id: P04062
gene_symbol: GBA
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  GBA (GBA1) encodes lysosomal acid glucosylceramidase (glucocerebrosidase, GCase;
  EC 3.2.1.45), a glycoside hydrolase that carries out the penultimate step of
  glycosphingolipid degradation. Within the lysosome it hydrolyses glucosylceramide
  (glucocerebroside) to ceramide and glucose, and also hydrolyses glucosylsphingosine.
  Full activity requires the sphingolipid activator protein saposin C (produced from
  prosaposin/PSAP) together with negatively charged phospholipids, which promote the
  enzyme's association with the substrate-bearing membrane. Because it lacks
  mannose-6-phosphate, GCase reaches the lysosome by a mannose-6-phosphate-independent
  route: it binds the lysosomal integral membrane protein LIMP-2 (SCARB2) in the
  endoplasmic reticulum and is co-transported through the Golgi and trans-Golgi network
  to the lysosome. As a retaining beta-glucosidase it can also catalyse transglucosylation
  side reactions in vitro, transferring glucose between glucosylceramide and cholesterol
  (forming/degrading cholesteryl-glucoside) and acting weakly on galactosylceramide.
  Deficiency of GCase causes Gaucher disease, the most common lysosomal storage disorder,
  and heterozygous GBA1 variants are the numerically greatest genetic risk factor for
  Parkinson disease and dementia with Lewy bodies.
alternative_products:
- name: Long
  id: P04062-1
- name: Short
  id: P04062-2
  sequence_note: VSP_018800
- name: '3'
  id: P04062-3
  sequence_note: VSP_025216, VSP_025217, VSP_025218
- name: '4'
  id: P04062-4
  sequence_note: VSP_054655
- name: '5'
  id: P04062-5
  sequence_note: VSP_054656
existing_annotations:
- term:
    id: GO:0006680
    label: glucosylceramide catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation to the core biological process of GBA1:
      lysosomal degradation of glucosylceramide. This is the central, best-supported
      function of the gene and is corroborated by multiple experimental annotations.
    action: ACCEPT
    reason: >-
      GBA hydrolyses glucosylceramide to ceramide and glucose in the lysosome; this
      is the defining catabolic role of the enzyme and its deficiency causes lysosomal
      GlcCer accumulation (Gaucher disease). The IBA term is at the correct level of
      specificity.
    supported_by:
    - reference_id: file:human/GBA/GBA-uniprot.txt
      supporting_text: >-
        Glucosylceramidase that catalyzes, within the lysosomal compartment, the
        hydrolysis of glucosylceramides
- term:
    id: GO:0004348
    label: glucosylceramidase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) annotation to the core molecular function: glucosylceramidase
      (glucocerebrosidase, EC 3.2.1.45). This is the exact molecular activity that
      defines GBA1 and is supported by numerous IDA/IMP annotations.
    action: ACCEPT
    reason: >-
      This is the primary catalytic activity of GBA and matches the enzyme's defining
      EC number 3.2.1.45. Correct term, correct specificity. Selected as the core
      molecular function.
    supported_by:
    - reference_id: file:human/GBA/GBA-uniprot.txt
      supporting_text: >-
        Glucosylceramidase that catalyzes, within the lysosomal compartment, the
        hydrolysis of glucosylceramides
- term:
    id: GO:0004336
    label: galactosylceramidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic annotation (RHEA/EC 3.2.1.46 mapping) to galactosylceramidase activity.
      GBA can hydrolyse galactosylceramides in vitro, but with substantially lower
      activity than glucosylceramides.
    action: KEEP_AS_NON_CORE
    reason: >-
      This is a genuine but minor/secondary in-vitro activity of GBA, not its
      physiological role (that is glucosylceramide hydrolysis). The IEA mapping is
      biologically defensible; retain as a non-core secondary activity rather than
      remove.
    supported_by:
    - reference_id: file:human/GBA/GBA-uniprot.txt
      supporting_text: >-
        Catalyzes the hydrolysis of galactosylceramides/GalCers
- term:
    id: GO:0004348
    label: glucosylceramidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic annotation (ARBA/InterPro/RHEA, EC 3.2.1.45) to the core
      glucosylceramidase activity. Redundant with the experimental and IBA annotations
      to the same term.
    action: ACCEPT
    reason: >-
      Correct core molecular function, independently derived from sequence/reaction
      mappings; consistent with the experimental evidence.
    supported_by:
    - reference_id: file:human/GBA/GBA-uniprot.txt
      supporting_text: >-
        Glucosylceramidase that catalyzes, within the lysosomal compartment, the
        hydrolysis of glucosylceramides
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation to lysosomal membrane. GBA is a peripheral (lumenal-side)
      lysosomal membrane-associated protein; its membrane association is promoted by
      saposin C and by binding to LIMP-2.
    action: ACCEPT
    reason: >-
      Consistent with UniProt subcellular location (Lysosome membrane; peripheral
      membrane protein, lumenal side) and with experimental (IDA/HDA) annotations to
      the same term.
    supported_by:
    - reference_id: file:human/GBA/GBA-uniprot.txt
      supporting_text: Lysosome membrane
- term:
    id: GO:0006665
    label: sphingolipid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro-based electronic annotation to the broad parent process sphingolipid
      metabolic process. GBA's GlcCer catabolism is a step of sphingolipid/glycosphingolipid
      metabolism.
    action: KEEP_AS_NON_CORE
    reason: >-
      Biologically correct but general; the more specific glucosylceramide catabolic
      process (GO:0006680) is the core annotation. Retain this broader IEA as non-core.
    supported_by:
    - reference_id: file:human/GBA/GBA-uniprot.txt
      supporting_text: Sphingolipid metabolism.
- term:
    id: GO:0008422
    label: beta-glucosidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: >-
      ARBA electronic annotation to the broad parent activity beta-glucosidase. GBA is
      a retaining beta-glucosidase; it also hydrolyses other beta-glucosides such as
      bile-acid-3-O-beta-glucoside and cholesteryl-beta-glucoside.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but broad relative to the specific glucosylceramidase activity. Supported
      experimentally (e.g. bile acid beta-glucosidase activity, PMID:22659419). Retain
      as a non-core parent-level activity.
    supported_by:
    - reference_id: PMID:22659419
      supporting_text: Here we show that GBA1 also hydrolyses BG.
- term:
    id: GO:0016241
    label: regulation of macroautophagy
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA electronic annotation to regulation of macroautophagy. Effects of GBA on
      autophagy are downstream consequences of loss of GCase activity (impaired
      autophagy-lysosome pathway), not a distinct molecular action of the enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GCase deficiency compromises autophagic lysosome reformation and macroautophagy
      (PMID:27378698), but this is an indirect, disease-state consequence of losing the
      catabolic enzyme rather than a direct regulatory role of GBA. Over-annotation of
      the causal chain.
    supported_by:
    - reference_id: PMID:27378698
      supporting_text: >-
        ALR dysfunction was accompanied by impairment of macroautophagy and
        chaperone-mediated autophagy
- term:
    id: GO:0030163
    label: protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA electronic annotation to protein catabolic process. GBA is a lipid-degrading
      glycosidase, not a protease; any effect on protein catabolism is indirect (via the
      autophagy-lysosome pathway).
    action: REMOVE
    reason: >-
      This IEA is a spurious/over-general electronic inference. GBA does not catalyse
      protein catabolism; it hydrolyses glucosylceramide. The apparent link runs through
      lysosomal/autophagic dysfunction in GCase-deficient cells, which does not justify a
      direct 'protein catabolic process' annotation.
