id: P07686
gene_symbol: HEXB
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  HEXB encodes the beta subunit of lysosomal beta-hexosaminidase, a glycoside
  hydrolase family 20 (GH20) exo-glycosidase. The beta subunit is shared by two
  isozymes: hexosaminidase A, an alpha-beta heterodimer of HEXA and HEXB, and
  hexosaminidase B, a beta-beta homodimer of HEXB alone (a third labile isozyme,
  hexosaminidase S, is the HEXA alpha-alpha homodimer). The enzyme hydrolyses
  terminal non-reducing N-acetyl-beta-D-hexosamine (beta-GalNAc/GlcNAc) residues
  (EC 3.2.1.52) from a range of glycoconjugates, including gangliosides (GM2 and
  GA2), glycosaminoglycans (dermatan sulfate, keratan sulfate and hyaluronan
  fragments), neutral oligosaccharides and glycoproteins. Each subunit contributes
  a distinct active site: the beta-active site (present in both Hex A and Hex B)
  hydrolyses neutral substrates efficiently, whereas the alpha-active site
  additionally cleaves sulfated/negatively charged substrates; only Hex A together
  with the GM2 activator protein degrades GM2 ganglioside at physiologically
  significant rates. The mature enzyme resides in the lysosome / lysosomal lumen.
  Loss of the beta subunit disables both Hex A and Hex B and causes Sandhoff
  disease (GM2 gangliosidosis type 2), an autosomal recessive lysosomal storage
  disorder marked by neuronal GM2 ganglioside accumulation and progressive
  neurodegeneration.
existing_annotations:
- term:
    id: GO:0004563
    label: beta-N-acetylhexosaminidase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Core molecular function. beta-N-acetylhexosaminidase activity (EC 3.2.1.52)
      is the defining enzymatic activity of the beta subunit, directly supported
      by biochemical characterization of Hex B and Hex A and consistent across the
      GH20 phylogenetic clade.
    action: ACCEPT
    reason: >-
      The IBA at the exact right level of specificity matches multiple experimental
      annotations (IDA/EXP) on the same term. The catalytic activity is
      well-established biochemically and by active-site mutagenesis.
    supported_by:
    - reference_id: PMID:11707436
      supporting_text: >-
        Human lysosomal beta-hexosaminidases remove terminal beta-glycosidically bound
        N-acetylhexosamine residues from a number of glycoconjugates
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "Hydrolyzes the non-reducing end N-acetyl-D-hexosamine"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      IBA placing the enzyme in the extracellular region. HEXB is a lysosomal
      hydrolase that also traffics through secretory routes; a minor secreted pool
      exists (secreted precursor complexes, exosomes, neutrophil granule release),
      but the extracellular region is not where the enzyme predominantly acts.
    action: KEEP_AS_NON_CORE
    reason: >-
      A genuine minor secreted/extracellular pool is documented (secreted precursor
      alpha-beta complexes; exosome and neutrophil-granule proteomics), so this is
      not wrong, but it is peripheral to the core lysosomal catabolic function.
    supported_by:
    - reference_id: PMID:6230359
      supporting_text: >-
        Precursor alpha beta
        complexes were secreted, along with some precursor alpha monomers
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Core cellular location. The mature enzyme is a lysosomal hydrolase and is
      active in the lysosome, consistent with experimental subcellular localization
      and with its role in lysosomal catabolism.
    action: ACCEPT
    reason: >-
      Well-supported by experimental localization (PMID:9694901) and by UniProt
      subcellular location; the IBA is at the correct level.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0030203
    label: glycosaminoglycan metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Core biological process. Hex A and Hex B degrade glycosaminoglycan fragments
      by removing terminal beta-hexosamine residues (e.g. from dermatan sulfate and
      keratan sulfate), and defective HEXB blocks GAG degradation.
    action: ACCEPT
    reason: >-
      Supported by experimental IDA annotations on the same term (PMID:11707436,
      PMID:25645918) and by biochemical demonstration of GAG-fragment hydrolysis.
    supported_by:
    - reference_id: PMID:11707436
      supporting_text: >-
        recombinant Hex S was highly
    - reference_id: PMID:6458607
      supporting_text: >-
        Incubation of
        keratan sulfate-derived oligosaccharides with beta-N-acetylhexosaminidase A
        analogously resulted in the liberation of N-acetylglucosamine-6-sulfate
- term:
    id: GO:0006689
    label: ganglioside catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Core biological process. The beta subunit is an essential component of Hex A,
      the only isozyme that degrades GM2 ganglioside (with the GM2 activator
      protein); loss of the beta subunit causes GM2 ganglioside storage (Sandhoff
      disease).
    action: ACCEPT
    reason: >-
      Directly supported by experimental IDA annotations on the same term
      (PMID:8123671, PMID:8672428) and by the disease mechanism.
