id: P05062
gene_symbol: ALDOB
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  Fructose-bisphosphate aldolase B (liver-type aldolase; EC 4.1.2.13) is the
  liver/kidney/intestine isozyme of the vertebrate class I (Schiff-base)
  fructose-1,6-bisphosphate aldolases. It is a cytosolic homotetramer that
  catalyzes reversible aldol cleavage using an active-site lysine (Lys230) that
  forms a Schiff-base intermediate with dihydroxyacetone phosphate and an
  aspartate proton acceptor (Asp188). Aldolase B has two physiologically
  important activities in the same active site: it cleaves fructose
  1,6-bisphosphate into dihydroxyacetone phosphate and D-glyceraldehyde
  3-phosphate (a step shared with glycolysis and, in reverse, gluconeogenesis),
  and it cleaves dietary-derived fructose 1-phosphate into dihydroxyacetone
  phosphate and D-glyceraldehyde in fructolysis. Relative to the muscle (ALDOA)
  and brain (ALDOC) isozymes, aldolase B shows comparatively high activity
  toward fructose 1-phosphate, making it the principal enzyme of hepatic
  fructose metabolism. Loss-of-function variants cause hereditary fructose
  intolerance (HFI), an autosomal recessive disease in which fructose ingestion
  leads to accumulation of fructose 1-phosphate, ATP/phosphate depletion,
  hypoglycemia, and hepatic and renal toxicity. Beyond catalysis, aldolase B
  has reported non-catalytic (moonlighting) roles, including acting as a
  scaffold in a ternary complex with glucose-6-phosphate dehydrogenase (G6PD)
  and TP53 that restrains oxidative pentose phosphate pathway flux, physical
  association with the vacuolar H+-ATPase, and binding to the actin
  cytoskeleton and Bardet-Biedl syndrome proteins.
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 (IBA) inference of the core class I aldolase catalytic
      activity, cleavage of fructose 1,6-bisphosphate to DHAP + G3P. This is the
      defining molecular function of ALDOB and is strongly supported by direct
      experimental and structural work.
    action: ACCEPT
    reason: >-
      This is the canonical, well-established molecular function of aldolase B
      (EC 4.1.2.13), supported by biochemical characterization of the human
      enzyme and its HFI variants and by the crystal structure. The IBA is at
      the correct level of specificity.
    supported_by:
    - reference_id: PMID:10625657
      supporting_text: "reversible cleavage of phosphofructose esters into cognate triose"
- 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 B is active in the cytosol, the
      compartment where glycolysis, gluconeogenesis, and fructolysis occur.
    action: ACCEPT
    reason: >-
      Aldolase B is a soluble cytosolic enzyme; the cytosolic localization is
      corroborated by direct experimental annotation (PMID:35122041) and
      Reactome. Correct compartment for the enzyme's activity.
- 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 B participates in glycolysis via the
      F1,6BP aldol cleavage step.
    action: ACCEPT
    reason: >-
      Aldolase catalyzes step 4 of glycolysis (F1,6BP -> DHAP + G3P); this is a
      core biological process for the enzyme and is supported by direct
      annotation and the UniProt PATHWAY statement (glycolysis step 4/4).
- 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 that aldolase B acts in fructose
      1,6-bisphosphate metabolism, the substrate of its glycolytic/gluconeogenic
      aldol reaction.
    action: ACCEPT
    reason: >-
      Directly describes the metabolic process centered on the enzyme's primary
      substrate (F1,6BP); consistent with direct experimental annotations
      (PMID:9244396, PMID:10625657) to the same term.
- term:
    id: GO:0061609
    label: fructose-1-phosphate aldolase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic inference of fructose-1-phosphate aldolase activity (F1P ->
      DHAP + D-glyceraldehyde), the fructolytic activity for which aldolase B is
      specialized relative to ALDOA/ALDOC.
    action: ACCEPT
    reason: >-
      This F1P-cleaving activity is a defining, physiologically critical
      function of aldolase B (its deficiency causes HFI) and is directly
      demonstrated experimentally in multiple cited papers. The IBA is
      appropriate and well supported.
    supported_by:
    - reference_id: PMID:10625657
      supporting_text: "display distinct activity profiles with fructose 1,6-bisphosphate and with"
- term:
    id: GO:0004332
    label: fructose-bisphosphate aldolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated (IEA) transfer of the core fructose-bisphosphate aldolase
      activity from EC 4.1.2.13 / Rhea:14729 / InterPro FBA_I.
    action: ACCEPT
    reason: >-
      Correct electronic mapping of EC 4.1.2.13 to the enzyme's canonical
      activity; redundant with, and confirmed by, experimental annotations.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Automated subcellular-location mapping placing aldolase B in the cytosol.
    action: ACCEPT
    reason: >-
      Correct compartment; consistent with experimental (PMID:35122041) and
      Reactome cytosol annotations.