- term:
    id: GO:0042176
    label: regulation of protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA electronic annotation to regulation of protein catabolic process. As with
      protein catabolic process, this is an indirect consequence of GCase deficiency on
      lysosomal/autophagic degradation, not a direct function of GBA.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GCase loss impairs lysosomal degradation of substrates such as alpha-synuclein, but
      GBA does not itself regulate protein catabolism; this electronic mapping over-annotates
      a downstream disease phenotype.
    supported_by:
    - reference_id: PMID:27378698
      supporting_text: >-
        neurons are unable to maintain the pool of mature and functional lysosomes required
        for the autophagic clearance of α-synuclein
- term:
    id: GO:0042391
    label: regulation of membrane potential
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA electronic annotation to regulation of membrane potential. There is no direct
      evidence that GBA, a lysosomal lipid hydrolase, regulates membrane potential; any
      link is indirect (mitochondrial membrane potential changes in GCase-deficient neurons).
    action: REMOVE
    reason: >-
      Over-general electronic inference with no biological support for a direct role.
      Changes in mitochondrial membrane potential in GCase-deficient cells (PMID:26388395)
      are secondary consequences of enzyme loss, not a molecular function of GBA.
- term:
    id: GO:0050295
    label: steryl-beta-glucosidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: >-
      RHEA-based electronic annotation to steryl-beta-glucosidase activity. GBA can
      hydrolyse cholesteryl-3-beta-D-glucoside (GlcChol) to cholesterol and glucose
      (RHEA:11956), a demonstrated in-vitro activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine secondary activity supported experimentally (PMID:24211208, PMID:26724485)
      but distinct from and much less prominent than GlcCer hydrolysis. Retain as non-core.
    supported_by:
    - reference_id: file:human/GBA/GBA-uniprot.txt
      supporting_text: >-
        Can also hydrolyze cholesteryl 3-beta-D-glucoside producing glucose and cholesterol
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21098288
  qualifier: enables
  review:
    summary: >-
      IPI protein-binding annotation from an IntAct interaction; the partner (UniProtKB:P17987)
      is TCP1/CCT, a chaperonin subunit implicated in GCase folding.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare 'protein binding' is uninformative. The underlying interaction with TCP1 (TRiC/CCT)
      relates to GCase maturation/quality control (PMID:21098288), but the GO term itself
      conveys no functional specificity and should not be treated as a core function.
    supported_by:
    - reference_id: PMID:21098288
      supporting_text: >-
        reduced binding of GCase to TCP1 ring complex (TRiC), a regulator of correct protein
        folding, may result in defective maturation of nascent GCase in GD cells
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic annotation (ARBA + transfer from mouse ortholog) to signaling receptor
      binding. This most plausibly reflects GBA binding to its trafficking receptor
      LIMP-2/SCARB2.
    action: KEEP_AS_NON_CORE
    reason: >-
      The biologically meaningful binding partner is LIMP-2/SCARB2 (a CD36-family
      scavenger-receptor protein). 'Signaling receptor binding' is imprecise but points to
      the real LIMP-2 interaction; retain as non-core rather than as a molecular function.
    supported_by:
    - reference_id: file:human/GBA/GBA-uniprot.txt
      supporting_text: Interacts with SCARB2
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation (Ensembl transfer from mouse ortholog) to lysosome. GBA is a
      lysosomal enzyme; this is a core localization.
    action: ACCEPT
    reason: >-
      Well established: GCase acts within the lysosome and reaches it via the LIMP-2 route.
      Consistent with experimental IMP annotation to lysosome (PMID:25202012).
    supported_by:
    - reference_id: file:human/GBA/GBA-uniprot.txt
      supporting_text: >-
        Glucosylceramidase that catalyzes, within the lysosomal compartment, the
        hydrolysis of glucosylceramides
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation to endoplasmic reticulum, a biosynthetic/transit compartment
      where the GCase-LIMP-2 transport complex forms.
    action: KEEP_AS_NON_CORE
    reason: >-
      GBA transits the ER, where it associates with LIMP-2 before lysosomal delivery
      (PMID:40159502). Real but not the site of function; retain as non-core transit location.
    supported_by:
    - reference_id: PMID:40159502
      supporting_text: The GCase/LIMP-2 transport complex forms within the endoplasmic reticulum
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation to Golgi apparatus, a transit compartment on the GCase-LIMP-2
      route to the lysosome.
    action: KEEP_AS_NON_CORE
    reason: >-
      GBA traverses the Golgi/TGN en route to the lysosome. Transit location, not the site
      of catalytic function; retain as non-core.
    supported_by:
    - reference_id: PMID:40159502
      supporting_text: travels through the trans-Golgi network to the lysosome
- term:
    id: GO:0005802
    label: trans-Golgi network
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation to trans-Golgi network, a transit compartment on the
      GCase-LIMP-2 trafficking route.
    action: KEEP_AS_NON_CORE
    reason: >-
      The GCase-LIMP-2 complex travels through the trans-Golgi network to the lysosome.
      Transit location; retain as non-core.
    supported_by:
    - reference_id: PMID:40159502
      supporting_text: travels through the trans-Golgi network to the lysosome
- term:
    id: GO:0006680
    label: glucosylceramide catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation (ARBA + mouse ortholog transfer) to the core biological process,
      glucosylceramide catabolism. Redundant with the IBA and experimental annotations.
    action: ACCEPT
    reason: >-
      Correct core process, independently supported by sequence-based inference and by
      multiple experimental annotations to the same term.
    supported_by:
    - reference_id: file:human/GBA/GBA-uniprot.txt
      supporting_text: >-
        Glucosylceramidase that catalyzes, within the lysosomal compartment, the
        hydrolysis of glucosylceramides
- term:
    id: GO:0006914
    label: autophagy
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation to autophagy. GBA's connection to autophagy is indirect: loss
      of GCase activity impairs the autophagy-lysosome pathway.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Autophagy defects are a downstream consequence of GCase deficiency (PMID:27378698),
      not a direct function of GBA in autophagy. Over-annotation via the disease phenotype.
    supported_by:
    - reference_id: PMID:27378698
      supporting_text: autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase
- term:
    id: GO:0007040
    label: lysosome organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation to lysosome organization. Effects of GBA on lysosome
      biogenesis/reformation are indirect consequences of enzyme deficiency.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GCase deficiency impairs autophagic lysosome reformation (PMID:27378698), but GBA is
      a lumenal hydrolase and does not directly organize the lysosome. Downstream phenotype,
      over-annotated as a direct process.
    supported_by:
    - reference_id: PMID:27378698
      supporting_text: which regenerates functional lysosomes from autolysosomes formed during macroautophagy
- term:
    id: GO:0008203
    label: cholesterol metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation to cholesterol metabolic process. GBA can transglucosylate
      cholesterol (forming/degrading cholesteryl-glucoside), linking it to cholesterol
      metabolism.
    action: KEEP_AS_NON_CORE
    reason: >-
      GBA participates in cholesterol glucosylation/de-glucosylation via transglucosylation
      (PMID:24211208, PMID:26724485), a genuine but secondary activity. Retain as non-core;
      the primary role is glycosphingolipid catabolism.
    supported_by:
    - reference_id: file:human/GBA/GBA-uniprot.txt
      supporting_text: Catalyzes the glucosylation of cholesterol
- term:
    id: GO:0009247
    label: glycolipid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation to glycolipid biosynthetic process, reflecting the
      transglucosylation reaction by which GBA can form cholesteryl-glucoside from GlcCer.
    action: KEEP_AS_NON_CORE
    reason: >-
      GBA can synthesize glucosylated cholesterol (a glycolipid) by transglucosylation
      (PMID:24211208), so the annotation is defensible, but this is a minor side reaction
      of a fundamentally catabolic enzyme. Retain as non-core.
    supported_by:
    - reference_id: file:human/GBA/GBA-uniprot.txt
      supporting_text: Catalyzes the glucosylation of cholesterol
- term:
    id: GO:0009267
    label: cellular response to starvation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation transferred from the mouse ortholog to cellular response to
      starvation, likely reflecting the autophagy/mTOR link in GCase-deficient cells.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      No direct evidence that GBA mediates a starvation response; the association runs
      through autophagy/TOR signalling downstream of enzyme deficiency. Over-annotation.
