic assignment (InterPro/UniPathway) of the glycolytic process, redundant
      with the experimental and IBA glycolysis annotations.
    action: ACCEPT
    reason: >-
      Correct core biological process, consistent with the UniPathway glycolysis step 4/4
      mapping.
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "glycolysis and gluconeogenesis (PubMed:14766013). In addition, also"
- term:
    id: GO:0030388
    label: fructose 1,6-bisphosphate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA electronic assignment of the F1,6BP metabolic process, redundant with the IBA
      and IDA annotations of the same term.
    action: ACCEPT
    reason: >-
      Correct substrate-level metabolic process for aldolase A.
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "Reaction=beta-D-fructose 1,6-bisphosphate = D-glyceraldehyde 3-"
- term:
    id: GO:0031430
    label: M band
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      SubCell keyword mapping placing aldolase A at the sarcomeric M band. UniProt records
      that in skeletal muscle aldolase A accumulates around the M line and within the I
      band (colocalizing with FBP2), by similarity to the rabbit enzyme. This reflects a
      muscle-specific structural association rather than the enzyme's core catalytic role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported as a muscle-specific localization/moonlighting association with the
      contractile apparatus, but not the core (cytosolic) site of glycolytic function.
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "Cytoplasm, myofibril, sarcomere, M line"
- term:
    id: GO:0031674
    label: I band
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      SubCell keyword mapping placing aldolase A at the sarcomeric I band, matching the
      described accumulation within the I band on both sides of the Z line in skeletal
      muscle.
    action: KEEP_AS_NON_CORE
    reason: >-
      Muscle-specific structural localization (moonlighting with the sarcomere), not the
      core cytosolic catalytic site.
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "Cytoplasm, myofibril, sarcomere, I band"
- term:
    id: GO:0070061
    label: fructose binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: >-
      ARBA electronic inference of fructose(-phosphate) binding, matching the direct
      binding of the fructose-1,6-bisphosphate substrate demonstrated crystallographically
      and biochemically.
    action: ACCEPT
    reason: >-
      Correct substrate-binding molecular function directly supported by the crystal
      structure of human muscle aldolase complexed with fructose 1,6-bisphosphate.
    supported_by:
    - reference_id: PMID:10048322
      supporting_text: >-
        Crystals were also soaked with the natural substrate (fructose
        1,6-bisphosphate)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20849852
  qualifier: enables
  review:
    summary: >-
      IntAct-curated binary interaction (with PCNA, P12004) from a study reporting that
      cytoplasmic PCNA associates with several glycolytic enzymes. The bare "protein
      binding" term is uninformative about aldolase A function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation policy, bare protein binding IPIs are marked as over-annotated rather
      than removed; the interaction itself is real but does not convey a specific
      molecular function.
    supported_by:
    - reference_id: PMID:20849852
      supporting_text: >-
        PCNA is also associated with six glycolytic enzymes
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  qualifier: enables
  review:
    summary: >-
      IntAct binary interaction (with ALDOB, P05062) from a large-scale human liver
      protein-interaction network study. Bare protein-binding term, uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding IPI; interaction is real (isozyme co-purification) but conveys
      no specific function.
    supported_by:
    - reference_id: PMID:21988832
      supporting_text: protein interaction network of the human liver
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  qualifier: enables
  review:
    summary: >-
      IntAct binary interaction (with ALDOC, P09972) from a quantitative human interactome
      study. Bare protein-binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding IPI; not informative about aldolase A's molecular function.
    supported_by:
    - reference_id: PMID:26496610
      supporting_text: human interactome in three quantitative dimensions
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: >-
      IntAct binary interaction (with ALDOC, P09972) from a large-scale interactome map.
      Bare protein-binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding IPI; uninformative for molecular function.
    supported_by:
    - reference_id: PMID:28514442
      supporting_text: Architecture of the human interactome
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: >-
      IntAct binary interaction (with ALDOC, P09972) from a study of interaction disruption
      by genetic variants. Bare protein-binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding IPI; uninformative for molecular function.
    supported_by:
    - reference_id: PMID:31515488
      supporting_text: disruption of protein interactions by genetic variants
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      IntAct binary interactions (with ALDOB/ALDOC/CARM1) from dual proteome-scale
      interactome networks. Bare protein-binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding IPI; interactions are real but the term conveys no specific
      function.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: Dual proteome-scale networks reveal cell-specific remodeling
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:10944123
  qualifier: enables
  review:
    summary: >-
      IntAct self-interaction annotation (ALDOA-ALDOA). Aldolase A is a physiological
      homotetramer, so self-association is real, but this generic binding term is not
      the core molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Homo-oligomerization is genuine (homotetramer) and more informative than bare
      protein binding, but it is a structural/assembly property rather than the catalytic
      core function.