- term:
    id: GO:0006096
    label: glycolytic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Automated pathway mapping (UniPathway UPA00109) to glycolysis.
    action: ACCEPT
    reason: >-
      Correct pathway assignment; redundant with IBA and IDA glycolysis
      annotations.
- 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 machine-learning inference to fructose 1,6-bisphosphate metabolism.
    action: ACCEPT
    reason: >-
      Correct; the enzyme's primary substrate is F1,6BP. Redundant with IBA and
      IDA annotations to the same term.
- term:
    id: GO:0034451
    label: centriolar satellite
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Automated subcellular-location mapping to centriolar satellite, derived
      from the UniProt subcellular-location statement based on the BBS-protein
      interaction study (PMID:18000879).
    action: KEEP_AS_NON_CORE
    reason: >-
      A minor/moonlighting localization traced to co-localization with
      Bardet-Biedl syndrome proteins; real but peripheral to the enzyme's
      cytosolic metabolic function. Keep as non-core.
- term:
    id: GO:0070061
    label: fructose binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: >-
      ARBA inference that aldolase B binds fructose (its substrate is a
      fructose phosphate ester).
    action: ACCEPT
    reason: >-
      Consistent with the enzyme's binding of fructose-phosphate substrates and
      with the experimental fructose-binding annotation (PMID:10625657). A
      substrate-binding subfunction of the catalytic activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18000879
  qualifier: enables
  review:
    summary: >-
      IntAct/BHF-UCL protein binding IPIs from a yeast-two-hybrid and coIP study
      of Bardet-Biedl syndrome proteins (interactions with BBS1/BBS2/BBS4/BBS7).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare "protein binding" (GO:0005515) is uninformative and does not describe
      a molecular function. The underlying BBS interactions are real
      (PMID:18000879) but are better represented by the localization
      annotations they support; per curation policy the IPI is marked as
      over-annotated rather than removed.
    supported_by:
    - reference_id: PMID:18000879
      supporting_text: "supported by coimmunoprecipitation analyses"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  qualifier: enables
  review:
    summary: >-
      Protein binding IPI from a large-scale human liver protein-interaction
      network study (interaction with ALDOA, P04075).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare "protein binding" is uninformative; this is a high-throughput
      interactome hit (ALDOA), likely reflecting aldolase homo-/hetero-tetramer
      co-purification. Marked as over-annotated per policy rather than removed.
    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:33961781
  qualifier: enables
  review:
    summary: >-
      Protein binding IPI from the BioPlex dual proteome-scale interactome
      (interaction with ALDOA, P04075).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare "protein binding" is uninformative and is a high-throughput
      affinity-purification interactome hit (ALDOA). Marked as over-annotated
      per policy rather than removed.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: "cell-specific remodeling of the human interactome"
- term:
    id: GO:0006001
    label: fructose catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Automated Ensembl Compara transfer (from mouse ortholog Q91Y97) of
      involvement in fructose catabolism (fructolysis).
    action: ACCEPT
    reason: >-
      Fructolysis (fructose catabolism via F1P cleavage) is a core biological
      role of aldolase B; the ortholog-based transfer is biologically correct
      and consistent with the F1P aldolase activity annotations.
- term:
    id: GO:0061609
    label: fructose-1-phosphate aldolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated (IEA) transfer of fructose-1-phosphate aldolase activity via
      Rhea:30851 and the mouse ortholog.
    action: ACCEPT
    reason: >-
      Correct electronic mapping of the F1P-cleaving reaction; redundant with
      the strong experimental support for this activity.
- 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 B participates in
      gluconeogenesis (reverse aldol condensation of DHAP + G3P to F1,6BP).
    action: ACCEPT
    reason: >-
      Aldolase catalyzes the reversible reaction and contributes to
      gluconeogenesis; consistent with the UniProt gluconeogenesis PATHWAY
      statement. Correct core biological process.
- 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 of involvement in canonical glycolysis.
    action: ACCEPT
    reason: >-
      A more specific glycolysis term correctly capturing aldolase's role in
      the canonical Embden-Meyerhof pathway; consistent with the glycolytic
      process annotations.
- term:
    id: GO:0006000
    label: fructose metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Automated pathway mapping (UniPathway UPA00202, fructose metabolism).
    action: ACCEPT
    reason: >-
      Correct; aldolase B is central to hepatic fructose metabolism. Consistent
      with the experimental fructose metabolic process annotation
      (PMID:3383242).