- term:
    id: GO:0009268
    label: response to pH
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation (rat ortholog transfer) to response to pH. GBA has an acidic pH
      optimum (~5.3) suited to the lysosome, but 'response to pH' as a biological process is
      not a documented function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The enzyme's acidic pH optimum reflects its lysosomal working environment, not
      participation in a 'response to pH' process. Electronic transfer over-annotation.
- term:
    id: GO:0032006
    label: regulation of TOR signaling
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation to regulation of TOR signaling. In GCase-deficient cells mTOR
      activity (phospho-S6K) is altered, but this is a downstream consequence of impaired
      autophagic lysosome reformation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Altered mTOR signalling in GCase-deficient cells (PMID:27378698) is an indirect effect
      of enzyme loss, not a direct regulatory role of GBA in TOR signalling.
    supported_by:
    - reference_id: PMID:27378698
      supporting_text: >-
        A decrease in phopho-S6K levels, a marker of mTOR activity, was observed in models
        of GCase deficiency
- term:
    id: GO:0033574
    label: response to testosterone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation transferred from the rat ortholog to response to testosterone.
      This is a peripheral, expression-level physiological response with no direct mechanistic
      role for GBA.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Hormone-response terms transferred electronically from a rodent ortholog do not
      describe a molecular/biological function of human GBA. Peripheral over-annotation.
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation to lysosomal lumen. GBA acts on the lumenal side of the lysosomal
      membrane and is a lumenal/lumenal-side-membrane-associated hydrolase.
    action: ACCEPT
    reason: >-
      Consistent with UniProt (lumenal side, lysosome) and with the enzyme's function acting
      on lumenal glucosylceramide. Appropriate core localization term.
    supported_by:
    - reference_id: file:human/GBA/GBA-uniprot.txt
      supporting_text: Lumenal side
- term:
    id: GO:0043627
    label: response to estrogen
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation transferred from the rat ortholog to response to estrogen; a
      peripheral hormone-response term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Electronically transferred rodent hormone-response annotation; not a direct function of
      human GBA. Peripheral over-annotation.
- term:
    id: GO:0046527
    label: glucosyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic annotation to glucosyltransferase activity, reflecting GBA's transglucosylation
      side reaction (glucose transfer from GlcCer to cholesterol).
    action: KEEP_AS_NON_CORE
    reason: >-
      As a retaining glycosidase, GBA can transfer glucose to acceptors such as cholesterol
      (PMID:24211208, PMID:26724485). This is a genuine but secondary transglucosylase side
      activity, not a canonical anabolic glucosyltransferase role. Retain as non-core.
    supported_by:
    - reference_id: file:human/GBA/GBA-uniprot.txt
      supporting_text: >-
        a transglucosylation reaction where glucose is transferred from GlcCer to cholesterol
- term:
    id: GO:0061436
    label: establishment of skin barrier
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation (rat ortholog transfer) to establishment of skin barrier. GlcCer
      hydrolysis in the epidermis contributes to the lipid lamellae of the stratum corneum, so
      there is a physiological connection, but this is a tissue-level developmental outcome.
    action: KEEP_AS_NON_CORE
    reason: >-
      Epidermal GCase activity contributes to skin permeability-barrier lipids; the link is
      real but tissue-specific and downstream of the core catabolic activity. Retain as non-core.
- term:
    id: GO:0071548
    label: response to dexamethasone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation transferred from the rat ortholog to response to dexamethasone; a
      peripheral pharmacological-response term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Rodent electronic transfer of a drug-response term; not a direct function of human GBA.
      Peripheral over-annotation.
- term:
    id: GO:0097066
    label: response to thyroid hormone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation transferred from the rat ortholog to response to thyroid hormone; a
      peripheral hormone-response term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Electronically transferred rodent hormone-response annotation; not a direct function of
      human GBA. Peripheral over-annotation.
- term:
    id: GO:0098773
    label: skin epidermis development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation (rat ortholog transfer) to skin epidermis development, related to the
      role of epidermal GlcCer metabolism in skin barrier formation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Connected to epidermal glucosylceramide processing but a tissue-level developmental term,
      downstream of the enzyme's catabolic activity. Retain as non-core.
- term:
    id: GO:1901805
    label: beta-glucoside catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation (rat ortholog transfer) to beta-glucoside catabolic process, a parent
      process consistent with GBA's beta-glucosidase activity on various beta-glucosides.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but broad; the specific glucosylceramide catabolic process is the core BP. Retain
      as a non-core parent-level process.
    supported_by:
    - reference_id: PMID:22659419
      supporting_text: Here we show that GBA1 also hydrolyses BG.
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IPI
  original_reference_id: PMID:40159502
  qualifier: located_in
  review:
    summary: >-
      ComplexPortal annotation (from the cryo-EM GCase-LIMP-2 complex study) placing GBA at the
      lysosomal membrane via its LIMP-2 complex.
    action: ACCEPT
    reason: >-
      GBA associates with the lysosomal membrane, in part through its complex with the LIMP-2
      membrane protein. Consistent with UniProt and other membrane-localization annotations.
    supported_by:
    - reference_id: PMID:40159502
      supporting_text: >-
        the lysosomal hydrolase β-glucocerebrosidase (GCase) is a prominent example for such an
        M6PR-independent transport mechanism
- term:
    id: GO:0019377
    label: glycolipid catabolic process
  evidence_type: NAS
  original_reference_id: PMID:40159502
  qualifier: involved_in
  review:
    summary: >-
      NAS (ComplexPortal) annotation to glycolipid catabolic process. GBA hydrolyses the glycolipid
      glucosylceramide, so this parent-level catabolic process is correct.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but broader than the specific glucosylceramide catabolic process (GO:0006680) chosen
      as core. Retain as a non-core parent-level process.
    supported_by:
    - reference_id: PMID:40159502
      supporting_text: hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide
- term:
    id: GO:0009247
    label: glycolipid biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:24211208
  qualifier: involved_in
  review:
    summary: >-
      IDA annotation: purified GBA catalyses cholesterol glucosylation (formation of the glycolipid
      cholesteryl-glucoside) by transglucosylation from GlcCer.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally demonstrated transglucosylation forming a glycolipid (cholesteryl-glucoside), a
      genuine secondary/anabolic side reaction of this catabolic enzyme. Retain as non-core.
