id: Q14376
gene_symbol: GALE
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  GALE is the human cytosolic, NAD+-dependent UDP-galactose 4-epimerase
  (galactowaldenase; EC 5.1.3.2), which catalyses the fourth, recycling step of
  the Leloir pathway of galactose catabolism: the reversible interconversion of
  UDP-alpha-D-glucose and UDP-alpha-D-galactose. This activity regenerates the
  UDP-glucose consumed by galactose-1-phosphate uridylyltransferase (GALT) and
  supplies UDP-galactose for the biosynthesis of glycoproteins, glycolipids and
  other galactosylated glycoconjugates. The human enzyme is bifunctional and also
  interconverts UDP-N-acetyl-alpha-D-glucosamine and UDP-N-acetyl-alpha-D-
  galactosamine (EC 5.1.3.7), providing UDP-GalNAc for glycosylation; this second
  activity, absent in the bacterial ortholog, reflects an enlarged active-site
  sugar-binding pocket. The active enzyme is a homodimer with one tightly bound
  NAD+ per subunit; catalysis proceeds through transient oxidation of the sugar at
  C4, rotation, and stereospecific reduction, with Tyr157 acting as the active-site
  proton acceptor. Loss-of-function variants cause epimerase-deficiency galactosemia
  (galactosemia type III), which ranges from a benign peripheral form limited to
  circulating blood cells to a rare severe generalized form, and biallelic variants
  that predominantly impair the UDP-GalNAc/GlcNAc activity and N-glycosylation cause
  a syndromic macrothrombocytopenia.
alternative_products:
- name: '1'
  id: Q14376-1
- name: '2'
  id: Q14376-2
  sequence_note: VSP_056822
existing_annotations:
- term:
    id: GO:0003978
    label: UDP-glucose 4-epimerase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      UDP-glucose 4-epimerase (UDP-Glc <-> UDP-Gal, EC 5.1.3.2) is the defining,
      phylogenetically conserved molecular function of GALE across the panther
      family. This is the core molecular function and is independently supported by
      direct biochemical assay of the human enzyme.
    action: ACCEPT
    reason: >-
      Core molecular function. The IBA is consistent with direct experimental
      characterization of purified human GALE catalysing UDP-glucose/UDP-galactose
      interconversion, and with the crystal structure of the enzyme in complex with
      NAD and UDP-glucose.
    supported_by:
    - reference_id: PMID:16302980
      supporting_text: >-
        UDP-galactose 4-epimerase (GALE, EC 5.1.3.2) catalyses the interconversion
        of UDP-glucose and UDP-galactose.
- term:
    id: GO:0033499
    label: beta-D-galactose catabolic process via UDP-galactose, Leloir pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      GALE catalyses the recycling (fourth) step of the Leloir pathway, regenerating
      UDP-glucose and supplying UDP-galactose, so that dietary galactose is ultimately
      routed to glycolytic intermediates. This is the most specific and informative
      biological-process term for the gene and is the primary process annotation.
    action: ACCEPT
    reason: >-
      Accurately captures GALE's role in the Leloir pathway of galactose catabolism.
      Supported by UniProt pathway annotation and by the enzyme's established
      biochemistry.
    supported_by:
    - reference_id: PMID:16302980
      supporting_text: >-
        UDP-galactose 4-epimerase (GALE, EC 5.1.3.2) catalyses the interconversion
        of UDP-glucose and UDP-galactose.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      GALE is a soluble cytosolic enzyme; it has no signal peptide, transmembrane
      region, or organellar targeting sequence, and Reactome models the catalytic
      step as occurring in the cytosol.
    action: ACCEPT
    reason: >-
      Consistent with the cytosolic localization documented by Reactome and with the
      absence of any targeting features in the UniProt sequence.
    supported_by:
    - reference_id: Reactome:R-HSA-70369
      supporting_text: >-
        Cytosolic UDP-galactose 4-epimerase catalyzes the interconversion of
        UDP-D-galactose and UDP-D-glucose
- term:
    id: GO:0003974
    label: UDP-N-acetylglucosamine 4-epimerase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      The human enzyme is bifunctional and also catalyses the reversible epimerization
      of UDP-N-acetyl-D-glucosamine and UDP-N-acetyl-D-galactosamine (EC 5.1.3.7,
      RHEA:20517), supplying UDP-GalNAc for glycoconjugate synthesis. This second
      activity is experimentally established for human GALE (unlike the E. coli ortholog)
      and is central to the N-glycosylation defect seen in GALE-related thrombocytopenia.