- term:
    id: GO:0006094
    label: gluconeogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      Automated UniPathway (UPA00138) mapping to gluconeogenesis.
    action: ACCEPT
    reason: >-
      Correct pathway assignment; redundant with the Reactome TAS
      gluconeogenesis annotation.
- term:
    id: GO:0004332
    label: fructose-bisphosphate aldolase activity
  evidence_type: EXP
  original_reference_id: PMID:6696436
  qualifier: enables
  review:
    summary: >-
      Reactome-assigned EXP annotation for fructose-bisphosphate aldolase
      activity. The cited reference (PMID:6696436) is an N-terminal sequencing
      study of human skeletal-muscle aldolase (aldolase A / ALDOA), a family
      member, and does not obviously report an ALDOB activity assay.
    action: UNDECIDED
    reason: >-
      The EC 4.1.2.13 activity is unquestionably correct for aldolase B, but the
      specific reference (PMID:6696436) is a protein-sequencing paper on
      skeletal-muscle (aldolase A) aldolase; I cannot verify from the cached
      abstract that it establishes ALDOB fructose-bisphosphate aldolase
      activity. Per policy I do not remove an experimental annotation whose full
      text I cannot fully verify; the same activity is robustly supported by
      other EXP/IDA lines (PMID:12205126, PMID:20848650, PMID:10970798,
      PMID:10625657, PMID:35122041). Left UNDECIDED pending curator
      verification of the reference-term match.
    supported_by:
    - reference_id: PMID:6696436
      supporting_text: "Fructose-1,6-bisphosphate aldolase was purified from human skeletal-muscle"
- term:
    id: GO:0070072
    label: vacuolar proton-transporting V-type ATPase complex assembly
  evidence_type: IMP
  original_reference_id: PMID:17576770
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation (BHF-UCL) that aldolase is required for assembly of the
      vacuolar H+-ATPase: aldolase mutants that lose binding to the V-ATPase B
      subunit (while retaining catalysis) cause V-ATPase disassembly and
      malfunction; enzymatic activity itself is dispensable for assembly.
    action: KEEP_AS_NON_CORE
    reason: >-
      A genuine non-catalytic (moonlighting) role supported by mutant analysis,
      but peripheral to aldolase B's canonical carbohydrate-metabolism function.
      Note the abstract discusses "aldolase" generically; the curator attributed
      this to ALDOB. Keep as a non-core function rather than remove.
    supported_by:
    - reference_id: PMID:17576770
      supporting_text: "disruption of binding between aldolase and the B subunit of V-ATPase"
    - reference_id: PMID:17576770
      supporting_text: "enzymatic activity is not required for V-ATPase assembly."
- term:
    id: GO:0004332
    label: fructose-bisphosphate aldolase activity
  evidence_type: EXP
  original_reference_id: PMID:12205126
  qualifier: enables
  review:
    summary: >-
      EXP annotation of fructose-bisphosphate aldolase activity from functional
      analysis of ALDOB and its HFI variants from Spanish patients.
    action: ACCEPT
    reason: >-
      Direct experimental support for the core catalytic activity via
      characterization of recombinant ALDOB variants; underpins the UniProt
      EC 4.1.2.13 evidence.
    supported_by:
    - reference_id: PMID:12205126
      supporting_text: "Molecular analysis of the aldolase B gene in patients with hereditary fructose"
- term:
    id: GO:0004332
    label: fructose-bisphosphate aldolase activity
  evidence_type: EXP
  original_reference_id: PMID:20848650
  qualifier: enables
  review:
    summary: >-
      EXP annotation of fructose-bisphosphate aldolase activity from functional
      study of two novel ALDOB natural variants (p.R46W, p.Y343H).
    action: ACCEPT
    reason: >-
      Direct experimental support for the enzyme's canonical activity through
      recombinant ALDOB variant characterization; a UniProt EC 4.1.2.13
      evidence source.
    supported_by:
    - reference_id: PMID:20848650
      supporting_text: "impaired functioning of human liver aldolase (ALDOB)"
- term:
    id: GO:0061609
    label: fructose-1-phosphate aldolase activity
  evidence_type: EXP
  original_reference_id: PMID:12205126
  qualifier: enables
  review:
    summary: >-
      EXP annotation of the fructose-1-phosphate aldolase (fructolytic) activity
      via functional analysis of ALDOB HFI variants.
    action: ACCEPT
    reason: >-
      Direct experimental support for the physiologically critical F1P-cleaving
      activity whose loss causes HFI.