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "Homotetramer (By similarity). Interacts with SNX9 and WAS (By"
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  qualifier: enables
  review:
    summary: >-
      IntAct self-interaction annotation (ALDOA-ALDOA) from the human liver interactome
      study, consistent with the homotetrameric assembly.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reflects the real homotetramer, but is a structural property rather than the core
      catalytic function.
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "Homotetramer (By similarity). Interacts with SNX9 and WAS (By"
- term:
    id: GO:0006094
    label: gluconeogenesis
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70263
  qualifier: involved_in
  review:
    summary: >-
      Reactome traceable assertion that aldolase A participates in gluconeogenesis, where
      it catalyzes the reverse aldol condensation of DHAP + G3P into fructose-1,6-bisphosphate.
    action: ACCEPT
    reason: >-
      Correct core process; the aldolase reaction is reversible and functions in both
      glycolysis and gluconeogenesis.
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "glycolysis and gluconeogenesis (PubMed:14766013). In addition, also"
- term:
    id: GO:0061621
    label: canonical glycolysis
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70171
  qualifier: involved_in
  review:
    summary: >-
      Reactome traceable assertion for the canonical (glucose-derived) glycolytic pathway,
      the specific glycolysis subtype for aldolase A.
    action: ACCEPT
    reason: >-
      Correct and appropriately specific core process term.
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "bisphosphate (FBP) into two triose phosphate and plays a key role in"
- term:
    id: GO:0004332
    label: fructose-bisphosphate aldolase activity
  evidence_type: EXP
  original_reference_id: PMID:6696436
  qualifier: enables
  review:
    summary: >-
      Experimental annotation of the core catalytic activity, tied to characterization of
      human skeletal-muscle aldolase (purified from human muscle, sequenced). Supports the
      identity and catalytic function of the muscle isozyme.
    action: ACCEPT
    reason: >-
      Core molecular function, experimentally grounded in the purified human muscle enzyme.
    supported_by:
    - reference_id: PMID:6696436
      supporting_text: >-
        Fructose-1,6-bisphosphate aldolase was purified from human skeletal-muscle
- term:
    id: GO:0061621
    label: canonical glycolysis
  evidence_type: IDA
  original_reference_id: PMID:14766013
  qualifier: involved_in
  review:
    summary: >-
      Direct-assay annotation of the canonical glycolysis role, from functional
      characterization of wild-type and GSD12 mutant human aldolase A enzymes.
    action: ACCEPT
    reason: >-
      Core process; functional/kinetic characterization of the human enzyme supports its
      glycolytic role.
    supported_by:
    - reference_id: PMID:14766013
      supporting_text: >-
        We have identified a new mutation in the FBP (fructose 1,6-bisphosphate)
- term:
    id: GO:0006096
    label: glycolytic process
  evidence_type: IDA
  original_reference_id: PMID:14766013
  qualifier: involved_in
  review:
    summary: >-
      Direct-assay annotation of the glycolytic process, from kinetic characterization of
      human aldolase A and its disease mutants.
    action: ACCEPT
    reason: >-
      Core biological process, directly supported by enzymatic characterization.
    supported_by:
    - reference_id: PMID:14766013
      supporting_text: >-
        We have identified a new mutation in the FBP (fructose 1,6-bisphosphate)
- term:
    id: GO:0035774
    label: positive regulation of insulin secretion involved in cellular response
      to glucose stimulus
  evidence_type: IDA
  original_reference_id: PMID:40446798
  qualifier: involved_in
  review:
    summary: >-
      IDA from a 2025 study showing that a microbial bile acid (Trp-CA) acting through the
      orphan GPCR MRGPRE signals via an MRGPRE-beta-arrestin-1-ALDOA pathway to improve
      glucose homeostasis, implicating aldolase A downstream of a glucose-regulatory
      signaling axis.
    action: KEEP_AS_NON_CORE
    reason: >-
      A genuine but specialized, context-specific signaling role (beta-arrestin-1-ALDOA
      branch of MRGPRE signaling); not the core glycolytic function. Kept as non-core per
      the experimental IDA (curator read the full text).
    supported_by:
    - reference_id: PMID:40446798
      supporting_text: >-
        MRGPRE-β-arrestin-1-aldolase A (ALDOA) signaling pathways contribute to the
        metabolic benefits
- term:
    id: GO:0045296
    label: cadherin binding
  evidence_type: HDA
  original_reference_id: PMID:25468996
  qualifier: enables
  review:
    summary: >-
      High-throughput proximity-biotinylation (BioID) proteomics detected aldolase A among
      hundreds of proteins near the E-cadherin cytoplasmic tail. This is a proximity hit,
      not a demonstrated direct/functional cadherin interaction.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bystander detection in a large proximity-proteomics dataset; not a specific
      functional binding activity of aldolase A. Retained (not removed) as it derives from
      a real experimental dataset.
    supported_by:
    - reference_id: PMID:25468996
      supporting_text: >-
        identify 561 proteins in the vicinity of the cytoplasmic tail of
        E-cadherin
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23355646
  qualifier: enables
  review:
    summary: >-
      IPI (with partner Q12836) from the sperm-head zona-pellucida proteomics study. Bare
      protein-binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding IPI; uninformative about molecular function.