    supported_by:
    - reference_id: PMID:8672428
      supporting_text: >-
        Heterodimeric hexosaminidase A (alpha beta) is the only isozyme
        that can hydrolyze GM2 ganglioside in vivo, requiring the presence of the GM2
        activator protein
- term:
    id: GO:0004553
    label: hydrolase activity, hydrolyzing O-glycosyl compounds
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO parent term for the glycoside-hydrolase activity. Correct but
      more general than the specific beta-N-acetylhexosaminidase activity that is
      experimentally established.
    action: MODIFY
    reason: >-
      The term is accurate but too broad; the specific child term GO:0004563
      (beta-N-acetylhexosaminidase activity) is well supported and should be used.
    proposed_replacement_terms:
    - id: GO:0004563
      label: beta-N-acetylhexosaminidase activity
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "Belongs to the glycosyl hydrolase 20 family"
- term:
    id: GO:0004563
    label: beta-N-acetylhexosaminidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated (ARBA/multi-method, includes EC:3.2.1.52 mapping) assignment of the
      exact core molecular function, matching the experimental annotations.
    action: ACCEPT
    reason: >-
      Correct core MF term; redundant with the experimental IDA/EXP annotations on
      GO:0004563.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "Hydrolyzes the non-reducing end N-acetyl-D-hexosamine"
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UniProt SubCell mapping to lysosome, matching the experimental localization.
    action: ACCEPT
    reason: >-
      Correct core location; redundant with the experimental EXP annotation
      (PMID:9694901).
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0005975
    label: carbohydrate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO high-level carbohydrate metabolism term. Correct but very general
      relative to the specific ganglioside/GAG catabolic processes.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Not wrong, but uninformatively broad; the specific catabolic BP terms
      (GO:0006689, GO:0030203) capture the biology.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "Belongs to the glycosyl hydrolase 20 family"
- term:
    id: GO:0008375
    label: acetylglucosaminyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: >-
      ARBA-predicted glycosyltransferase activity. HEXB is a GH20 exo-glycosidase
      (a hydrolase, EC 3.2.1.52), not a glycosyltransferase; the paucimannose
      generation described for the enzyme is N-glycan trimming (hydrolysis), not
      sugar transfer.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Transferase activity is inconsistent with the well-established hydrolase
      mechanism and fold; this is a mis-typing of the glycosidase activity. Per
      curation policy the paired experimental IDA is retained but flagged rather
      than removed.
    supported_by:
    - reference_id: PMID:25645918
      supporting_text: >-
        azurophilic granule-resident
        β-hexosaminidase A displayed the capacity to generate paucimannosidic N-glycans
        by trimming hybrid/complex type N-glycan intermediates
- term:
    id: GO:0016042
    label: lipid catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA-predicted lipid catabolism. HEXB does participate in glycosphingolipid
      (ganglioside) catabolism, so this broad term is consistent, but the specific
      ganglioside catabolic process term is more informative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Correct in spirit (ganglioside/glycosphingolipid degradation is lipid
      catabolism) but too general; GO:0006689 is preferred.
    supported_by:
    - reference_id: PMID:8672428
      supporting_text: >-
        Heterodimeric hexosaminidase A (alpha beta) is the only isozyme
        that can hydrolyze GM2 ganglioside in vivo
- term:
    id: GO:0042582
    label: azurophil granule
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: >-
      ARBA-predicted azurophil granule localization, corroborated by an
      experimental IDA (PMID:25645918) showing HEXB in human neutrophil azurophilic
      granules. Reflects the secreted/granule pool of this lysosomal enzyme.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine localization for the neutrophil granule pool, but peripheral to the
      core lysosomal catabolic role.
    supported_by:
    - reference_id: PMID:25645918
      supporting_text: >-
        azurophilic granule-resident
        β-hexosaminidase A
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: >-
      ARBA mapping to lysosomal lumen, the correct compartment for this soluble
      lysosomal hydrolase, matching numerous Reactome TAS annotations.
    action: ACCEPT
    reason: >-
      Correct core location for a soluble lysosomal enzyme.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0060473
    label: cortical granule
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Cortical-granule localization inferred by orthology from mouse Hexb
      (UniProtKB:P20060). Documented for oocytes in the zona-block-to-polyspermy
      role; not directly demonstrated for the human protein.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported by orthology to the well-characterized mouse cortical-granule
      function; a legitimate but non-core, tissue-specific localization.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "Cytoplasmic vesicle, secretory vesicle, Cortical granule"
- term:
    id: GO:1901135
    label: carbohydrate derivative metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA high-level carbohydrate-derivative metabolism term; extremely broad
      relative to the specific catabolic functions.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformatively general; specific catabolic BP terms are preferred.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "Belongs to the glycosyl hydrolase 20 family"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16698036
  qualifier: enables
  review:
    summary: >-
      IPI from the Hex A crystal-structure study, with HEXA (P06865) as partner.