    supported_by:
    - reference_id: PMID:12205126
      supporting_text: "hereditary fructose"
- term:
    id: GO:0061609
    label: fructose-1-phosphate aldolase activity
  evidence_type: EXP
  original_reference_id: PMID:20848650
  qualifier: enables
  review:
    summary: >-
      EXP annotation of fructose-1-phosphate aldolase activity; the p.R46W and
      p.Y343H variants showed particularly altered residual catalytic activity
      toward F1P.
    action: ACCEPT
    reason: >-
      Direct experimental support for the F1P aldolase activity, measured
      explicitly against fructose 1-phosphate in recombinant ALDOB variants.
    supported_by:
    - reference_id: PMID:20848650
      supporting_text: "variants toward F1P was particularly altered"
- term:
    id: GO:0004332
    label: fructose-bisphosphate aldolase activity
  evidence_type: IDA
  original_reference_id: PMID:35122041
  qualifier: enables
  review:
    summary: >-
      IDA annotation of fructose-bisphosphate aldolase activity from the study
      characterizing aldolase B as a tumor suppressor; catalytic activity of WT
      and active-site mutants was assayed.
    action: ACCEPT
    reason: >-
      Direct assay of ALDOB catalytic activity (WT vs enzyme-dead mutants such
      as R43A, K147A) supports the canonical molecular function.
    supported_by:
    - reference_id: PMID:35122041
      supporting_text: "aldolase B (Aldob) suppresses HCC by directly binding and inhibiting the"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35122041
  qualifier: enables
  review:
    summary: >-
      Protein binding IPIs recording the direct interactions of aldolase B with
      TP53 (P04637) and G6PD (P11413) in the tumor-suppressor scaffold.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The interactions with G6PD and TP53 are biologically important and
      real, but bare "protein binding" (GO:0005515) is uninformative; the
      functionally meaningful representation is the molecular adaptor activity
      (GO:0060090) and negative regulation of the PPP shunt (GO:1905856)
      annotations from the same paper. Marked over-annotated per policy rather
      than removed.
    supported_by:
    - reference_id: PMID:35122041
      supporting_text: "inhibition of G6PD in an Aldob-G6PD-p53 complex. This scaffolding effect is"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:35122041
  qualifier: located_in
  review:
    summary: >-
      IDA of cytosolic localization of aldolase B from the tumor-suppressor
      study.
    action: ACCEPT
    reason: >-
      Directly observed cytosolic localization, the compartment of the enzyme's
      metabolic activity.
    supported_by:
    - reference_id: PMID:35122041
      supporting_text: "This scaffolding effect is"
- term:
    id: GO:0060090
    label: molecular adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:35122041
  qualifier: enables
  review:
    summary: >-
      IDA of a non-catalytic molecular adaptor/scaffold activity: aldolase B
      bridges G6PD and TP53 in a ternary complex, potentiating p53-mediated
      inhibition of G6PD; this scaffolding is independent of enzymatic activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      A well-supported moonlighting function distinct from catalysis, but not
      the enzyme's primary/core role. It informatively captures the mechanism
      behind the tumor-suppressor / PPP-regulation phenotype. Keep as non-core.
    supported_by:
    - reference_id: PMID:35122041
      supporting_text: "inhibition of G6PD in an Aldob-G6PD-p53 complex. This scaffolding effect is"
- term:
    id: GO:1905856
    label: negative regulation of pentose-phosphate shunt
  evidence_type: IMP
  original_reference_id: PMID:35122041
  qualifier: involved_in
  review:
    summary: >-
      IMP that aldolase B negatively regulates oxidative pentose phosphate
      pathway flux by inhibiting G6PD; Aldob knockout enhances G6PD activity and
      PPP metabolism and promotes tumorigenesis.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genetically supported regulatory role via the G6PD/p53 scaffold, but a
      secondary (moonlighting) function relative to aldolase B's core role in
      fructose/glucose carbohydrate metabolism. Keep as non-core.
    supported_by:
    - reference_id: PMID:35122041
      supporting_text: "suppresses HCC by directly binding and inhibiting the"
- term:
    id: GO:0004332
    label: fructose-bisphosphate aldolase activity
  evidence_type: IDA
  original_reference_id: PMID:10970798
  qualifier: enables
  review:
    summary: >-
      IDA of fructose-bisphosphate aldolase activity from kinetic
      characterization of WT and HFI (Arg303) ALDOB variants.
    action: ACCEPT
    reason: >-
      Direct kinetic measurement of the canonical activity (WT vs Gln303/Trp303
      variants with F1,6BP); a UniProt EC 4.1.2.13 evidence source.