    supported_by:
    - reference_id: PMID:24211208
      supporting_text: Cholesterol glucosylation is catalyzed by transglucosylation reaction of
- term:
    id: GO:0009247
    label: glycolipid biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:26724485
  qualifier: involved_in
  review:
    summary: >-
      IDA annotation: recombinant GBA forms glucosylated cholesterol (GlcChol) via transglucosylation,
      supporting a glycolipid-biosynthetic (transglucosylase) capacity in vitro.
    action: KEEP_AS_NON_CORE
    reason: >-
      Demonstrated transglucosylation-based synthesis of a sterol-glycolipid; a real but secondary
      activity of a fundamentally catabolic enzyme. Retain as non-core.
    supported_by:
    - reference_id: PMID:26724485
      supporting_text: both GBA and GBA2 are able to catalyze in vitro the transfer of glucosyl-moieties from GlcCer to cholesterol
- term:
    id: GO:1905146
    label: lysosomal protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:26392287
  qualifier: involved_in
  review:
    summary: >-
      IDA annotation (ParkinsonsUK-UCL) linking GBA to lysosomal protein catabolism, via GCase gene
      therapy reducing alpha-synuclein accumulation in PD models.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Restoring GCase reduces lysosomal accumulation of alpha-synuclein (PMID:26392287), but GBA is a
      lipid glycosidase, not a protease; its effect on lysosomal protein catabolism is indirect (via
      restored lysosomal/autophagic function). Over-annotation of a downstream phenotype.
    supported_by:
    - reference_id: PMID:26392287
      supporting_text: >-
        increasing GCase through AAV-GBA1 intra-cerebral gene delivery in two PD rodent models would
        reduce the accumulation of α-synuclein
- term:
    id: GO:0050728
    label: negative regulation of inflammatory response
  evidence_type: IMP
  original_reference_id: PMID:19279008
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation: knockdown of GBA1 enhances a pro-inflammatory (p38delta/IL-6) response in MCF-7
      cells, implying an anti-inflammatory role via ceramide production.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported experimentally, but the effect is an indirect signalling consequence of GBA-generated
      ceramide (an anti-inflammatory lipid) rather than a direct role of GBA in inflammation. Retain as
      non-core downstream physiology.
    supported_by:
    - reference_id: PMID:19279008
      supporting_text: possible role for ceramide as an anti-inflammatory lipid
- term:
    id: GO:0043409
    label: negative regulation of MAPK cascade
  evidence_type: IMP
  original_reference_id: PMID:19279008
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation: the GBA1-ceramide pathway terminates p38 (MAPK) activation; GBA knockdown
      potentiates p38 activation in MCF-7 cells.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real but indirect: GBA affects MAPK (p38) signalling through the ceramide it produces, not by
      acting on the MAPK cascade directly. Retain as non-core downstream signalling role.
    supported_by:
    - reference_id: PMID:19279008
      supporting_text: implicating the GBA1-ceramide pathway in the termination of p38 activation
- term:
    id: GO:0004348
    label: glucosylceramidase activity
  evidence_type: IMP
  original_reference_id: PMID:25584808
  qualifier: enables
  review:
    summary: >-
      IMP annotation: miRNAs that modulate GBA1 change glucocerebrosidase activity in Gaucher cells,
      confirming the enzyme's glucosylceramidase (GCase) activity as the assayed readout.
    action: ACCEPT
    reason: >-
      Supports the core molecular function via functional modulation experiments in patient cells.
      Correct core activity.
    supported_by:
    - reference_id: PMID:25584808
      supporting_text: To determine whether miRNAs can affect glucocerebrosidase activity
- term:
    id: GO:0006680
    label: glucosylceramide catabolic process
  evidence_type: IMP
  original_reference_id: PMID:25584808
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation linking GBA1 modulation to glucosylceramide catabolism, the enzyme's core process,
      in Gaucher disease cells.
    action: ACCEPT
    reason: >-
      Consistent with the core catabolic role; modulating GBA1 activity affects GlcCer degradation.
    supported_by:
    - reference_id: PMID:25584808
      supporting_text: miRNAs that modulate glucocerebrosidase activity in Gaucher
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1605591
  qualifier: located_in
  review:
    summary: >-
      TAS annotation from Reactome (GBA1:SAPC hydrolyzes GlcCer) placing GBA at the lysosomal membrane,
      where it acts together with saposin C on membrane-inserted glucosylceramide.
    action: ACCEPT
    reason: >-
      Consistent with UniProt subcellular location and with the saposin-C-dependent, membrane-associated
      mode of action. Appropriate localization.
    supported_by:
    - reference_id: file:human/GBA/GBA-uniprot.txt
      supporting_text: Lysosome membrane
- term:
    id: GO:0004348
    label: glucosylceramidase activity
  evidence_type: IDA
  original_reference_id: PMID:22659419
  qualifier: enables
  review:
    summary: >-
      IDA annotation: recombinant GBA1 (lysosomal glucocerebrosidase) hydrolyses glucosylceramide and
      also bile-acid-beta-glucoside, confirming its glucosylceramidase activity.
    action: ACCEPT
    reason: >-
      Direct assay of GBA1 glucosylceramidase activity; supports the core molecular function.
    supported_by:
    - reference_id: PMID:22659419
      supporting_text: >-
        Beta-glucosidase 1 (GBA1; lysosomal glucocerebrosidase) and β-glucosidase 2 (GBA2, non-lysosomal
        glucocerebrosidase) both have glucosylceramide as a main natural substrate
- term:
    id: GO:0004348
    label: glucosylceramidase activity
  evidence_type: IMP
  original_reference_id: PMID:22659419
  qualifier: enables
  review:
    summary: >-
      IMP annotation: comparison of GBA1-deficient and wild-type material (mice/humans) demonstrates GBA1's
      glucosylceramidase activity as the natural role.
    action: ACCEPT
    reason: >-
      Loss-of-function comparison confirms the core glucosylceramidase activity of GBA1.
    supported_by:
    - reference_id: PMID:22659419
      supporting_text: >-
        both have glucosylceramide as a main natural substrate
- term:
    id: GO:0008422
    label: beta-glucosidase activity
  evidence_type: IDA
  original_reference_id: PMID:22659419
  qualifier: enables
  review:
    summary: >-
      IDA annotation: GBA1 directly hydrolyses bile-acid-3-O-beta-glucoside, demonstrating broad
      beta-glucosidase activity beyond glucosylceramide.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct broad activity supported by direct assay, but general relative to the specific
      glucosylceramidase activity. Retain as non-core parent-level activity.
    supported_by:
    - reference_id: PMID:22659419
      supporting_text: Here we show that GBA1 also hydrolyses BG.