    action: ACCEPT
    reason: >-
      The EC 5.1.3.7 / RHEA:20517 mapping is a correct, experimentally corroborated secondary
      catalytic activity of the human enzyme, not an over-broad IEA. UniProt documents both
      catalytic activities (EC 5.1.3.2 and EC 5.1.3.7) on the basis of direct assay, and
      structural studies show the enlarged active site accommodates the N-acetyl group. No
      verbatim supporting quote is attached here because the cached publications and Reactome
      reaction document only the UDP-Glc/UDP-Gal (EC 5.1.3.2) activity; the N-acetylhexosamine
      activity rests on the UniProt catalytic-activity annotation (RHEA:20517).
- term:
    id: GO:0003978
    label: UDP-glucose 4-epimerase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic assertion of the core UDP-glucose 4-epimerase activity from the EC
      5.1.3.2 / RHEA:22168 mapping and InterPro family membership. Redundant with, and
      corroborated by, the IBA and IDA annotations to the same term.
    action: ACCEPT
    reason: >-
      Correct EC/RHEA/InterPro-based mapping of the core molecular function; consistent
      with direct experimental evidence.
    supported_by:
    - reference_id: PMID:16302980
      supporting_text: >-
        UDP-galactose 4-epimerase (GALE, EC 5.1.3.2) catalyses the interconversion
        of UDP-glucose and UDP-galactose.
- term:
    id: GO:0006012
    label: galactose metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Involvement in galactose metabolism is correct but is a broad parent of the more
      specific Leloir-pathway catabolic term (GO:0033499). Retained as a valid, if
      general, process annotation.
    action: ACCEPT
    reason: >-
      Accurate at the general level (galactose metabolic process); the more specific
      GO:0033499 and GO:0019388 annotations provide the informative process terms. No
      reason to remove a correct broader parent.
    supported_by:
    - reference_id: PMID:16302980
      supporting_text: >-
        the genetic disease, type III galactosemia
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: >-
      Self-interaction (Q14376-Q14376) detected in a large-scale human protein
      interactome map. This reflects the enzyme's known homodimeric state but is a
      low-information molecular-function term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The self-interaction is real and consistent with the established homodimer, but
      "identical protein binding" is an uninformative term relative to the more specific
      GO:0042803 protein homodimerization activity already annotated for this gene, and it
      is repeated five times from high-throughput interactome screens. Kept but flagged as
      over-annotated; the homodimer is best represented by GO:0042803.
    supported_by:
    - reference_id: PMID:16189514
      supporting_text: >-
        Towards a proteome-scale map of the human protein-protein interaction network.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: >-
      Self-interaction reported in a proteome-scale human interactome map, consistent with
      the GALE homodimer. Low-information duplicate of the same identical-protein-binding
      assertion.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Same rationale as the other identical-protein-binding annotations: real but
      uninformative relative to GO:0042803 protein homodimerization activity; one of five
      duplicate high-throughput self-interaction annotations.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: >-
        A proteome-scale map of the human interactome network.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25502805
  qualifier: enables
  review:
    summary: >-
      Self-interaction reported in a large-scale variant/interaction phenotyping pipeline,
      consistent with the GALE homodimer.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Real self-interaction but uninformative relative to GO:0042803; duplicate
      high-throughput identical-protein-binding annotation.
    supported_by:
    - reference_id: PMID:25502805
      supporting_text: >-
        A massively parallel pipeline to clone DNA variants and examine molecular
        phenotypes of human disease mutations.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: >-
      Self-interaction reported in a systematic study of interaction disruption by human
      genetic variants, consistent with the GALE homodimer.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Real self-interaction but uninformative relative to GO:0042803; duplicate
      high-throughput identical-protein-binding annotation.
    supported_by:
    - reference_id: PMID:31515488
      supporting_text: >-
        Extensive disruption of protein interactions by genetic variants across the
        allele frequency spectrum in human populations.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Self-interaction reported in the HuRI reference map of the human binary protein
      interactome, consistent with the GALE homodimer.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Real self-interaction but uninformative relative to GO:0042803; duplicate
      high-throughput identical-protein-binding annotation.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: >-
        A reference map of the human binary protein interactome.