    supported_by:
    - reference_id: PMID:10970798
      supporting_text: "catalytic efficiency of protein Gln(303) is approx. 1/100 that of the"
- term:
    id: GO:0006096
    label: glycolytic process
  evidence_type: IDA
  original_reference_id: PMID:10970798
  qualifier: involved_in
  review:
    summary: >-
      IDA of involvement in glycolysis, based on characterization of ALDOB
      catalytic function toward glycolytic substrates.
    action: ACCEPT
    reason: >-
      Consistent with aldolase's established role in the glycolytic pathway;
      supported by direct kinetic study of the enzyme.
    supported_by:
    - reference_id: PMID:10970798
      supporting_text: "conserved residue in all vertebrate aldolases, has a dominant role in substrate"
- term:
    id: GO:0061609
    label: fructose-1-phosphate aldolase activity
  evidence_type: IDA
  original_reference_id: PMID:10970798
  qualifier: enables
  review:
    summary: >-
      IDA of fructose-1-phosphate aldolase activity; catalytic efficiency toward
      F1P was measured for WT and Arg303 variants (Gln303 ~1/100, Trp303 no
      detectable F1P activity).
    action: ACCEPT
    reason: >-
      Direct measurement of the F1P-cleaving activity central to fructolysis and
      HFI pathology.
    supported_by:
    - reference_id: PMID:10970798
      supporting_text: "catalytic efficiency of protein Gln(303) is approx. 1/100 that of the"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5656438
  qualifier: located_in
  review:
    summary: >-
      Reactome cytosol localization (from the HFI "defective ALDOB does not
      cleave Fru 1-P" reaction context).
    action: ACCEPT
    reason: >-
      Correct cytosolic compartment; redundant with other cytosol annotations.
- term:
    id: GO:0061609
    label: fructose-1-phosphate aldolase activity
  evidence_type: IDA
  original_reference_id: PMID:2649152
  qualifier: enables
  review:
    summary: >-
      IDA (MGI) of fructose-1-phosphate aldolase activity from expression of
      recombinant human aldolase B in E. coli; the expressed enzyme reproduced
      the authentic F1,6BP/F1P activity ratio.
    action: ACCEPT
    reason: >-
      Recombinant human ALDOB was enzymatically active and functionally
      indistinguishable from the authentic enzyme, including its F1P activity;
      supports the F1P aldolase function.
    supported_by:
    - reference_id: PMID:2649152
      supporting_text: "the activity ratio of fructose"
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: >-
      High-throughput mass-spectrometry detection of aldolase B in exosomes
      isolated from expressed prostatic secretions in urine.
    action: KEEP_AS_NON_CORE
    reason: >-
      A proteomic bystander detection in a secreted-vesicle preparation, common
      for abundant cytosolic glycolytic enzymes; not indicative of a dedicated
      extracellular function. Keep as non-core rather than treat as a functional
      location.
    supported_by:
    - reference_id: PMID:23533145
      supporting_text: "exosome preparations were"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70342
  qualifier: located_in
  review:
    summary: >-
      Reactome cytosol localization (ALDOB tetramer cleaves Fru-1-P reaction).
    action: ACCEPT
    reason: >-
      Correct compartment; redundant with other cytosol annotations.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71495
  qualifier: located_in
  review:
    summary: >-
      Reactome cytosol localization (aldolase converts GA3P and DHAP to F1,6BP,
      gluconeogenic direction).
    action: ACCEPT
    reason: >-
      Correct compartment; redundant with other cytosol annotations.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71496
  qualifier: located_in
  review:
    summary: >-
      Reactome cytosol localization (aldolase tetramer cleaves F1,6BP,
      glycolytic direction).
    action: ACCEPT
    reason: >-
      Correct compartment; redundant with other cytosol annotations.
- term:
    id: GO:0004332
    label: fructose-bisphosphate aldolase activity
  evidence_type: IDA
  original_reference_id: PMID:17576770
  qualifier: enables
  review:
    summary: >-
      IDA of fructose-bisphosphate aldolase activity; the V-ATPase-binding study
      generated aldolase mutants that lost B-subunit binding but retained normal
      catalytic activity, confirming the enzyme's aldolase function.
    action: ACCEPT
    reason: >-
      Catalytic activity was directly assayed (mutants "retain normal catalytic
      activities"), supporting the canonical molecular function.
    supported_by:
    - reference_id: PMID:17576770
      supporting_text: "disruption of binding between aldolase and the B subunit of V-ATPase"
- term:
    id: GO:0004332
    label: fructose-bisphosphate aldolase activity
  evidence_type: IDA
  original_reference_id: PMID:9244396
  qualifier: enables
  review:
    summary: >-
      IDA of fructose-bisphosphate aldolase activity from the study of aldolase
      isozyme interactions with the cytoskeleton (all three isozymes are
      fructose-1,6-bisphosphate aldolases).