- term:
    id: GO:0008422
    label: beta-glucosidase activity
  evidence_type: IMP
  original_reference_id: PMID:22659419
  qualifier: enables
  review:
    summary: >-
      IMP annotation: residual bile-acid-beta-glucoside hydrolysis in GBA1-deficient vs wild-type material
      supports GBA1's beta-glucosidase activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supports broad beta-glucosidase activity via loss-of-function comparison; general relative to the
      core glucosylceramidase term. Retain as non-core.
    supported_by:
    - reference_id: PMID:22659419
      supporting_text: GBA1 and GBA2 activities had characteristic differences between the studied fibroblast, liver and brain samples
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      ISS annotation (from mouse ortholog) to endoplasmic reticulum, the biosynthetic/transit compartment
      where GCase associates with LIMP-2.
    action: KEEP_AS_NON_CORE
    reason: >-
      ER is a transit/complex-formation compartment (PMID:40159502), not the site of function. Retain as
      non-core, consistent with the IEA ER annotation.
    supported_by:
    - reference_id: PMID:40159502
      supporting_text: The GCase/LIMP-2 transport complex forms within the endoplasmic reticulum
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      ISS annotation (from mouse ortholog) to Golgi apparatus, a transit compartment on the GCase-LIMP-2
      route to the lysosome.
    action: KEEP_AS_NON_CORE
    reason: >-
      Transit location; not the site of catalytic function. Retain as non-core.
    supported_by:
    - reference_id: PMID:40159502
      supporting_text: travels through the trans-Golgi network to the lysosome
- term:
    id: GO:0005802
    label: trans-Golgi network
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      ISS annotation (from mouse ortholog) to trans-Golgi network, a transit compartment on the GCase-LIMP-2
      trafficking route.
    action: KEEP_AS_NON_CORE
    reason: >-
      Transit location; retain as non-core.
    supported_by:
    - reference_id: PMID:40159502
      supporting_text: travels through the trans-Golgi network to the lysosome
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27789271
  qualifier: enables
  review:
    summary: >-
      IPI protein-binding annotation; partner UniProtKB:P28799 is progranulin (GRN/PGRN), which binds GCase
      and recruits HSP70 as a co-chaperone.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare 'protein binding' is uninformative. The underlying GRN/HSP70 chaperone interaction is real
      (PMID:27789271) but the GO term conveys no functional specificity; do not treat as a core function.
    supported_by:
    - reference_id: PMID:27789271
      supporting_text: we report that PGRN binds directly to GCase
- term:
    id: GO:0004348
    label: glucosylceramidase activity
  evidence_type: IDA
  original_reference_id: PMID:16293621
  qualifier: enables
  review:
    summary: >-
      IDA annotation: purified wild-type and variant GCases assayed for glucosylceramidase (acid
      beta-glucosidase) activity and kinetics.
    action: ACCEPT
    reason: >-
      Direct enzymatic characterization of the core glucosylceramidase activity across Gaucher disease
      variants. Correct core molecular function.
    supported_by:
    - reference_id: PMID:16293621
      supporting_text: >-
        Acid beta-glucosidase (GCase) is a 497-amino acid, membrane-associated lysosomal
        exo-beta-glucosidase whose defective activity leads to the Gaucher disease phenotypes
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IDA
  original_reference_id: PMID:17187079
  qualifier: located_in
  review:
    summary: >-
      IDA/structural annotation to lysosomal membrane from the GCase crystal structure work; GCase is a
      membrane-associated lysosomal enzyme.
    action: ACCEPT
    reason: >-
      Consistent with the enzyme's peripheral lysosomal-membrane association and UniProt subcellular
      location. Appropriate localization.
    supported_by:
    - reference_id: file:human/GBA/GBA-uniprot.txt
      supporting_text: Lysosome membrane
- term:
    id: GO:0006680
    label: glucosylceramide catabolic process
  evidence_type: IDA
  original_reference_id: PMID:16293621
  qualifier: involved_in
  review:
    summary: >-
      IDA annotation to glucosylceramide catabolism, from direct enzymatic assay of GCase and its
      Gaucher-disease variants.
    action: ACCEPT
    reason: >-
      Directly supports the core catabolic process; assays measure GlcCer/substrate hydrolysis by GCase.
    supported_by:
    - reference_id: PMID:16293621
      supporting_text: whose defective activity leads to the Gaucher disease phenotypes
- term:
    id: GO:0006914
    label: autophagy
  evidence_type: IMP
  original_reference_id: PMID:27378698
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation: GCase-deficient cells show compromised autophagic lysosome reformation and impaired
      macroautophagy.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Autophagy impairment is a downstream consequence of losing GCase activity (PMID:27378698), not a
      direct function of GBA in autophagy. Over-annotation of a disease-state phenotype.
    supported_by:
    - reference_id: PMID:27378698
      supporting_text: autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase
- term:
    id: GO:0007040
    label: lysosome organization
  evidence_type: IMP
  original_reference_id: PMID:27378698
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation: GCase deficiency impairs regeneration of functional lysosomes from autolysosomes
      (autophagic lysosome reformation).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Effect on lysosome reformation is indirect (consequence of enzyme loss), not a direct organizing
      role of the lumenal hydrolase GBA. Over-annotation of a downstream phenotype.
    supported_by:
    - reference_id: PMID:27378698
      supporting_text: which regenerates functional lysosomes from autolysosomes formed during macroautophagy
- term:
    id: GO:0008203
    label: cholesterol metabolic process
  evidence_type: IDA
  original_reference_id: PMID:26724485
  qualifier: involved_in
  review:
    summary: >-
      IDA annotation: GBA participates in cholesterol metabolism by forming and degrading glucosylated
      cholesterol (GlcChol) through transglucosylation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine but secondary activity (GlcChol formation/degradation via transglucosylation); the primary
      role is glycosphingolipid catabolism. Retain as non-core.
    supported_by:
    - reference_id: PMID:26724485
      supporting_text: we document the ability of both GBA and GBA2 to degrade, as well as synthesize, GlcChol
- term:
    id: GO:0032006
    label: regulation of TOR signaling
  evidence_type: IMP
  original_reference_id: PMID:27378698
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation: mTOR activity (phospho-S6K) is decreased in GCase-deficient cells, reflecting
      impaired autophagic lysosome reformation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Altered TOR signalling is an indirect downstream effect of enzyme deficiency (PMID:27378698), not a
      direct role of GBA in regulating TOR. Over-annotation.
    supported_by:
    - reference_id: PMID:27378698
      supporting_text: >-
        A decrease in phopho-S6K levels, a marker of mTOR activity, was observed in models
        of GCase deficiency
- term:
    id: GO:0046527
    label: glucosyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:26724485
  qualifier: enables
  review:
    summary: >-
      IDA annotation: GBA transfers glucosyl moieties from GlcCer to cholesterol in vitro (transglucosylation),
      forming glucosylated cholesterol.
    action: KEEP_AS_NON_CORE
    reason: >-
      Demonstrated transglucosylase side activity of the retaining glycosidase; genuine but secondary to the
      core glucosylceramidase (hydrolase) role. Retain as non-core.
    supported_by:
    - reference_id: PMID:26724485
      supporting_text: both GBA and GBA2 are able to catalyze in vitro the transfer of glucosyl-moieties from GlcCer to cholesterol
- term:
    id: GO:0050295
    label: steryl-beta-glucosidase activity
  evidence_type: IDA
  original_reference_id: PMID:26724485
  qualifier: enables
  review:
    summary: >-
      IDA annotation: GBA hydrolyses glucosylated cholesterol (cholesteryl-beta-glucoside, GlcChol),
      demonstrating steryl-beta-glucosidase activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine secondary hydrolase activity on a sterol-glucoside; distinct from and minor relative to GlcCer
      hydrolysis. Retain as non-core.
    supported_by:
    - reference_id: PMID:26724485
      supporting_text: we document the ability of both GBA and GBA2 to degrade, as well as synthesize, GlcChol
- term:
    id: GO:0004348
    label: glucosylceramidase activity
  evidence_type: IDA
  original_reference_id: PMID:24211208
  qualifier: enables
  review:
    summary: >-
      IDA annotation: purified recombinant GBA1 assayed for glucosylceramide-related (glucocerebrosidase)
      activity as part of characterizing its cholesterol-glucosylation transglucosylation.