    supported_by:
    - reference_id: PMID:23355646
      supporting_text: >-
        sperm proteins are multifaceted or moonlighting proteins
- term:
    id: GO:0007339
    label: binding of sperm to zona pellucida
  evidence_type: IMP
  original_reference_id: PMID:23355646
  qualifier: involved_in
  review:
    summary: >-
      IMP from a study identifying sperm-head glycolytic enzymes (including aldolase A)
      recognized by antisperm antibodies and reactive with recombinant zona-pellucida
      proteins, and validated in functional zona-binding tests. The authors explicitly
      frame these as moonlighting roles.
    action: KEEP_AS_NON_CORE
    reason: >-
      A plausible moonlighting reproductive role reported experimentally; not the core
      metabolic function. Retained as non-core (defer to the curator's IMP; full text not
      in cache).
    supported_by:
    - reference_id: PMID:23355646
      supporting_text: >-
        functional zona binding tests
- term:
    id: GO:0061827
    label: sperm head
  evidence_type: IDA
  original_reference_id: PMID:23355646
  qualifier: located_in
  review:
    summary: >-
      IDA localizing aldolase A (among other glycolytic enzymes) to the sperm head, though
      the same proteins also function in the flagellum.
    action: KEEP_AS_NON_CORE
    reason: >-
      Specialized cell-type localization consistent with a moonlighting sperm role; not
      the core cytosolic site.
    supported_by:
    - reference_id: PMID:23355646
      supporting_text: >-
        Several of the proteins were localized on the sperm head
- term:
    id: GO:0034774
    label: secretory granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798748
  qualifier: located_in
  review:
    summary: >-
      Reactome localization to secretory granule lumen via the neutrophil-degranulation
      exocytosis pathway, where abundant cytosolic proteins such as aldolase A are cargo
      of granule/secretion events.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reflects granule/secretion proteomics rather than the core cytosolic function; kept
      as non-core.
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "Reactome; R-HSA-6798695; Neutrophil degranulation."
- term:
    id: GO:1904724
    label: tertiary granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798745
  qualifier: located_in
  review:
    summary: >-
      Reactome localization to tertiary granule lumen via the neutrophil-degranulation
      pathway; aldolase A appears as granule cargo.
    action: KEEP_AS_NON_CORE
    reason: >-
      Secretion/granule-proteomics localization, non-core relative to cytosolic glycolysis.
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "Reactome; R-HSA-6798695; Neutrophil degranulation."
- term:
    id: GO:1904813
    label: ficolin-1-rich granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6800434
  qualifier: located_in
  review:
    summary: >-
      Reactome localization to ficolin-1-rich granule lumen via neutrophil degranulation;
      aldolase A is granule cargo.
    action: KEEP_AS_NON_CORE
    reason: >-
      Secretion/granule-proteomics localization, non-core.
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "Reactome; R-HSA-6798695; Neutrophil degranulation."
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:12519789
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomic detection of aldolase A in B cell-derived exosomes. As an
      abundant cytosolic protein, aldolase A is a frequent bystander in exosome proteomes.
    action: KEEP_AS_NON_CORE
    reason: >-
      Bystander localization in exosome proteomics; not the core cytosolic site of
      function.
    supported_by:
    - reference_id: PMID:12519789
      supporting_text: >-
        human B cell-derived exosomes
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: >-
      Proteomic detection of aldolase A in prostatic-secretion (urinary) exosomes; a
      bystander localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Exosome-proteomics bystander detection; non-core.
    supported_by:
    - reference_id: PMID:23533145
      supporting_text: >-
        exosomes isolated from expressed prostatic
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: >-
      Aldolase A detected in an NK-cell membrane-proteome dataset. This likely reflects
      co-purification of the abundant cytosolic enzyme; not a bona fide integral-membrane
      localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-broad/likely-contaminant localization from a membrane-proteome dataset;
      aldolase A has no membrane-spanning features. Retained (not removed) as it derives
      from a real dataset.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: >-
        membrane proteome of NK cells
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:21630459
  qualifier: located_in
  review:
    summary: >-
      Aldolase A detected in a human sperm-nucleus proteome. A bystander/partitioning
      detection rather than an established nuclear function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Proteomic nuclear detection without a demonstrated nuclear function; kept as
      non-core.
    supported_by:
    - reference_id: PMID:21630459
      supporting_text: >-
        human sperm nucleus
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22681889
  qualifier: enables
  review:
    summary: >-
      mRNA-interactome capture (UV-crosslinking + oligo(dT)) identified aldolase A among
      the mRNA-bound proteome. Several glycolytic enzymes are known RNA-binding
      moonlighters, so this is a plausible non-catalytic activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real moonlighting RNA-binding activity detected by interactome capture, but not the
      core catalytic function; kept as non-core.