      This captures the genuine, biologically central beta-alpha interaction that
      forms the Hex A heterodimer, but the term itself (bare protein binding) is
      uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The underlying HEXA interaction is real and central (Hex A heterodimer),
      better represented by the beta-N-acetylhexosaminidase complex annotation
      (GO:1905379); bare protein binding adds no functional information.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: >-
        hexosaminidase A is
        CC       a heterodimer composed of one subunit alpha and one subunit beta
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: >-
      High-throughput AP-MS interactome IPI (BioPlex). Uninformative bare protein
      binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Systematic-screen protein binding without a defined functional partner
      relationship; provides no informative molecular function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      High-throughput binary (Y2H) interactome IPI (HuRI). Uninformative bare
      protein binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Systematic-screen protein binding; not informative for molecular function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: >-
      High-throughput neurodegenerative-disease interactome IPI. Uninformative bare
      protein binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Systematic-screen protein binding; not informative for molecular function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      High-throughput AP-MS interactome IPI (BioPlex 3.0), with HEXA (P06865).
      Recapitulates the HEXA interaction but via a bare protein binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      As for PMID:16698036, the HEXA interaction is meaningful but bare protein
      binding is uninformative and better captured by the complex annotation.
- term:
    id: GO:0006044
    label: N-acetylglucosamine metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl orthology projection (rat). Consistent with release of GlcNAc
      residues during glycoconjugate degradation, but broad and indirect.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with the enzyme liberating N-acetylglucosamine from substrates,
      but not a core process descriptor; retained as non-core.
    supported_by:
    - reference_id: PMID:6458607
      supporting_text: >-
        liberation of N-acetylglucosamine-6-sulfate
- term:
    id: GO:0007338
    label: single fertilization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Fertilization role projected by orthology from mouse Hexb. In mouse, the
      cortical-granule enzyme contributes to the zona block to polyspermy; a
      legitimate but non-core, organism-specific developmental role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported by the well-documented mouse ortholog function; peripheral to the
      core lysosomal catabolic function of the human enzyme.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: >-
        During fertilization
        CC       is responsible, at least in part, for the zona block to polyspermy
- term:
    id: GO:0008360
    label: regulation of cell shape
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl orthology projection from mouse. A weak, indirect phenotype
      association with no mechanistic link to the enzyme's glycosidase function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      No molecular basis connects a lysosomal exo-glycosidase to direct regulation
      of cell shape; likely an over-propagated phenotype-based projection.
- term:
    id: GO:0015929
    label: hexosaminidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Ensembl orthology projection of hexosaminidase activity. Correct but a parent
      of the specific beta-N-acetylhexosaminidase activity.
    action: MODIFY
    reason: >-
      Accurate but too general; the specific child term GO:0004563 is well
      supported experimentally.
    proposed_replacement_terms:
    - id: GO:0004563
      label: beta-N-acetylhexosaminidase activity
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "Hydrolyzes the non-reducing end N-acetyl-D-hexosamine"
- term:
    id: GO:0016231
    label: beta-N-acetylglucosaminidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Ensembl orthology projection. The beta-active site does hydrolyse terminal
      beta-GlcNAc residues; this is a valid, slightly narrower sibling of the
      beta-N-acetylhexosaminidase activity (which spans GlcNAc and GalNAc).
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with the enzyme's substrate range (releases N-acetylglucosamine
      from keratan sulfate and N-glycans); the broader GO:0004563 is the primary
      core MF, so this narrower term is retained as non-core.
    supported_by:
    - reference_id: PMID:6458607
      supporting_text: >-
        Incubation of
        keratan sulfate-derived oligosaccharides with beta-N-acetylhexosaminidase A
        analogously resulted in the liberation of N-acetylglucosamine-6-sulfate
- term:
    id: GO:0030203
    label: glycosaminoglycan metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl orthology projection of GAG metabolism, matching the experimental
      IDA annotations on the same term.
    action: ACCEPT
    reason: >-
      Correct core BP; redundant with experimental annotations (PMID:11707436,
      PMID:25645918).
    supported_by:
    - reference_id: PMID:11707436
      supporting_text: >-
        sulfated GAG fragments, and the sulfated glycosphingolipid SM2
- term:
    id: GO:0030246
    label: carbohydrate binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Ensembl orthology projection of carbohydrate binding. The enzyme necessarily
      binds carbohydrate substrates in its active site, but as an independent MF
      this is redundant with the catalytic activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Substrate binding is subsumed by the catalytic activity annotation; a
      standalone carbohydrate binding MF adds little.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Ensembl orthology projection of identical protein binding. Reflects the
      beta-beta homodimer (Hex B), a genuine self-association.
    action: KEEP_AS_NON_CORE
    reason: >-
      The beta-beta homodimerization is real (Hex B) and supported experimentally
      (PMID:6230359); better captured by the complex annotation, so retained as
      non-core.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "hexosaminidase B is a homodimer of two beta subunits"
- term:
    id: GO:0043615
    label: astrocyte cell migration
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl orthology projection from mouse. A phenotype-level association (Hexb
      loss affects CNS/glial biology) with no direct mechanistic tie to the
      enzyme's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Indirect, phenotype-derived process not representing a direct molecular role
      of the human enzyme.
- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Ensembl orthology projection. Generic complex-binding term with no defined
      partner complex.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative generic binding term; the meaningful complex membership is the
      hexosaminidase complex (GO:1905379).
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl orthology projection. No mechanism links a lysosomal exo-glycosidase
      to direct positive regulation of RNA polymerase II transcription.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Biologically implausible as a direct molecular role for HEXB; over-propagated
      projection.
- term:
    id: GO:0004563
    label: beta-N-acetylhexosaminidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9035982
  qualifier: enables
  review:
    summary: >-
      Reactome TAS for the core catalytic activity (in the context of defective
      HEXB failing to cleave terminal GalNAc from hyaluronan fragments).
    action: ACCEPT
    reason: >-
      Correct core MF term, consistent with experimental evidence.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "Hydrolyzes the non-reducing end N-acetyl-D-hexosamine"
- term:
    id: GO:0030203
    label: glycosaminoglycan metabolic process
  evidence_type: IDA
  original_reference_id: PMID:11707436
  qualifier: involved_in
  review:
    summary: >-
      ComplexPortal IDA. Hex isozymes were shown to act on sulfated GAG fragments
      (dermatan sulfate) and neutral N-glycan fragments, establishing a direct role
      in glycosaminoglycan metabolism.
    action: ACCEPT
    reason: >-
      Direct experimental evidence for GAG-fragment hydrolysis by the enzyme.
    supported_by:
    - reference_id: PMID:11707436
      supporting_text: >-
        sulfated GAG fragments, and the sulfated glycosphingolipid SM2
- term:
    id: GO:0030203
    label: glycosaminoglycan metabolic process
  evidence_type: IDA
  original_reference_id: PMID:25645918
  qualifier: involved_in
  review:
    summary: >-
      ComplexPortal IDA linking HEXB activity to processing of glycan substrates
      (N-glycan trimming in neutrophils). Supports involvement in
      glycan/glycosaminoglycan metabolism.
    action: ACCEPT
    reason: >-
      Direct experimental demonstration of the enzyme acting on glycan substrates.
    supported_by:
    - reference_id: PMID:25645918
      supporting_text: >-
        azurophilic granule-resident
        β-hexosaminidase A displayed the capacity to generate paucimannosidic N-glycans
        by trimming hybrid/complex type N-glycan intermediates
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: NAS
  original_reference_id: PMID:6458607
  qualifier: located_in
  review:
    summary: >-
      ComplexPortal NAS for lysosomal lumen localization of the soluble lysosomal
      hydrolase.
    action: ACCEPT
    reason: >-
      Correct core compartment; consistent with experimental lysosomal
      localization and the enzyme's biology.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:1905379
    label: beta-N-acetylhexosaminidase complex
  evidence_type: IPI
  original_reference_id: PMID:16698036
  qualifier: part_of
  review:
    summary: >-
      Core complex membership. The beta subunit is part of the
      beta-N-acetylhexosaminidase complex (Hex A alpha-beta heterodimer and Hex B
      beta-beta homodimer). This is the informative representation of the HEXA
      interaction and the homodimer.
    action: ACCEPT
    reason: >-
      Directly supported by the Hex A crystal structure and by the biochemistry of
      subunit association; captures the biologically central complexes.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: >-
        hexosaminidase A is
        CC       a heterodimer composed of one subunit alpha and one subunit beta
    - reference_id: PMID:16698036
      supporting_text: >-
        essential for the degradation of GM2
        gangliosides in the central and peripheral nervous system
- term:
    id: GO:0004563
    label: beta-N-acetylhexosaminidase activity
  evidence_type: EXP
  original_reference_id: PMID:11329289
  qualifier: enables
  review:
    summary: >-
      Experimental characterization of the Hex B (beta-beta) active site,
      identifying beta-Glu355 as the general acid/base catalytic residue and
      Asp354/Asp241 as catalytically important. Direct evidence for the beta
      subunit's catalytic activity.
    action: ACCEPT
    reason: >-
      Active-site mutagenesis and kinetics directly establish the
      beta-N-acetylhexosaminidase catalytic activity of the beta subunit.
    supported_by:
    - reference_id: PMID:11329289
      supporting_text: >-
        the general acid/base catalytic residue (Glu 314 in chitobiase and β Glu 355 in human β -hexosaminidase)
- term:
    id: GO:0004563
    label: beta-N-acetylhexosaminidase activity
  evidence_type: EXP
  original_reference_id: PMID:11707436
  qualifier: enables
  review:
    summary: >-
      Experimental catalytic activity of the beta-active site on neutral and
      sulfated glycoconjugate substrates (soluble/amphiphilic substrates, sulfated
      GAG fragments, SM2).