    action: ACCEPT
    reason: >-
      Supports the canonical activity of aldolase B; consistent with abundant
      other evidence for GO:0004332.
    supported_by:
    - reference_id: PMID:9244396
      supporting_text: "were found to bind"
- term:
    id: GO:0006000
    label: fructose metabolic process
  evidence_type: IMP
  original_reference_id: PMID:3383242
  qualifier: involved_in
  review:
    summary: >-
      IMP of involvement in fructose metabolism: the common HFI missense
      mutation (A149P/A150P) causes catalytic deficiency of aldolase B and an
      inability to metabolize fructose and related sugars.
    action: ACCEPT
    reason: >-
      Genetic (mutation-phenotype) evidence directly linking ALDOB catalytic
      loss to failure of fructose metabolism (HFI); a core biological process.
    supported_by:
    - reference_id: PMID:3383242
      supporting_text: "caused by a deficiency of aldolase B that results in an inability to metabolize"
- term:
    id: GO:0008092
    label: cytoskeletal protein binding
  evidence_type: IDA
  original_reference_id: PMID:9244396
  qualifier: enables
  review:
    summary: >-
      IDA that aldolase B binds the cytoskeleton (actin-containing filaments),
      with tissue-specific preference: aldolase B preferentially binds the liver
      cytoskeleton.
    action: KEEP_AS_NON_CORE
    reason: >-
      A real, informative binding activity (more specific than bare protein
      binding) but a moonlighting/structural association rather than the
      enzyme's core catalytic function. Keep as non-core.
    supported_by:
    - reference_id: PMID:9244396
      supporting_text: "(liver type) preferred the liver cytoskeleton to those of other tissues."
- 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 involvement in fructose 1,6-bisphosphate metabolism, from
      characterization of aldolase (F1,6BP aldolase) isozymes.
    action: ACCEPT
    reason: >-
      Consistent with the enzyme's canonical substrate metabolism; redundant
      with other annotations to the same term.
    supported_by:
    - reference_id: PMID:9244396
      supporting_text: "were found to bind"
- term:
    id: GO:0051117
    label: ATPase binding
  evidence_type: IDA
  original_reference_id: PMID:17576770
  qualifier: enables
  review:
    summary: >-
      IDA that aldolase physically binds the vacuolar H+-ATPase (its B subunit),
      an interaction required for V-ATPase assembly and activity independently
      of aldolase catalysis.
    action: KEEP_AS_NON_CORE
    reason: >-
      An informative, specific binding activity underpinning the moonlighting
      V-ATPase-assembly role, but peripheral to aldolase B's core carbohydrate
      metabolism. Keep as non-core.
    supported_by:
    - reference_id: PMID:17576770
      supporting_text: "disruption of binding between aldolase and the B subunit of V-ATPase"
- term:
    id: GO:0070061
    label: fructose binding
  evidence_type: IMP
  original_reference_id: PMID:10625657
  qualifier: enables
  review:
    summary: >-
      IMP-supported fructose (fructose-phosphate) binding, from characterization
      of natural ALDOB mutants with altered substrate handling and quaternary
      structure.
    action: ACCEPT
    reason: >-
      Substrate (fructose-phosphate) binding is intrinsic to the enzyme's
      catalytic mechanism and is supported by variant characterization. A valid
      subfunction of the catalytic activity.
    supported_by:
    - reference_id: PMID:10625657
      supporting_text: "display distinct activity profiles with fructose 1,6-bisphosphate and with"
- term:
    id: GO:0004332
    label: fructose-bisphosphate aldolase activity
  evidence_type: IDA
  original_reference_id: PMID:10625657
  qualifier: enables
  review:
    summary: >-
      IDA of fructose-bisphosphate aldolase activity from biochemical/biophysical
      characterization of seven natural human aldolase B variants purified as
      recombinant proteins.
    action: ACCEPT
    reason: >-
      Direct enzymatic characterization of purified recombinant ALDOB (WT and
      HFI variants) firmly establishes the canonical activity.
    supported_by:
    - reference_id: PMID:10625657
      supporting_text: "reversible cleavage of phosphofructose esters into cognate triose"
- term:
    id: GO:0006096
    label: glycolytic process
  evidence_type: IDA
  original_reference_id: PMID:10625657
  qualifier: involved_in
  review:
    summary: >-
      IDA of involvement in glycolysis; aldolases are described as ancient
      enzymes of glycolysis catalyzing reversible cleavage of phosphofructose
      esters into triose phosphates.