    supported_by:
    - reference_id: PMID:22681889
      supporting_text: >-
        identify the mRNA-bound proteome
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: HDA
  original_reference_id: PMID:23580065
  qualifier: located_in
  review:
    summary: >-
      Aldolase A detected in tear-fluid shotgun proteomics; a bystander extracellular
      detection of an abundant cytosolic enzyme.
    action: KEEP_AS_NON_CORE
    reason: >-
      Extracellular-fluid proteomics detection; non-core relative to cytosolic function.
    supported_by:
    - reference_id: PMID:23580065
      supporting_text: >-
        in tears of
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19199708
  qualifier: located_in
  review:
    summary: >-
      Aldolase A detected in parotid-gland exosome proteomics; bystander localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Exosome-proteomics bystander detection; non-core.
    supported_by:
    - reference_id: PMID:19199708
      supporting_text: >-
        human parotid gland exosomes
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: >-
      Aldolase A detected in urinary-exosome proteomics; bystander localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Exosome-proteomics bystander detection; non-core.
    supported_by:
    - reference_id: PMID:19056867
      supporting_text: >-
        proteomics and phosphoproteomics of urinary exosomes
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:20458337
  qualifier: located_in
  review:
    summary: >-
      Aldolase A detected in B-cell exosome proteomics; bystander localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Exosome-proteomics bystander detection; non-core.
    supported_by:
    - reference_id: PMID:20458337
      supporting_text: >-
        MHC class II-associated proteins in B-cell exosomes
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-481007
  qualifier: located_in
  review:
    summary: >-
      Reactome localization to extracellular region via platelet alpha-granule exocytosis;
      abundant cytosolic aldolase A appears as granule/secretion cargo.
    action: KEEP_AS_NON_CORE
    reason: >-
      Secretion-pathway localization, non-core relative to cytosolic function.
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "Reactome; R-HSA-114608; Platelet degranulation."
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798745
  qualifier: located_in
  review:
    summary: >-
      Reactome extracellular-region localization via neutrophil-degranulation exocytosis.
    action: KEEP_AS_NON_CORE
    reason: >-
      Secretion-pathway localization, non-core.
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "Reactome; R-HSA-6798695; Neutrophil degranulation."
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798748
  qualifier: located_in
  review:
    summary: >-
      Reactome extracellular-region localization via neutrophil-degranulation exocytosis.
    action: KEEP_AS_NON_CORE
    reason: >-
      Secretion-pathway localization, non-core.
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "Reactome; R-HSA-6798695; Neutrophil degranulation."
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6800434
  qualifier: located_in
  review:
    summary: >-
      Reactome extracellular-region localization via neutrophil-degranulation exocytosis.
    action: KEEP_AS_NON_CORE
    reason: >-
      Secretion-pathway localization, non-core.
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "Reactome; R-HSA-6798695; Neutrophil degranulation."
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71495
  qualifier: located_in
  review:
    summary: >-
      Reactome cytosol localization for the aldolase reaction (DHAP + G3P -> F1,6BP,
      gluconeogenic direction). Correct core localization.
    action: ACCEPT
    reason: >-
      Correct primary cytosolic localization for aldolase A catalysis.
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "glycolysis and gluconeogenesis (PubMed:14766013). In addition, also"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71496
  qualifier: located_in
  review:
    summary: >-
      Reactome cytosol localization for the aldolase reaction (F1,6BP cleavage, glycolytic
      direction). Correct core localization.
    action: ACCEPT
    reason: >-
      Correct primary cytosolic localization for aldolase A catalysis.
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "glycolysis and gluconeogenesis (PubMed:14766013). In addition, also"
- term:
    id: GO:0031093
    label: platelet alpha granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-481007
  qualifier: located_in
  review:
    summary: >-
      Reactome localization to platelet alpha-granule lumen via the platelet-degranulation
      pathway; aldolase A appears as granule cargo.
    action: KEEP_AS_NON_CORE
    reason: >-
      Secretion/granule-proteomics localization, non-core.
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "Reactome; R-HSA-114608; Platelet degranulation."
- term:
    id: GO:0051289
    label: protein homotetramerization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer (from rabbit ALDOA, P00883) that aldolase A forms a homotetramer, the
      functional quaternary state established structurally and biochemically.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine (aldolase A is a homotetramer) but a structural/assembly property rather
      than the core catalytic function.