    action: ACCEPT
    reason: >-
      Direct biochemical demonstration of the core catalytic activity.
    supported_by:
    - reference_id: PMID:11707436
      supporting_text: >-
        Human lysosomal beta-hexosaminidases remove terminal beta-glycosidically bound
        N-acetylhexosamine residues from a number of glycoconjugates
- term:
    id: GO:0004563
    label: beta-N-acetylhexosaminidase activity
  evidence_type: EXP
  original_reference_id: PMID:9694901
  qualifier: enables
  review:
    summary: >-
      Experimental characterization of Hex A catalytic activity via a beta-subunit
      variant (Pro504Ser) affecting GM2 hydrolysis, confirming the beta subunit's
      contribution to enzymatic activity.
    action: ACCEPT
    reason: >-
      Direct experimental evidence for the catalytic activity of the Hex A
      complex containing the beta subunit.
    supported_by:
    - reference_id: PMID:9694901
      supporting_text: >-
        The GM2 gangliosidoses are caused by mutations in the genes encoding the alpha-
        (Tay-Sachs) or beta- (Sandhoff) subunits of heterodimeric beta-hexosaminidase A
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: EXP
  original_reference_id: PMID:9694901
  qualifier: located_in
  review:
    summary: >-
      Experimental subcellular localization to the lysosome (the study analysed
      transport and processing of the Hex A heterodimer bearing the beta subunit).
    action: ACCEPT
    reason: >-
      Direct experimental evidence for lysosomal localization; core compartment.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1605595
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS for lysosomal lumen localization (GM2 degradation reaction
      context).
    action: ACCEPT
    reason: >-
      Correct core compartment for the soluble lysosomal enzyme.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1605632
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS for lysosomal lumen localization (glycosphingolipid degradation
      context).
    action: ACCEPT
    reason: >-
      Correct core compartment; redundant with other lysosomal lumen annotations.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1638053
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS for lysosomal lumen localization (keratan sulfate degradation
      context).
    action: ACCEPT
    reason: >-
      Correct core compartment; redundant with other lysosomal lumen annotations.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2105001
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS for lysosomal lumen localization (dermatan sulfate degradation
      context).
    action: ACCEPT
    reason: >-
      Correct core compartment; redundant with other lysosomal lumen annotations.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2162225
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS for lysosomal lumen localization (hyaluronan fragment
      degradation context).
    action: ACCEPT
    reason: >-
      Correct core compartment; redundant with other lysosomal lumen annotations.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9638075
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS for lysosomal lumen localization (HEXB cleaving terminal GalNAc
      from dermatan sulfate).
    action: ACCEPT
    reason: >-
      Correct core compartment; redundant with other lysosomal lumen annotations.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9638076
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS for lysosomal lumen localization (HEXB cleaving terminal GlcNAc
      from hyaluronan fragments).
    action: ACCEPT
    reason: >-
      Correct core compartment; redundant with other lysosomal lumen annotations.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9638078
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS for lysosomal lumen localization (HEXB cleaving terminal GlcNAc
      from keratan sulfate).
    action: ACCEPT
    reason: >-
      Correct core compartment; redundant with other lysosomal lumen annotations.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9840833
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS for lysosomal lumen localization (Hex A/Hex B hydrolysing
      GM2A:GA2 to GM2A:LacCer).
    action: ACCEPT
    reason: >-
      Correct core compartment; redundant with other lysosomal lumen annotations.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9840884
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS for lysosomal lumen localization (Hex A/Hex S hydrolysing
      GM2A:SM2).
    action: ACCEPT
    reason: >-
      Correct core compartment; redundant with other lysosomal lumen annotations.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0007338
    label: single fertilization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS fertilization role transferred from mouse Hexb (zona block to
      polyspermy). Non-core, organism-specific developmental function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported by the mouse ortholog's characterized cortical-granule role;
      peripheral to the core lysosomal catabolic function.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: >-
        During fertilization
        CC       is responsible, at least in part, for the zona block to polyspermy
- term:
    id: GO:0060473
    label: cortical granule
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      ISS cortical-granule localization transferred from mouse Hexb. Non-core,
      oocyte-specific localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported by orthology to the mouse cortical-granule enzyme; a legitimate but
      non-core localization.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "Cytoplasmic vesicle, secretory vesicle, Cortical granule"
- term:
    id: GO:0004563
    label: beta-N-acetylhexosaminidase activity
  evidence_type: IDA
  original_reference_id: PMID:8123671
  qualifier: enables
  review:
    summary: >-
      Direct experimental assay of GM2 ganglioside hydrolysis distinguishing normal,
      Tay-Sachs and Sandhoff cells, demonstrating the enzyme's catalytic activity.