- term:
    id: GO:0033499
    label: beta-D-galactose catabolic process via UDP-galactose, Leloir pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic (Ensembl Compara ortholog-based) transfer of the Leloir-pathway galactose
      catabolic process, transferred from the mouse ortholog (Q8R059). Consistent with the
      IBA annotation to the same term and with GALE's established function.
    action: ACCEPT
    reason: >-
      Correct process assignment; the ortholog-based inference agrees with the manual IBA
      annotation and with the enzyme's biochemistry. No over-propagation concern for this
      well-conserved Leloir enzyme.
    supported_by:
    - reference_id: PMID:16302980
      supporting_text: >-
        UDP-galactose 4-epimerase (GALE, EC 5.1.3.2) catalyses the interconversion
        of UDP-glucose and UDP-galactose.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5610036
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author-statement localizing GALE to the cytosol, in the context of
      defective GALE failing to epimerise UDP-Gal to UDP-Glc. Consistent with the other
      cytosol annotations.
    action: ACCEPT
    reason: >-
      GALE is a soluble cytosolic enzyme; localization is well established. Duplicate of the
      other cytosol annotations, which is acceptable.
    supported_by:
    - reference_id: Reactome:R-HSA-70369
      supporting_text: >-
        Cytosolic UDP-galactose 4-epimerase catalyzes the interconversion of
        UDP-D-galactose and UDP-D-glucose
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70369
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author-statement placing the GALE:NAD+ dimer epimerization reaction
      in the cytosol. Directly supports the cytosolic localization of the active enzyme.
    action: ACCEPT
    reason: >-
      Well-supported cytosolic localization of the catalytically active homodimer.
    supported_by:
    - reference_id: Reactome:R-HSA-70369
      supporting_text: >-
        Cytosolic UDP-galactose 4-epimerase catalyzes the interconversion of
        UDP-D-galactose and UDP-D-glucose
- term:
    id: GO:0003978
    label: UDP-glucose 4-epimerase activity
  evidence_type: IDA
  original_reference_id: PMID:16302980
  qualifier: enables
  review:
    summary: >-
      Direct assay of recombinant purified human GALE established UDP-glucose/UDP-galactose
      epimerase activity and its kinetic parameters, including the effects of disease-causing
      mutations on turnover and specificity. This is the strongest direct evidence for the
      core molecular function.
    action: ACCEPT
    reason: >-
      Experimental (IDA) confirmation of the core catalytic activity in the human enzyme.
    supported_by:
    - reference_id: PMID:16302980
      supporting_text: >-
        UDP-galactose 4-epimerase (GALE, EC 5.1.3.2) catalyses the interconversion
        of UDP-glucose and UDP-galactose.
- term:
    id: GO:0019388
    label: galactose catabolic process
  evidence_type: IDA
  original_reference_id: PMID:16302980
  qualifier: involved_in
  review:
    summary: >-
      GALE's epimerase activity is required for galactose catabolism, and impairment causes
      type III galactosemia; the direct functional characterization links the enzyme to
      galactose breakdown. GO:0033499 is the more specific Leloir-pathway child, but this
      general catabolic term is correct.
    action: ACCEPT
    reason: >-
      Accurate process assignment supported by direct functional/disease evidence. Retained
      alongside the more specific GO:0033499.
    supported_by:
    - reference_id: PMID:16302980
      supporting_text: >-
        Point mutations in this enzyme are associated with the genetic disease, type III
        galactosemia
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:16302980
  qualifier: enables
  review:
    summary: >-
      The active enzyme is a homodimer; protein-protein crosslinking of wild-type and mutant
      GALE demonstrated homodimer formation, and the crystal structure is dimeric. This is
      the informative representation of GALE's self-association.
    action: ACCEPT
    reason: >-
      Well-supported homodimerization, established both biochemically (crosslinking) and
      structurally. Preferred over the bare identical-protein-binding annotations for
      representing the same underlying self-association.
    supported_by:
    - reference_id: PMID:16302980
      supporting_text: >-
        Protein-protein crosslinking suggests that none of the mutants are impaired in
        homodimer formation.
- term:
    id: GO:0051287
    label: NAD binding
  evidence_type: IDA
  original_reference_id: PMID:10801319
  qualifier: enables
  review:
    summary: >-
      GALE binds NAD+ as a tightly bound cofactor, one molecule per subunit, essential for the
      transient oxidation/reduction chemistry of epimerization. The crystal structure resolves
      the bound NAD, and UniProt annotates multiple NAD(+)-binding residues.
    action: NEW
    reason: >-
      NAD binding is a well-established, structurally and biochemically documented molecular
      function of GALE that is missing from the existing annotation set. Added as a new
      annotation for the enzyme's cofactor-binding role.