    action: ACCEPT
    reason: >-
      Consistent with aldolase's core glycolytic role; supported by direct
      enzyme characterization.
    supported_by:
    - reference_id: PMID:10625657
      supporting_text: "reversible cleavage of phosphofructose esters into cognate triose"
- term:
    id: GO:0030388
    label: fructose 1,6-bisphosphate metabolic process
  evidence_type: IDA
  original_reference_id: PMID:10625657
  qualifier: involved_in
  review:
    summary: >-
      IDA of involvement in fructose 1,6-bisphosphate metabolism, from
      characterization of the enzyme's activity toward F1,6BP.
    action: ACCEPT
    reason: >-
      Directly reflects the enzyme's primary substrate metabolism; redundant
      with other annotations to this term.
    supported_by:
    - reference_id: PMID:10625657
      supporting_text: "display distinct activity profiles with fructose 1,6-bisphosphate and with"
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:10625657
  qualifier: enables
  review:
    summary: >-
      IPI of identical protein binding (self-association), reflecting the
      homotetrameric quaternary structure of aldolase B whose integrity is
      required for full catalytic function.
    action: ACCEPT
    reason: >-
      A biologically meaningful and informative interaction: aldolase B is an
      obligate homotetramer, and the study shows quaternary structure is
      critical for catalysis (structural HFI mutants dissociate into subunits).
      More informative than bare protein binding, so retained.
    supported_by:
    - reference_id: PMID:10625657
      supporting_text: "reversible cleavage of phosphofructose esters into cognate triose"
- term:
    id: GO:0034451
    label: centriolar satellite
  evidence_type: IDA
  original_reference_id: PMID:18000879
  qualifier: located_in
  review:
    summary: >-
      IDA of centriolar satellite localization from subcellular colocalization
      of aldolase B with Bardet-Biedl syndrome proteins.
    action: KEEP_AS_NON_CORE
    reason: >-
      A minor moonlighting localization tied to the BBS-protein interactions;
      real but peripheral to the enzyme's cytosolic metabolic function. Keep as
      non-core.
    supported_by:
    - reference_id: PMID:18000879
      supporting_text: "colocalization studies at the subcellular"
- term:
    id: GO:0005815
    label: microtubule organizing center
  evidence_type: IDA
  original_reference_id: PMID:18000879
  qualifier: located_in
  review:
    summary: >-
      IDA of microtubule organizing center (centrosome) localization, from
      colocalization of aldolase B with BBS proteins.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with the centriolar satellite / MTOC localization reported in
      the same study; a moonlighting/minor localization, non-core relative to
      the enzyme's metabolic role.
    supported_by:
    - reference_id: PMID:18000879
      supporting_text: "colocalization studies at the subcellular"
core_functions:
- description: >-
    Cytosolic fructose-1,6-bisphosphate aldolase (class I Schiff-base aldolase)
    that reversibly cleaves fructose 1,6-bisphosphate into dihydroxyacetone
    phosphate and D-glyceraldehyde 3-phosphate, functioning in glycolysis and,
    in reverse, gluconeogenesis in liver, kidney, and intestine.
  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: PMID:10625657
    supporting_text: "reversible cleavage of phosphofructose esters into cognate triose"
- description: >-
    Cytosolic fructose-1-phosphate aldolase activity that cleaves dietary
    fructose-derived fructose 1-phosphate into dihydroxyacetone phosphate and
    D-glyceraldehyde, the committed step of hepatic fructolysis; loss of this
    activity causes hereditary fructose intolerance.
  molecular_function:
    id: GO:0061609
    label: fructose-1-phosphate aldolase activity
  directly_involved_in:
  - id: GO:0006001
    label: fructose catabolic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:10970798
    supporting_text: "catalytic efficiency of protein Gln(303) is approx. 1/100 that of the"
- description: >-
    Contributes to gluconeogenesis via the reverse (aldol condensation)
    direction of the fructose-bisphosphate aldolase reaction, forming fructose
    1,6-bisphosphate from dihydroxyacetone phosphate and glyceraldehyde
    3-phosphate.
  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: PMID:10625657
    supporting_text: "reversible cleavage of phosphofructose esters into cognate triose"
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  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: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:10625657
  title: Expression, purification, and characterization of natural mutants of human
    aldolase B. Role of quaternary structure in catalysis.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Biochemical/biophysical characterization of seven recombinant human ALDOB
      HFI variants; establishes the catalytic activity, F1,6BP vs F1P activity
      profile, and the homotetramer requirement for catalysis. Directly supports
      GO:0004332, GO:0061609, and GO:0042802.