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "Homotetramer (By similarity). Interacts with SNX9 and WAS (By"
- term:
    id: GO:0004332
    label: fructose-bisphosphate aldolase activity
  evidence_type: IDA
  original_reference_id: PMID:9244396
  qualifier: enables
  review:
    summary: >-
      IDA of the core catalytic activity in a study of human aldolase isozyme interactions
      with the cytoskeleton (aldolase A activity assayed alongside its actin binding).
    action: ACCEPT
    reason: >-
      Core molecular function, directly assayed for the human enzyme.
    supported_by:
    - reference_id: PMID:9244396
      supporting_text: >-
        Three isoforms of fructose-1,6-bisphosphate aldolase
- term:
    id: GO:0008092
    label: cytoskeletal protein binding
  evidence_type: IDA
  original_reference_id: PMID:9244396
  qualifier: enables
  review:
    summary: >-
      IDA that aldolase A binds cytoskeletal (actin-containing) filaments; aldolase A binds
      the skeletal-muscle cytoskeleton most tightly among the isozymes, and binding is
      inhibited by substrate (F1,6BP/F1P).
    action: KEEP_AS_NON_CORE
    reason: >-
      Well-documented moonlighting cytoskeletal binding activity, but not the core
      catalytic function.
    supported_by:
    - reference_id: PMID:9244396
      supporting_text: >-
        bound more tightly to the skeletal muscle cytoskeleton among the three isozymes
- term:
    id: GO:0008360
    label: regulation of cell shape
  evidence_type: IDA
  original_reference_id: PMID:9244396
  qualifier: involved_in
  review:
    summary: >-
      IDA that aldolase A, via its actin/cytoskeleton association, reversibly inhibited the
      contraction of permeabilized MRC-5 fibroblasts, suggesting a role in regulating cell
      contraction/shape.
    action: KEEP_AS_NON_CORE
    reason: >-
      A moonlighting cytoskeletal/cell-shape role tied to actin binding, not the core
      metabolic function.
    supported_by:
    - reference_id: PMID:9244396
      supporting_text: >-
        reversibly inhibited the contraction of MRC-5 cells
- term:
    id: GO:0015629
    label: actin cytoskeleton
  evidence_type: IDA
  original_reference_id: PMID:9244396
  qualifier: located_in
  review:
    summary: >-
      IDA localizing aldolase A to the actin cytoskeleton: it bound actin filaments in the
      stress fibers of permeabilized fibroblasts.
    action: KEEP_AS_NON_CORE
    reason: >-
      Moonlighting cytoskeletal localization tied to actin binding; not the core cytosolic
      catalytic site.
    supported_by:
    - reference_id: PMID:9244396
      supporting_text: >-
        A bound to the actin filaments in the stress fibers within the cell. Aldolase A
- term:
    id: GO:0030388
    label: fructose 1,6-bisphosphate metabolic process
  evidence_type: IDA
  original_reference_id: PMID:9244396
  qualifier: involved_in
  review:
    summary: >-
      IDA of the F1,6BP metabolic process, consistent with the catalytic activity assayed
      in this study.
    action: ACCEPT
    reason: >-
      Correct substrate-level metabolic process for aldolase A.
    supported_by:
    - reference_id: PMID:9244396
      supporting_text: >-
        Three isoforms of fructose-1,6-bisphosphate aldolase
- term:
    id: GO:0070061
    label: fructose binding
  evidence_type: IDA
  original_reference_id: PMID:10048322
  qualifier: enables
  review:
    summary: >-
      IDA of fructose(-1,6-bisphosphate) binding, directly supported by the crystal
      structure of human muscle aldolase soaked with the natural substrate.
    action: ACCEPT
    reason: >-
      Correct substrate-binding molecular function, structurally demonstrated.
    supported_by:
    - reference_id: PMID:10048322
      supporting_text: >-
        Crystals were also soaked with the natural substrate (fructose
        1,6-bisphosphate)
- term:
    id: GO:0070061
    label: fructose binding
  evidence_type: IDA
  original_reference_id: PMID:14766013
  qualifier: enables
  review:
    summary: >-
      IDA of substrate (fructose 1,6-bisphosphate) binding from kinetic characterization
      (KM for FBP) of human aldolase A and its mutants.
    action: ACCEPT
    reason: >-
      Correct substrate-binding function, supported by measured KM values for F1,6BP.
    supported_by:
    - reference_id: PMID:14766013
      supporting_text: >-
        We have identified a new mutation in the FBP (fructose 1,6-bisphosphate)
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: IDA
  original_reference_id: PMID:17641064
  qualifier: located_in
  review:
    summary: >-
      Aldolase A detected in human breast-milk exosomes; a bystander localization of an
      abundant cytosolic protein.
    action: KEEP_AS_NON_CORE
    reason: >-
      Exosome-proteomics bystander detection; non-core.
    supported_by:
    - reference_id: PMID:17641064
      supporting_text: >-
        Exosomes with immune modulatory features are present in human breast milk
- term:
    id: GO:0003779
    label: actin binding
  evidence_type: TAS
  original_reference_id: PMID:1008835
  qualifier: enables
  review:
    summary: >-
      TAS that aldolase binds actin-containing filaments (F-actin / F-actin-tropomyosin),
      forming ordered paracrystalline bundles. A classic demonstration of the moonlighting
      actin-binding activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine moonlighting actin-binding activity, distinct from the core catalytic
      function.