    action: ACCEPT
    reason: >-
      Direct experimental evidence for the core catalytic activity.
    supported_by:
    - reference_id: PMID:8123671
      supporting_text: >-
        cell extracts from Sandhoff
        disease patients hydrolyzed GM2 at about 10% of normal rates
- term:
    id: GO:0004563
    label: beta-N-acetylhexosaminidase activity
  evidence_type: IDA
  original_reference_id: PMID:8672428
  qualifier: enables
  review:
    summary: >-
      Direct experimental determination of the substrate specificity of the alpha-
      and beta-active sites in Hex A, using a Hex A with an inactivated beta
      subunit; establishes the catalytic activity of the beta-active site.
    action: ACCEPT
    reason: >-
      Direct experimental evidence for the beta subunit's catalytic activity within
      Hex A.
    supported_by:
    - reference_id: PMID:8672428
      supporting_text: >-
        the alpha and beta subunits in hexosaminidase A
        participate equally in the hydrolysis of neutral substrates
- term:
    id: GO:0006689
    label: ganglioside catabolic process
  evidence_type: IDA
  original_reference_id: PMID:8123671
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental evidence that the enzyme degrades GM2 ganglioside, with
      Sandhoff (HEXB-deficient) cells failing to hydrolyse GM2.
    action: ACCEPT
    reason: >-
      Direct evidence for the core ganglioside catabolic process; consistent with
      the disease mechanism.
    supported_by:
    - reference_id: PMID:8123671
      supporting_text: >-
        cell extracts from Sandhoff
        disease patients hydrolyzed GM2 at about 10% of normal rates
- term:
    id: GO:0006689
    label: ganglioside catabolic process
  evidence_type: IDA
  original_reference_id: PMID:8672428
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental evidence tied to GM2 ganglioside hydrolysis by Hex A,
      which contains the beta subunit.
    action: ACCEPT
    reason: >-
      Direct evidence for the core ganglioside catabolic process.
    supported_by:
    - reference_id: PMID:8672428
      supporting_text: >-
        Heterodimeric hexosaminidase A (alpha beta) is the only isozyme
        that can hydrolyze GM2 ganglioside in vivo
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IDA
  original_reference_id: PMID:6230359
  qualifier: enables
  review:
    summary: >-
      Direct evidence relating to beta-subunit association during Hex biosynthesis;
      reflects the beta-beta homodimerization forming Hex B.
    action: KEEP_AS_NON_CORE
    reason: >-
      The homodimerization is genuine (Hex B), but is better captured by the
      complex annotation (GO:1905379); retained as non-core.
    supported_by:
    - reference_id: PMID:6230359
      supporting_text: >-
        association with beta-chains is necessary not only for acquisition of catalytic
        activity but also for transport of alpha-chains to lysosomes
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798751
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS for extracellular localization via exocytosis of azurophil
      granule lumen proteins (neutrophil degranulation). Reflects the secreted
      granule pool.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine secreted/granule-release pool, but peripheral to the core lysosomal
      catabolic function.
    supported_by:
    - reference_id: PMID:25645918
      supporting_text: >-
        azurophilic granule-resident
        β-hexosaminidase A
- term:
    id: GO:0035578
    label: azurophil granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798751
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS for azurophil granule lumen localization, corroborated by
      neutrophil proteomics (PMID:25645918). Non-core granule pool.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real neutrophil-granule localization but peripheral to the core lysosomal
      role.
    supported_by:
    - reference_id: PMID:25645918
      supporting_text: >-
        azurophilic granule-resident
        β-hexosaminidase A
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9035982
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS for lysosomal lumen localization (defective HEXB hyaluronan
      reaction context).
    action: ACCEPT
    reason: >-
      Correct core compartment; redundant with other lysosomal lumen annotations.
    supported_by:
    - reference_id: file:human/HEXB/HEXB-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0008375
    label: acetylglucosaminyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:25645918
  qualifier: enables
  review:
    summary: >-
      IDA from the neutrophil paucimannosidic-protein study. The described activity
      is N-glycan trimming (hydrolysis) generating paucimannose, i.e. glycosidase
      (hydrolase) activity, not a glycosyltransferase reaction. The transferase
      term mis-types the enzyme's exo-glycosidase mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      HEXB is a GH20 hydrolase (EC 3.2.1.52); transferase activity contradicts the
      established mechanism/fold. Per policy the experimental annotation is flagged
      as over-annotation rather than removed; the correct MF is GO:0004563.