    action: ACCEPT
    reason: >-
      Supports the core glucosylceramidase activity of GBA1 (used as the glucose donor system for the
      transglucosylation assays). Correct core molecular function.
    supported_by:
    - reference_id: PMID:24211208
      supporting_text: purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity
- term:
    id: GO:0006680
    label: glucosylceramide catabolic process
  evidence_type: IDA
  original_reference_id: PMID:24211208
  qualifier: involved_in
  review:
    summary: >-
      IDA annotation to glucosylceramide catabolism, based on characterization of GBA1's GlcCer-dependent
      activities in fibroblasts and Gaucher patient cells.
    action: ACCEPT
    reason: >-
      Consistent with the core catabolic role; GBA1 uses GlcCer as substrate/donor and its deficiency reduces
      GlcCer-dependent activity in patient cells. Core process.
    supported_by:
    - reference_id: PMID:24211208
      supporting_text: >-
        Using a cell line generated from type 2 Gaucher disease patients with severe defects in GBA1 activity
- term:
    id: GO:0008203
    label: cholesterol metabolic process
  evidence_type: IDA
  original_reference_id: PMID:24211208
  qualifier: involved_in
  review:
    summary: >-
      IDA annotation: GBA1 glucosylates cholesterol by transglucosylation, linking it to cholesterol metabolism.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine but secondary transglucosylation activity toward cholesterol; primary role is glycosphingolipid
      catabolism. Retain as non-core.
    supported_by:
    - reference_id: PMID:24211208
      supporting_text: Overexpression of β-glucosidase 1 (GBA1, lysosomal acid β-glucocerebrosidase) led to an increase in cholesterol glucosylation activity
- term:
    id: GO:0046527
    label: glucosyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:24211208
  qualifier: enables
  review:
    summary: >-
      IDA annotation: GBA1 catalyses cholesterol glucosylation by a transglucosylation reaction, transferring
      glucose from GlcCer to cholesterol.
    action: KEEP_AS_NON_CORE
    reason: >-
      Demonstrated transglucosylase side reaction of the retaining glycosidase; genuine but secondary to the
      core hydrolase role. Retain as non-core.
    supported_by:
    - reference_id: PMID:24211208
      supporting_text: Cholesterol glucosylation is catalyzed by transglucosylation reaction of
- term:
    id: GO:0050295
    label: steryl-beta-glucosidase activity
  evidence_type: IDA
  original_reference_id: PMID:24211208
  qualifier: enables
  review:
    summary: >-
      IDA annotation: GBA1 can hydrolyse cholesteryl-beta-glucoside to cholesterol and glucose, a steryl-
      beta-glucosidase activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine secondary hydrolase activity on a sterol-glucoside; minor relative to GlcCer hydrolysis. Retain
      as non-core.
    supported_by:
    - reference_id: file:human/GBA/GBA-uniprot.txt
      supporting_text: >-
        Can also hydrolyze cholesteryl 3-beta-D-glucoside producing glucose and cholesterol
- term:
    id: GO:0006680
    label: glucosylceramide catabolic process
  evidence_type: IMP
  original_reference_id: PMID:24022302
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation: functional analysis of novel GBA disease alleles shows loss of acid beta-glucosidase
      activity, confirming GBA1's role in glucosylceramide catabolism.
    action: ACCEPT
    reason: >-
      Loss-of-function variant analysis confirms the enzyme's core catabolic activity (deficiency causes
      Gaucher disease / GlcCer accumulation). Core process.
    supported_by:
    - reference_id: PMID:24022302
      supporting_text: >-
        Gaucher disease is the most frequent lysosomal storage disorder due to the deficiency of the acid
        β-glucosidase, encoded by the GBA gene
- term:
    id: GO:0004348
    label: glucosylceramidase activity
  evidence_type: IDA
  original_reference_id: PMID:9201993
  qualifier: enables
  review:
    summary: >-
      IDA annotation: glucosylceramidase hydrolyses liposomal glucosylceramide, an activity stimulated
      synergistically by saposins A and C.
    action: ACCEPT
    reason: >-
      Direct assay of glucosylceramidase activity on the physiological substrate (liposomal GlcCer) with its
      saposin activators. Core molecular function.
    supported_by:
    - reference_id: PMID:9201993
      supporting_text: >-
        The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase with the
        assistance of, at least, another protein, saposin C
- term:
    id: GO:0006680
    label: glucosylceramide catabolic process
  evidence_type: IDA
  original_reference_id: PMID:9201993
  qualifier: involved_in
  review:
    summary: >-
      IDA annotation to lysosomal glucosylceramide catabolism, demonstrated by saposin-assisted hydrolysis
      of liposomal GlcCer.
    action: ACCEPT
    reason: >-
      Directly supports the core catabolic process, including the saposin-C dependence and requirement for
      anionic phospholipids. Core process.
    supported_by:
    - reference_id: PMID:9201993
      supporting_text: both Sap A and Sap C are required for maximal hydrolysis of glucosylceramide inserted in PS-containing LUV
- term:
    id: GO:0004348
    label: glucosylceramidase activity
  evidence_type: IMP
  original_reference_id: PMID:15916907
  qualifier: enables
  review:
    summary: >-
      IMP annotation: Gaucher-disease mutations reduce beta-glucocerebrosidase activity toward fluorescent
      glucosylceramide substrates, confirming the core glucosylceramidase activity.
    action: ACCEPT
    reason: >-
      Variant-based functional analysis confirms the enzyme's core glucosylceramidase activity. Correct term.
    supported_by:
    - reference_id: PMID:15916907
      supporting_text: Gaucher disease results from impaired activity of the lysosomal enzyme beta-glucocerebrosidase
- term:
    id: GO:0005124
    label: scavenger receptor binding
  evidence_type: IPI
  original_reference_id: PMID:25202012
  qualifier: enables
  review:
    summary: >-
      IPI annotation: GBA binds LIMP-2/SCARB2 (UniProtKB:Q14108), a CD36-family scavenger-receptor protein,
      via a defined 11-residue motif; this mediates lysosomal trafficking.
    action: KEEP_AS_NON_CORE
    reason: >-
      Informative binding annotation capturing the physiologically important GBA-LIMP-2 interaction required
      for lysosomal targeting, but this is a trafficking interaction rather than the enzyme's core catalytic
      function. Retain as non-core.
    supported_by:
    - reference_id: PMID:25202012
      supporting_text: >-
        The acid β-glucosidase (glucocerbrosidase (GCase)) binding sequence to LIMP-2 (lysosomal integral
        membrane protein 2), the receptor for intracellular GCase trafficking to the lysosome, has been identified
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IMP
  original_reference_id: PMID:25202012
  qualifier: located_in
  review:
    summary: >-
      IMP annotation: disrupting the LIMP-2-binding motif diminishes trafficking of GCase to the lysosome and
      increases its secretion, confirming lysosomal localization depends on LIMP-2.
    action: ACCEPT
    reason: >-
      Supports the core lysosomal localization of GBA (and its LIMP-2-dependent delivery). Correct localization.
    supported_by:
    - reference_id: PMID:25202012
      supporting_text: diminishing the trafficking of GCase to the lysosome and significantly increasing GCase secretion
- term:
    id: GO:0004348
    label: glucosylceramidase activity
  evidence_type: IMP
  original_reference_id: PMID:23580063
  qualifier: enables
  review:
    summary: >-
      IMP annotation: pharmacological inhibition of GCase activity in neuronal cells (assayed as
      beta-glucocerebrosidase activity) underlies the study, supporting the core glucosylceramidase activity.
    action: ACCEPT
    reason: >-
      Confirms the core glucosylceramidase activity as the manipulated variable (the study inhibits GCase
      activity). Correct core molecular function.
    supported_by:
    - reference_id: PMID:23580063
      supporting_text: >-
        results from the diminished activity of the lysosomal enzyme β-glucocerebrosidase (GCase), caused by
        mutations in the β-glucocerebrosidase gene (GBA)
- term:
    id: GO:0007005
    label: mitochondrion organization
  evidence_type: IMP
  original_reference_id: PMID:25456120
  qualifier: involved_in
  negated: true
  review:
    summary: >-
      NOT annotation: in GBA-N370S iPSC-derived dopamine neurons, mitochondria showed normal morphology and
      distribution, so GBA is annotated as NOT involved in mitochondrion organization.
    action: ACCEPT
    reason: >-
      The negation is directly supported: TEM showed normal mitochondrial morphology in GBA-N370S neurons.