    supported_by:
    - reference_id: PMID:1008835
      supporting_text: >-
        when aldolase binds to F-actin or F-actin-tropomyosin, highly ordered
        paracrystalline structures are formed
- term:
    id: GO:0006000
    label: fructose metabolic process
  evidence_type: IMP
  original_reference_id: PMID:14615364
  qualifier: involved_in
  review:
    summary: >-
      IMP from a GSD12 (aldolase A deficiency) case with compound heterozygous ALDOA
      mutations (Arg303X/Cys338Tyr) causing hemolytic anemia and rhabdomyolysis, linking
      loss of aldolase A to disrupted fructose/carbohydrate metabolism.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct in that aldolase A acts on a fructose-derived substrate, but general
      relative to the specific glycolytic role; kept as non-core context.
    supported_by:
    - reference_id: PMID:14615364
      supporting_text: >-
        converts fructose-1,6-bisphosphate to dihydroxyacetone phosphate and
- term:
    id: GO:0006096
    label: glycolytic process
  evidence_type: IMP
  original_reference_id: PMID:14615364
  qualifier: involved_in
  review:
    summary: >-
      IMP linking loss-of-function ALDOA mutations to impaired glycolysis in a severely
      affected aldolase A deficiency patient.
    action: ACCEPT
    reason: >-
      Core biological process; the deficiency phenotype supports the glycolytic role of
      aldolase A.
    supported_by:
    - reference_id: PMID:14615364
      supporting_text: >-
        converts fructose-1,6-bisphosphate to dihydroxyacetone phosphate and
- term:
    id: GO:0006754
    label: ATP biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:14615364
  qualifier: involved_in
  review:
    summary: >-
      IMP attributing an ATP-biosynthesis role to aldolase A, inferred from the muscle
      energy failure (rhabdomyolysis) in aldolase A deficiency. This is a downstream
      consequence of glycolytic flux rather than a direct aldolase function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Indirect/downstream role (glycolytic ATP production) rather than a direct molecular
      activity; kept as non-core, deferring to the curator's full-text IMP.
    supported_by:
    - reference_id: PMID:14615364
      supporting_text: >-
        splenectomy at age 3 and increasing muscle weakness, with death at age 4
- term:
    id: GO:0006941
    label: striated muscle contraction
  evidence_type: IMP
  original_reference_id: PMID:14615364
  qualifier: involved_in
  review:
    summary: >-
      IMP from aldolase A deficiency with muscle weakness and rhabdomyolysis, linking
      aldolase A (energy supply / cytoskeletal association) to striated muscle function.
    action: KEEP_AS_NON_CORE
    reason: >-
      A physiologically relevant but indirect muscle role (via energy metabolism and
      sarcomeric association), not the core molecular function; non-core.
    supported_by:
    - reference_id: PMID:14615364
      supporting_text: >-
        splenectomy at age 3 and increasing muscle weakness, with death at age 4
- term:
    id: GO:0007015
    label: actin filament organization
  evidence_type: TAS
  original_reference_id: PMID:1008835
  qualifier: involved_in
  review:
    summary: >-
      TAS that aldolase organizes actin filaments into ordered paracrystalline bundles,
      an in-vitro demonstration of its actin-crosslinking/organizing moonlighting activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      Moonlighting actin-organizing role (bundle/paracrystal formation), not the core
      catalytic function.
    supported_by:
    - reference_id: PMID:1008835
      supporting_text: >-
        tightly packed filament bundles cross-banded at 36 nm intervals
- term:
    id: GO:0015631
    label: tubulin binding
  evidence_type: TAS
  original_reference_id: PMID:17329259
  qualifier: enables
  review:
    summary: >-
      This annotation cites PMID:17329259, which reports the structural basis of aldolase
      binding to the Wiskott-Aldrich syndrome protein (WASP) via a hydrophobic active-site
      pocket, competitive with substrate and with actin/cortactin. The paper concerns
      actin-related (WASP) binding, not tubulin; tubulin binding is not supported by this
      reference.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The cited reference does not establish tubulin binding; it demonstrates WASP/actin-
      pathway binding at the aldolase active site. Marked as over-annotated rather than
      removed (aldolase is broadly promiscuous, and this is a TAS from the curator).
    supported_by:
    - reference_id: PMID:17329259
      supporting_text: >-
        aldolase binds to highly acidic amino acid sequences, including the C terminus of
        the Wiskott-Aldrich syndrome protein
- term:
    id: GO:0031674
    label: I band
  evidence_type: TAS
  original_reference_id: PMID:1008835
  qualifier: located_in
  review:
    summary: >-
      TAS placing aldolase at the sarcomeric I band, consistent with its documented actin/
      thin-filament association and the muscle-specific accumulation within the I band.
    action: KEEP_AS_NON_CORE
    reason: >-
      Muscle-specific structural localization (moonlighting with the sarcomere/thin
      filament), not the core cytosolic catalytic site.