    supported_by:
    - reference_id: PMID:25645918
      supporting_text: >-
        azurophilic granule-resident
        β-hexosaminidase A displayed the capacity to generate paucimannosidic N-glycans
        by trimming hybrid/complex type N-glycan intermediates
- term:
    id: GO:0042582
    label: azurophil granule
  evidence_type: IDA
  original_reference_id: PMID:25645918
  qualifier: located_in
  review:
    summary: >-
      Direct experimental localization of HEXB to human neutrophil azurophilic
      granules. Genuine non-core granule pool of the enzyme.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real, experimentally demonstrated granule localization, but peripheral to the
      core lysosomal catabolic function.
    supported_by:
    - reference_id: PMID:25645918
      supporting_text: >-
        azurophilic granule-resident
        β-hexosaminidase A
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: >-
      High-throughput exosome proteomics (prostatic secretions). Reflects the
      secreted/exosomal pool of the lysosomal enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bulk-proteomics detection in exosomes is a common finding for lysosomal
      enzymes; not informative about core function.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: >-
      High-throughput NK-cell membrane proteomics. HEXB is a soluble lumenal
      hydrolase; detection in a membrane-enriched fraction likely reflects
      membrane-associated vesicle/granule co-purification rather than an intrinsic
      membrane location.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative and potentially misleading generic membrane localization from a
      bulk proteomics dataset.
- term:
    id: GO:0004563
    label: beta-N-acetylhexosaminidase activity
  evidence_type: TAS
  original_reference_id: PMID:8663217
  qualifier: enables
  review:
    summary: >-
      TAS for the core catalytic activity from the domain/substrate-specificity
      study, which mapped the beta- and alpha-subunit active-site determinants.
    action: ACCEPT
    reason: >-
      Correct core MF, supported by the study's characterization of subunit active
      sites.
    supported_by:
    - reference_id: PMID:8663217
      supporting_text: >-
        The site on the beta-subunit primarily degrades neutral
        substrates, whereas the alpha-subunit site is, in addition, active against
        sulfated substrates
core_functions:
- description: >-
    Lysosomal beta-N-acetylhexosaminidase (EC 3.2.1.52): hydrolyses terminal
    non-reducing N-acetyl-beta-D-hexosamine residues from glycoconjugates. The
    beta subunit provides a catalytic active site (with beta-Glu355 as the general
    acid/base) in both Hex A (alpha-beta) and Hex B (beta-beta).
  molecular_function:
    id: GO:0004563
    label: beta-N-acetylhexosaminidase activity
  supported_by:
  - reference_id: PMID:11329289
    supporting_text: >-
      the general acid/base catalytic residue (Glu 314 in chitobiase and β Glu 355 in human β -hexosaminidase)
  - reference_id: file:human/HEXB/HEXB-uniprot.txt
    supporting_text: "Hydrolyzes the non-reducing end N-acetyl-D-hexosamine"
- description: >-
    As part of Hex A (with HEXA and the GM2 activator protein), the beta subunit
    is required for degradation of GM2 ganglioside; loss of the beta subunit
    causes ganglioside storage (Sandhoff disease).
  molecular_function:
    id: GO:0004563
    label: beta-N-acetylhexosaminidase activity
  directly_involved_in:
  - id: GO:0006689
    label: ganglioside catabolic process
  in_complex:
    id: GO:1905379
    label: beta-N-acetylhexosaminidase complex
  locations:
  - id: GO:0043202
    label: lysosomal lumen
  supported_by:
  - reference_id: PMID:8672428
    supporting_text: >-
      Heterodimeric hexosaminidase A (alpha beta) is the only isozyme
      that can hydrolyze GM2 ganglioside in vivo, requiring the presence of the GM2
      activator protein
  - reference_id: PMID:8123671
    supporting_text: >-
      cell extracts from Sandhoff
      disease patients hydrolyzed GM2 at about 10% of normal rates
- description: >-
    The lysosomal hexosaminidases degrade glycosaminoglycan fragments (dermatan
    sulfate, keratan sulfate, hyaluronan) by removing terminal beta-hexosamine
    residues, acting in the lysosomal lumen.
  molecular_function:
    id: GO:0004563
    label: beta-N-acetylhexosaminidase activity
  directly_involved_in:
  - id: GO:0030203
    label: glycosaminoglycan metabolic process
  in_complex:
    id: GO:1905379
    label: beta-N-acetylhexosaminidase complex
  locations:
  - id: GO:0043202
    label: lysosomal lumen
  supported_by:
  - reference_id: PMID:11707436
    supporting_text: >-
      sulfated GAG fragments, and the sulfated glycosphingolipid SM2
  - reference_id: PMID:6458607
    supporting_text: >-
      Incubation of
      keratan sulfate-derived oligosaccharides with beta-N-acetylhexosaminidase A
      analogously resulted in the liberation of N-acetylglucosamine-6-sulfate
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF: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: file:human/HEXB/HEXB-uniprot.txt
  title: UniProtKB entry P07686 (HEXB_HUMAN), Beta-hexosaminidase subunit beta
  findings: []
- id: PMID:11329289
  title: Characterization of the Glu and Asp residues in the active site of human
    beta-hexosaminidase B.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text available and cached; identifies beta-Glu355 as the general
      acid/base catalytic residue and Asp354/Asp241 as catalytically important,
      directly establishing the beta subunit active site.