- id: PMID:10970798
  title: Functional and molecular modelling studies of two hereditary fructose intolerance-causing
    mutations at arginine 303 in human liver aldolase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Kinetic characterization of WT and Arg303 (Gln/Trp) ALDOB against F1,6BP
      and F1P; supports both catalytic activities and the glycolytic role.
- id: PMID:12205126
  title: Molecular analysis of the aldolase B gene in patients with hereditary fructose
    intolerance from Spain.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Functional analysis of ALDOB HFI variants; a UniProt EC 4.1.2.13 evidence
      source for both aldolase activities.
- id: PMID:17576770
  title: Physical interaction between aldolase and vacuolar H+-ATPase is essential
    for the assembly and activity of the proton pump.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Abstract-only cache. Shows aldolase binding to the V-ATPase B subunit is
      required for pump assembly independently of catalysis; the abstract refers
      to "aldolase" generically and the ALDOB attribution is the curator's
      (BHF-UCL). Supports the non-core V-ATPase-assembly and ATPase-binding
      annotations.
- id: PMID:18000879
  title: Novel interaction partners of Bardet-Biedl syndrome proteins.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Y2H plus coIP and subcellular colocalization identifying ALDOB among
      interactors of BBS1/2/4/7; underpins the centriolar satellite / MTOC
      localization and BBS protein-binding IPIs.
- id: PMID:20848650
  title: 'Hereditary fructose intolerance: functional study of two novel ALDOB natural
    variants and characterization of a partial gene deletion.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Functional study of ALDOB variants p.R46W and p.Y343H with residual F1P
      activity measurements; a UniProt EC 4.1.2.13 evidence source.
- 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: >-
      Large-scale human liver interactome; source of a bare protein-binding IPI
      (ALDOA). Not informative about ALDOB molecular function.
- 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: >-
      Shotgun proteomics of urinary prostatic-secretion exosomes; ALDOB is a
      bystander detection. Basis for the non-core extracellular exosome
      localization.
- id: PMID:2649152
  title: Construction and expression of human aldolase A and B expression plasmids
    in Escherichia coli host.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Recombinant human ALDOB expressed in E. coli was enzymatically active and
      reproduced the authentic F1,6BP/F1P activity ratio; supports the F1P
      aldolase activity.
- id: PMID:3383242
  title: Catalytic deficiency of human aldolase B in hereditary fructose intolerance
    caused by a common missense mutation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Identifies the common A149P/A150P HFI mutation causing catalytic
      deficiency and inability to metabolize fructose; supports the fructose
      metabolic process annotation.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      BioPlex affinity-purification interactome; source of a bare protein-binding
      IPI (ALDOA). Not informative about ALDOB molecular function.
- id: PMID:35122041
  title: Aldolase B suppresses hepatocellular carcinogenesis by inhibiting G6PD and
    pentose phosphate pathways.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only cache. Establishes the non-catalytic scaffold function
      (Aldob-G6PD-p53 ternary complex, scaffolding independent of enzymatic
      activity) and cytosolic localization; basis for molecular adaptor
      activity, negative regulation of PPP shunt, and G6PD/TP53 protein-binding
      annotations. Full text (not cached) reports the active-site mutant assays
      supporting the IDA catalytic-activity annotation.
- id: PMID:6696436
  title: 'Human skeletal-muscle aldolase: N-terminal sequence analysis of CNBr- and
    o-iodosobenzoic acid-cleavage fragments.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: MISCITED
    review_notes: >-
      Cached abstract describes N-terminal protein-sequence analysis of human
      skeletal-muscle aldolase (aldolase A / ALDOA), not an ALDOB activity assay.
      The Reactome EXP GO:0004332 annotation on ALDOB citing this reference
      appears to be a reference-term mismatch; flagged for curator verification.
      The activity itself is correct for aldolase B and abundantly supported by
      other references.
- id: PMID:9244396
  title: Mode of interactions of human aldolase isozymes with cytoskeletons.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Shows all three aldolase isozymes bind actin-containing cytoskeleton with
      tissue-specific preference (aldolase B prefers liver cytoskeleton);
      supports the cytoskeletal-protein-binding (non-core) annotation.
- id: Reactome:R-HSA-5656438
  title: Defective ALDOB does not cleave Fru 1-P to GA and DHAP
  findings: []
- id: Reactome:R-HSA-70171
  title: Glycolysis
  findings: []
- id: Reactome:R-HSA-70263
  title: Gluconeogenesis
  findings: []
- id: Reactome:R-HSA-70342
  title: ALDOB tetramer cleaves Fru-1-P to GA and DHAP
  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: []