      The NOT annotation correctly records the absence of an effect on mitochondrion organization in this model.
    supported_by:
    - reference_id: PMID:25456120
      supporting_text: >-
        mitochondria in all differentiated neurons, including GBA N370S mutant mDA neurons, displayed normal
        morphology and regular distribution in cytoplasm and processes
- term:
    id: GO:0031175
    label: neuron projection development
  evidence_type: IMP
  original_reference_id: PMID:25456120
  qualifier: involved_in
  negated: true
  review:
    summary: >-
      NOT annotation: neurite outgrowth rates were similar between GBA-N370S and control neurons, so GBA is
      annotated as NOT involved in neuron projection development.
    action: ACCEPT
    reason: >-
      The negation is supported: the study found similar neurite outgrowth rates for both twins' neurons,
      indicating no GBA effect on neuron projection development in this model.
    supported_by:
    - reference_id: PMID:25456120
      supporting_text: the neurite outgrowth rates of both twin’s neurons were similar
- term:
    id: GO:1904457
    label: positive regulation of neuronal action potential
  evidence_type: IMP
  original_reference_id: PMID:25456120
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation: GBA-N370S dopamine neurons (affected twin) showed reduced spontaneous electrical activity,
      interpreted as a role in neuronal action potential.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The reduced spontaneous activity in affected-twin neurons is an indirect, disease-model phenotype confounded
      by additional factors (e.g. elevated MAO-B), not a direct role of the lysosomal enzyme GBA in generating action
      potentials. Over-annotation of a downstream neuronal phenotype.
    supported_by:
    - reference_id: PMID:25456120
      supporting_text: Spontaneous activity in mDA neurons from the affected twin was significantly lower
- term:
    id: GO:1905165
    label: regulation of lysosomal protein catabolic process
  evidence_type: TAS
  original_reference_id: PMID:25456120
  qualifier: involved_in
  review:
    summary: >-
      TAS annotation to regulation of lysosomal protein catabolic process, based on GBA's link to alpha-synuclein
      handling in the lysosome.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GBA influences lysosomal clearance of alpha-synuclein indirectly (via lysosomal/autophagic function); it does
      not directly regulate lysosomal protein catabolism. Over-annotation of a downstream disease link.
    supported_by:
    - reference_id: PMID:25456120
      supporting_text: GBA mutations lead to α-synuclein accumulation
- term:
    id: GO:0016241
    label: regulation of macroautophagy
  evidence_type: TAS
  original_reference_id: PMID:26388395
  qualifier: involved_in
  review:
    summary: >-
      TAS annotation (review) to regulation of macroautophagy; loss of GCase activity impairs the autophagy-lysosome
      pathway, including macroautophagy.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Effect on macroautophagy is a downstream consequence of GCase deficiency (PMID:26388395), not a direct regulatory
      function of GBA. Over-annotation of the disease-state phenotype.
    supported_by:
    - reference_id: PMID:26388395
      supporting_text: The loss of GCase activity results in impairment of the autophagy-lysosome pathway (ALP)
- term:
    id: GO:0004348
    label: glucosylceramidase activity
  evidence_type: IMP
  original_reference_id: PMID:21700325
  qualifier: enables
  review:
    summary: >-
      IMP annotation: functional loss of GCase in neurons/iPSC compromises lysosomal degradation, tying the
      glucosylceramidase activity to lysosomal function and alpha-synuclein handling.
    action: ACCEPT
    reason: >-
      Supports the core glucosylceramidase activity via loss-of-function experiments in neurons and human iPSC.
      Correct core molecular function.
    supported_by:
    - reference_id: PMID:21700325
      supporting_text: functional loss of GD-linked glucocerebrosidase (GCase) in primary cultures or human iPS neurons compromises lysosomal protein degradation
- term:
    id: GO:0006680
    label: glucosylceramide catabolic process
  evidence_type: IMP
  original_reference_id: PMID:21700325
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation: GCase cleaves the beta-glucosyl linkage of glucosylceramide; its functional loss causes GlcCer
      accumulation, supporting the core catabolic process.
    action: ACCEPT
    reason: >-
      Directly supports glucosylceramide catabolism; GCase is described as the lysosomal enzyme that cleaves GlcCer,
      and its substrate accumulates on loss of function. Core process.
    supported_by:
    - reference_id: PMID:21700325
      supporting_text: a lysosomal enzyme that cleaves the β-glucosyl linkage of GlcCer
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: >-
      HDA annotation: GBA detected by proteomics in exosomes from expressed prostatic secretions in urine.
    action: KEEP_AS_NON_CORE
    reason: >-
      A high-throughput mass-spectrometry detection in a secreted/exosomal proteome; consistent with the known
      partial secretion of GCase, but not its site of function. Retain as non-core.
    supported_by:
    - reference_id: PMID:23533145
      supporting_text: exosome preparations were characterized by a shotgun proteomics procedure
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24162852
  qualifier: enables
  review:
    summary: >-
      IPI protein-binding annotation; partner UniProtKB:Q14108 is LIMP-2/SCARB2, whose crystal structure shows the
      helical bundle where beta-glucocerebrosidase binds.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare 'protein binding' is uninformative. The underlying LIMP-2 interaction is captured more informatively by
      the scavenger-receptor-binding / SCARB2-trafficking annotations; do not treat this generic term as a function.
    supported_by:
    - reference_id: PMID:24162852
      supporting_text: LIMP-2 shows a helical bundle where β-glucocerebrosidase binds
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: HDA
  original_reference_id: PMID:17897319
  qualifier: located_in
  review:
    summary: >-
      HDA annotation: GBA identified by proteomics of purified placental lysosomal membranes, consistent with its
      peripheral lysosomal-membrane association.
    action: ACCEPT
    reason: >-
      Supports lysosomal-membrane localization via lysosomal membrane proteomics; consistent with the enzyme's
      peripheral membrane association. Correct localization.
    supported_by:
    - reference_id: PMID:17897319
      supporting_text: In membranes purified from placental lysosomes, we identified 58 proteins, known to reside at least partially in the lysosomal membrane
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: ISS
  original_reference_id: PMID:18022370
  qualifier: enables
  review:
    summary: >-
      ISS annotation to signaling receptor binding, based on GBA binding its trafficking receptor LIMP-2/SCARB2.
    action: KEEP_AS_NON_CORE
    reason: >-
      Captures the physiologically important GBA-LIMP-2 interaction (LIMP-2 is a receptor for lysosomal targeting of
      GCase), but 'signaling receptor binding' is imprecise and describes a trafficking interaction, not the core
      catalytic function. Retain as non-core.
    supported_by:
    - reference_id: PMID:18022370
      supporting_text: LIMP-2 as the mannose-6-phosphate-independent trafficking receptor for beta-glucocerebrosidase
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: ISS
  original_reference_id: PMID:18022370
  qualifier: located_in
  review:
    summary: >-
      ISS annotation to lysosomal membrane, based on GBA's LIMP-2-mediated lysosomal targeting and its membrane
      association.
    action: ACCEPT
    reason: >-
      Consistent with the enzyme's peripheral lysosomal-membrane association and LIMP-2-dependent delivery.