    supported_by:
    - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
      supporting_text: "Cytoplasm, myofibril, sarcomere, I band"
- term:
    id: GO:0046716
    label: muscle cell cellular homeostasis
  evidence_type: IMP
  original_reference_id: PMID:14615364
  qualifier: involved_in
  review:
    summary: >-
      IMP from aldolase A deficiency, where loss of aldolase A causes myopathy and
      rhabdomyolysis, indicating a role in maintaining muscle-cell homeostasis (energy
      supply / integrity).
    action: KEEP_AS_NON_CORE
    reason: >-
      A physiologically relevant but indirect role (downstream of glycolytic energy
      metabolism); non-core.
    supported_by:
    - reference_id: PMID:14615364
      supporting_text: >-
        splenectomy at age 3 and increasing muscle weakness, with death at age 4
- term:
    id: GO:0004332
    label: fructose-bisphosphate aldolase activity
  evidence_type: IDA
  original_reference_id: PMID:14766013
  qualifier: enables
  review:
    summary: >-
      IDA of the core catalytic activity from kinetic characterization of recombinant human
      aldolase A wild-type and disease mutants (KM/kcat/Tm measurements).
    action: ACCEPT
    reason: >-
      Core molecular function, directly measured for the human enzyme.
    supported_by:
    - reference_id: PMID:14766013
      supporting_text: >-
        We have identified a new mutation in the FBP (fructose 1,6-bisphosphate)
- term:
    id: GO:0030388
    label: fructose 1,6-bisphosphate metabolic process
  evidence_type: IDA
  original_reference_id: PMID:14766013
  qualifier: involved_in
  review:
    summary: >-
      IDA of the F1,6BP metabolic process from functional characterization of human
      aldolase A and its mutants.
    action: ACCEPT
    reason: >-
      Correct substrate-level metabolic process, directly supported.
    supported_by:
    - reference_id: PMID:14766013
      supporting_text: >-
        We have identified a new mutation in the FBP (fructose 1,6-bisphosphate)
core_functions:
- description: >-
    Cytosolic class-I fructose-bisphosphate aldolase that catalyzes the reversible aldol
    cleavage of fructose-1,6-bisphosphate to dihydroxyacetone phosphate and
    glyceraldehyde-3-phosphate in glycolysis (and the reverse condensation in
    gluconeogenesis).
  molecular_function:
    id: GO:0004332
    label: fructose-bisphosphate aldolase activity
  directly_involved_in:
  - id: GO:0006096
    label: glycolytic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
    supporting_text: "Reaction=beta-D-fructose 1,6-bisphosphate = D-glyceraldehyde 3-"
  - reference_id: PMID:14766013
    supporting_text: >-
      We have identified a new mutation in the FBP (fructose 1,6-bisphosphate)
- description: >-
    In gluconeogenesis, the same cytosolic aldolase reaction runs in reverse, condensing
    dihydroxyacetone phosphate and glyceraldehyde-3-phosphate into fructose-1,6-bisphosphate.
  molecular_function:
    id: GO:0004332
    label: fructose-bisphosphate aldolase activity
  directly_involved_in:
  - id: GO:0006094
    label: gluconeogenesis
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/ALDOA/ALDOA-uniprot.txt
    supporting_text: "glycolysis and gluconeogenesis (PubMed:14766013). In addition, also"
references:
- 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: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: file:human/ALDOA/ALDOA-uniprot.txt
  title: UniProtKB entry P04075 (ALDOA_HUMAN), fructose-bisphosphate aldolase A
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Curated UniProt record establishing the class-I aldolase family, Schiff-base
      mechanism, EC 4.1.2.13 reaction, glycolysis/gluconeogenesis roles, homotetramer,
      sarcomere (I band/M line) localization and GSD12 disease association.
- id: PMID:10048322
  title: 'Crystal structure of human muscle aldolase complexed with fructose 1,6-bisphosphate:
    mechanistic implications.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Structure of the human muscle enzyme with bound F1,6BP; supports substrate binding
      and the Schiff-base catalytic mechanism.
- id: PMID:1008835
  title: Aldolase binding to actin-containing filaments. Formation of paracrystals.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Classic demonstration of moonlighting actin binding and actin-filament organization
      (paracrystal formation).
- id: PMID:10944123
  title: Initial enzyme for glycosylphosphatidylinositol biosynthesis requires PIG-P
    and is regulated by DPM2.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Source of an IntAct ALDOA self-interaction annotation; not centrally about ALDOA.
- id: PMID:12519789
  title: Proteomic and biochemical analyses of human B cell-derived exosomes. Potential
    implications for their function and multivesicular body formation.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Exosome proteomics; ALDOA is a bystander localization hit.
- id: PMID:14615364
  title: Hemolytic anemia and severe rhabdomyolysis caused by compound heterozygous
    mutations of the gene for erythrocyte/muscle isozyme of aldolase, ALDOA(Arg303X/Cys338Tyr).
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Aldolase A deficiency (GSD12) case establishing the disease link and, via LOF,
      the glycolytic/muscle-homeostasis role.