- id: PMID:11707436
  title: Physiological substrates for human lysosomal beta -hexosaminidase S.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes substrate range of the human lysosomal hexosaminidases,
      including sulfated GAG fragments and neutral N-glycans.
- id: PMID:16698036
  title: 'Crystallographic structure of human beta-hexosaminidase A: interpretation
    of Tay-Sachs mutations and loss of GM2 ganglioside hydrolysis.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Hex A crystal structure; the IPI cites HEXA (P06865) as partner, i.e. the
      genuine alpha-beta heterodimer, supporting complex membership (GO:1905379).
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Bulk membrane proteomics; supports only a generic, non-core membrane
      detection of the soluble lysosomal enzyme.
- 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; supports only a non-core secreted/exosomal pool.
- id: PMID:25645918
  title: Human neutrophils secrete bioactive paucimannosidic proteins from azurophilic
    granules into pathogen-infected sputum.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Demonstrates azurophil-granule localization and N-glycan trimming
      (hydrolase) activity; does not support a glycosyltransferase MF.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput AP-MS interactome; supports only bare protein binding.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput Y2H interactome; supports only bare protein binding.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput interactome; supports only bare protein binding.
- 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: >-
      High-throughput AP-MS interactome (BioPlex 3.0), HEXA partner; supports only
      bare protein binding.
- id: PMID:6230359
  title: Association of alpha- and beta-subunits during the biosynthesis of beta-hexosaminidase
    in cultured human fibroblasts.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Subunit association during biosynthesis; supports beta-subunit homo/hetero
      association and lysosomal transport.
- id: PMID:6458607
  title: Liberation of N-acetylglucosamine-6-sulfate by human beta-N-acetylhexosaminidase
    A.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Direct evidence that the enzyme releases N-acetylglucosamine-6-sulfate from
      keratan sulfate-derived oligosaccharides (GAG catabolism).
- id: PMID:8123671
  title: Classification of disorders of GM2 ganglioside hydrolysis using 3H-GM2 as
    substrate.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      GM2 hydrolysis assays; Sandhoff (HEXB-deficient) cells fail to hydrolyse GM2,
      supporting ganglioside catabolism.
- id: PMID:8663217
  title: Identification of domains in human beta-hexosaminidase that determine substrate
    specificity.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Maps beta- vs alpha-subunit active-site substrate determinants (neutral vs
      sulfated substrates).
- id: PMID:8672428
  title: Direct determination of the substrate specificity of the alpha-active site
    in heterodimeric beta-hexosaminidase A.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Directly determines alpha- and beta-active-site specificities in Hex A;
      confirms only Hex A degrades GM2 in vivo.
- id: PMID:9694901
  title: A Pro504 --> Ser substitution in the beta-subunit of beta-hexosaminidase
    A inhibits alpha-subunit hydrolysis of GM2 ganglioside, resulting in chronic Sandhoff
    disease.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Beta-subunit variant characterization; links beta subunit to Hex A GM2
      hydrolysis and lysosomal transport (Sandhoff disease).
- id: Reactome:R-HSA-1605595
  title: bHEXA hydrolyzes GM2A:GM2 to GM2A:GM3
  findings: []
- id: Reactome:R-HSA-1605632
  title: bHEXA,bHEXB hydrolyze PSAP(195-273):Gb4Cer:PE
  findings: []
- id: Reactome:R-HSA-1638053
  title: HEXA cleaves the terminal GlcNAc from keratan sulfate
  findings: []
- id: Reactome:R-HSA-2105001
  title: HEXA cleaves the terminal GalNAc from DS
  findings: []
- id: Reactome:R-HSA-2162225
  title: HEXA cleaves the terminal GlcNAc from small HA fragments
  findings: []
- id: Reactome:R-HSA-6798751
  title: Exocytosis of azurophil granule lumen proteins
  findings: []
- id: Reactome:R-HSA-9035982
  title: Defective HEXB does not cleave the terminal GalNAc from HA fragments
  findings: []
- id: Reactome:R-HSA-9638075
  title: HEXB cleaves the terminal GalNAc from DS
  findings: []
- id: Reactome:R-HSA-9638076
  title: HEXB cleaves the terminal GlcNAc from small HA fragments
  findings: []
- id: Reactome:R-HSA-9638078
  title: HEXB cleaves the terminal GlcNAc from keratan sulfate
  findings: []
- id: Reactome:R-HSA-9840833
  title: bHEXA,bHEXB hydrolyze GM2A:GA2 to GM2A:LacCer
  findings: []
- id: Reactome:R-HSA-9840884
  title: bHEXA,bHEXS hydrolyze GM2A:SM2
  findings: []