    supported_by:
    - reference_id: PMID:10801319
      supporting_text: >-
        structures of human epimerase in the resting state (i.e., with bound NAD(+))
core_functions:
- description: >-
    NAD+-dependent UDP-glucose 4-epimerase catalysing the reversible interconversion of
    UDP-glucose and UDP-galactose, the recycling step of the Leloir pathway of galactose
    catabolism, acting as a cytosolic homodimer.
  molecular_function:
    id: GO:0003978
    label: UDP-glucose 4-epimerase activity
  directly_involved_in:
  - id: GO:0033499
    label: galactose catabolic process via UDP-galactose, Leloir pathway
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:16302980
    supporting_text: >-
      UDP-galactose 4-epimerase (GALE, EC 5.1.3.2) catalyses the interconversion of
      UDP-glucose and UDP-galactose.
- description: >-
    Bifunctional UDP-N-acetylglucosamine 4-epimerase activity interconverting UDP-GlcNAc and
    UDP-GalNAc, supplying UDP-GalNAc for glycoprotein and glycolipid biosynthesis; a
    cytosolic activity specific to the human enzyme.
  molecular_function:
    id: GO:0003974
    label: UDP-N-acetylglucosamine 4-epimerase activity
  locations:
  - id: GO:0005829
    label: cytosol
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput interactome screen; source of the Q14376-Q14376 self-interaction
      (identical protein binding) annotation. Consistent with the known homodimer but does
      not directly inform GALE's catalytic function.
- id: PMID:16302980
  title: Functional analysis of disease-causing mutations in human UDP-galactose 4-epimerase.
  findings:
  - statement: >-
      Human GALE (EC 5.1.3.2) catalyses the interconversion of UDP-glucose and UDP-galactose;
      disease-causing mutations reduce catalytic efficiency and increase proteolytic
      susceptibility, causing type III galactosemia.
    supporting_text: >-
      UDP-galactose 4-epimerase (GALE, EC 5.1.3.2) catalyses the interconversion of
      UDP-glucose and UDP-galactose.
  - statement: GALE forms a homodimer; disease mutations do not impair homodimer formation.
    supporting_text: >-
      Protein-protein crosslinking suggests that none of the mutants are impaired in
      homodimer formation.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Direct enzymatic characterization of recombinant human GALE and disease variants;
      supports the core epimerase activity, homodimerization, and role in galactose
      catabolism / type III galactosemia.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput interactome map; source of a GALE self-interaction annotation.
- id: PMID:25502805
  title: A massively parallel pipeline to clone DNA variants and examine molecular
    phenotypes of human disease mutations.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale variant/interaction phenotyping pipeline; source of a GALE self-interaction
      annotation.
- 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: >-
      Systematic study of variant-driven interaction disruption; source of a GALE
      self-interaction annotation.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI reference binary interactome; source of a GALE self-interaction annotation
      consistent with the homodimer.
- id: Reactome:R-HSA-5610036
  title: Defective GALE does not epimerise UDP-Gal to UDP-Glc
  findings: []
- id: Reactome:R-HSA-70369
  title: GALE:NAD+ dimer reversibly epimerises UDP-Gal to UDP-Glc
  findings:
  - statement: >-
      Cytosolic GALE catalyses the interconversion of UDP-D-galactose and UDP-D-glucose; the
      active enzyme is a homodimer with one molecule of bound NAD+ per monomer.
    supporting_text: >-
      The active form of the enzyme is a homodimer with one molecule of bound NAD+ per
      monomer
- id: PMID:10801319
  title: Crystallographic evidence for Tyr 157 functioning as the active site base in
    human UDP-galactose 4-epimerase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Crystal structure of human GALE in complex with NAD and UDP-glucose; establishes the
      bound NAD+ cofactor, the homodimer, and Tyr157 as the active-site proton acceptor.
proposed_new_terms: []
suggested_questions:
- question: >-
    To what extent does the UDP-GalNAc/GlcNAc 4-epimerase activity of GALE, versus its
    UDP-Gal/Glc activity, account for the distinct clinical phenotypes (galactosemia versus
    syndromic macrothrombocytopenia) seen with different GALE variants?
suggested_experiments:
- description: >-
    Systematically measure both UDP-Gal/Glc (EC 5.1.3.2) and UDP-GalNAc/GlcNAc (EC 5.1.3.7)
    epimerase activities for a panel of galactosemia- and thrombocytopenia-associated GALE
    variants, and correlate the differential loss of each activity with glycosylation status
    and clinical presentation.
  experiment_type: enzyme kinetics and glycomics