- id: PMID:14766013
  title: 'Human aldolase A natural mutants: relationship between flexibility of the
    C-terminal region and enzyme function.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Kinetic/functional characterization of human aldolase A wild-type and GSD12 mutants;
      primary support for the catalytic activity and glycolysis/gluconeogenesis roles.
- id: PMID:17329259
  title: A hydrophobic pocket in the active site of glycolytic aldolase mediates interactions
    with Wiskott-Aldrich syndrome protein.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: MISCITED
    review_notes: >-
      Concerns WASP/actin-pathway binding at the aldolase active site, not tubulin;
      the tubulin-binding annotation citing this paper is not supported by it.
- id: PMID:17641064
  title: Exosomes with immune modulatory features are present in human breast milk.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Exosome proteomics; ALDOA bystander localization.
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Exosome proteomics; ALDOA bystander localization.
- id: PMID:19199708
  title: Proteomic analysis of human parotid gland exosomes by multidimensional protein
    identification technology (MudPIT).
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Exosome proteomics; ALDOA bystander localization.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Membrane-proteome dataset; ALDOA membrane localization is likely a soluble-protein
      co-purification artifact.
- id: PMID:20458337
  title: MHC class II-associated proteins in B-cell exosomes and potential functional
    implications for exosome biogenesis.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Exosome proteomics; ALDOA bystander localization.
- id: PMID:20849852
  title: Proliferating cell nuclear antigen in the cytoplasm interacts with components
    of glycolysis and cancer.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Reports cytoplasmic PCNA associating with glycolytic enzymes; source of a bare
      protein-binding IPI.
- id: PMID:21630459
  title: Proteomic characterization of the human sperm nucleus.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Sperm-nucleus proteomics; ALDOA nuclear localization is a proteomic hit.
- id: PMID:21988832
  title: Toward an understanding of the protein interaction network of the human liver.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Liver interactome; source of ALDOA-ALDOB and ALDOA self-interaction IPIs.
- id: PMID:22681889
  title: The mRNA-bound proteome and its global occupancy profile on protein-coding
    transcripts.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      mRNA-interactome capture identifying ALDOA as RNA-binding (moonlighting).
- id: PMID:23355646
  title: Identification of sperm head proteins involved in zona pellucida binding.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Identifies ALDOA among sperm-head glycolytic enzymes with a possible moonlighting
      zona-pellucida-binding role; authors frame these as moonlighting proteins.
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic
    secretions in urine.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Exosome proteomics; ALDOA bystander localization.
- id: PMID:23580065
  title: Shotgun proteomics reveals specific modulated protein patterns in tears of
    patients with primary open angle glaucoma naïve to therapy.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Tear-fluid proteomics; ALDOA extracellular localization is a bystander hit.
- id: PMID:25468996
  title: E-cadherin interactome complexity and robustness resolved by quantitative
    proteomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      BioID proximity proteomics of the E-cadherin tail; ALDOA is one of hundreds of
      proximity hits (cadherin binding is over-annotated).
- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by stoichiometries
    and abundances.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Large-scale interactome; source of a bare protein-binding IPI.
- 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 interactome; source of a bare protein-binding IPI.
- 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: Interactome-perturbation study; source of a bare protein-binding IPI.
- 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: Large-scale interactome; source of bare protein-binding IPIs.
- id: PMID:40446798
  title: A microbial amino-acid-conjugated bile acid, tryptophan-cholic acid, improves
    glucose homeostasis via the orphan receptor MRGPRE.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Implicates ALDOA in an MRGPRE-beta-arrestin-1-ALDOA signaling branch regulating
      glucose homeostasis (specialized, non-core role).
- id: PMID:6696436
  title: 'Human skeletal-muscle aldolase: N-terminal sequence analysis of CNBr- and
    o-iodosobenzoic acid-cleavage fragments.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Purification and sequencing of human skeletal-muscle aldolase; establishes the
      identity of the muscle enzyme.
- id: PMID:9244396
  title: Mode of interactions of human aldolase isozymes with cytoskeletons.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Primary support for moonlighting cytoskeletal/actin binding by human aldolase A and
      its effect on cell contraction, plus catalytic activity assays.
- id: Reactome:R-HSA-481007
  title: Exocytosis of platelet alpha granule contents
  findings: []
- id: Reactome:R-HSA-6798745
  title: Exocytosis of tertiary granule lumen proteins
  findings: []
- id: Reactome:R-HSA-6798748
  title: Exocytosis of secretory granule lumen proteins
  findings: []
- id: Reactome:R-HSA-6800434
  title: Exocytosis of ficolin-rich granule lumen proteins
  findings: []
- id: Reactome:R-HSA-70171
  title: Glycolysis
  findings: []
- id: Reactome:R-HSA-70263
  title: Gluconeogenesis
  findings: []
- id: Reactome:R-HSA-71495
  title: Aldolase tetramers convert GA3P and DHAP to F1,6PP
  findings: []
- id: Reactome:R-HSA-71496
  title: Aldolase tetramer cleaves F1,6PP
  findings: []