      Correct localization.
    supported_by:
    - reference_id: file:human/GBA/GBA-uniprot.txt
      supporting_text: Lysosome membrane
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: ISS
  original_reference_id: PMID:18022370
  qualifier: located_in
  review:
    summary: >-
      ISS annotation to lysosomal lumen; GBA acts on the lumenal side of the lysosomal membrane after LIMP-2-mediated
      delivery.
    action: ACCEPT
    reason: >-
      Consistent with UniProt (lumenal side) and the enzyme's action on lumenal glucosylceramide. Core localization.
    supported_by:
    - reference_id: file:human/GBA/GBA-uniprot.txt
      supporting_text: Lumenal side
- term:
    id: GO:0046512
    label: sphingosine biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:19279011
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation: GBA1 generates sphingosine (from GlcCer-derived ceramide) for the salvage pathway; silencing GBA1
      decreases sphingosine generation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real but downstream of the core hydrolase reaction: sphingosine arises after GlcCer -> ceramide -> sphingosine.
      GBA does not directly synthesize sphingosine (a ceramidase does), so this is a pathway-level, non-core role.
    supported_by:
    - reference_id: PMID:19279011
      supporting_text: Silencing GBA1 blocked PMA-induced degradation of glucosylceramide and generation of sphingosine
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:19279011
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation: GBA1 activity generates ceramide (from glucosylceramide) in the PKC-activated salvage pathway;
      forced GBA1 expression increases ceramide.
    action: KEEP_AS_NON_CORE
    reason: >-
      Ceramide is the direct product of GBA's GlcCer hydrolysis, so this 'ceramide biosynthetic' role is really the
      catabolic reaction viewed from the product side, contributing to the salvage pathway. Retain as non-core; the
      core term is glucosylceramide catabolic process.
    supported_by:
    - reference_id: PMID:19279011
      supporting_text: forced expression of GBA1 increased ceramide levels
- term:
    id: GO:0004348
    label: glucosylceramidase activity
  evidence_type: IDA
  original_reference_id: PMID:19279011
  qualifier: enables
  review:
    summary: >-
      IDA annotation: GBA1 hydrolyses glucosylceramide to form lysosomal ceramide, providing sphingosine for the ceramide
      salvage pathway.
    action: ACCEPT
    reason: >-
      Directly supports the core glucosylceramidase activity (GlcCer hydrolysis to ceramide). Correct core molecular
      function.
    supported_by:
    - reference_id: PMID:19279011
      supporting_text: acid beta-glucosidase 1 (GBA1), which hydrolyzes glucosylceramide to form lysosomal ceramide
- term:
    id: GO:0006680
    label: glucosylceramide catabolic process
  evidence_type: IMP
  original_reference_id: PMID:19279011
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation: silencing GBA1 blocks PMA-induced degradation of glucosylceramide, confirming its role in
      glucosylceramide catabolism.
    action: ACCEPT
    reason: >-
      Loss-of-function (siRNA) directly links GBA1 to glucosylceramide degradation. Core process.
    supported_by:
    - reference_id: PMID:19279011
      supporting_text: Silencing GBA1 blocked PMA-induced degradation of glucosylceramide and generation of sphingosine
- term:
    id: GO:0023021
    label: termination of signal transduction
  evidence_type: IMP
  original_reference_id: PMID:19279008
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation: the GBA1-ceramide pathway terminates p38 (MAPK) signalling; GBA knockdown prolongs p38 activation
      in MCF-7 cells.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real but indirect: GBA affects signal termination through the ceramide it generates, not by directly acting on
      the signalling machinery. Retain as non-core downstream signalling role.
    supported_by:
    - reference_id: PMID:19279008
      supporting_text: implicating the GBA1-ceramide pathway in the termination of p38 activation
- term:
    id: GO:0032715
    label: negative regulation of interleukin-6 production
  evidence_type: IDA
  original_reference_id: PMID:19279008
  qualifier: involved_in
  review:
    summary: >-
      IDA annotation: increasing cellular ceramide (via the GBA1 pathway) attenuates IL-6 production; GBA knockdown
      causes IL-6 hyperproduction.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported experimentally, but the effect on IL-6 is mediated by GBA-generated ceramide acting on p38delta, i.e.
      a downstream signalling consequence rather than a direct GBA function. Retain as non-core.
    supported_by:
    - reference_id: PMID:19279008
      supporting_text: increasing cellular ceramide with cell-permeable ceramide treatment resulted in attenuation of the IL-6 response
- term:
    id: GO:0071356
    label: cellular response to tumor necrosis factor
  evidence_type: IMP
  original_reference_id: PMID:19279008
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation to cellular response to TNF, from the same GBA1-ceramide-p38delta signalling study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The study centers on PKC/PMA-induced p38delta/IL-6 signalling in MCF-7 cells; a direct GBA role in TNF response is
      not clearly established and would be an indirect ceramide-mediated effect at best. Over-annotation.
    supported_by:
    - reference_id: PMID:19279008
      supporting_text: possible role for ceramide as an anti-inflammatory lipid
core_functions:
- description: >-
    Lysosomal acid glucosylceramidase (glucocerebrosidase): hydrolyses glucosylceramide
    to ceramide and glucose within the lysosome, carrying out the penultimate step of
    glycosphingolipid catabolism. Activity requires the activator saposin C and negatively
    charged phospholipids.
  molecular_function:
    id: GO:0004348
    label: glucosylceramidase activity
  directly_involved_in:
  - id: GO:0006680
    label: glucosylceramide catabolic process
  locations:
  - id: GO:0043202
    label: lysosomal lumen
  - id: GO:0005764
    label: lysosome
  supported_by:
  - reference_id: file:human/GBA/GBA-uniprot.txt
    supporting_text: >-
      Glucosylceramidase that catalyzes, within the lysosomal compartment, the
      hydrolysis of glucosylceramides
  - reference_id: PMID:19279011
    supporting_text: acid beta-glucosidase 1 (GBA1), which hydrolyzes glucosylceramide to form lysosomal ceramide
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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  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/GBA/GBA-uniprot.txt
  title: UniProtKB P04062 (GBA_HUMAN) record
  findings: []
- id: PMID:15916907
  title: Use of fluorescent substrates for characterization of Gaucher disease mutations.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Supports the core glucosylceramidase activity via variant analysis with fluorescent
      GlcCer substrates. Abstract verified.
- id: PMID:16293621
  title: 'Analyses of variant acid beta-glucosidases: effects of Gaucher disease mutations.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Direct enzymatic characterization of wild-type and mutant GCase; establishes the
      core acid beta-glucosidase / glucosylceramidase activity and saposin-C dependence.
- id: PMID:17187079
  title: Structure of acid beta-glucosidase with pharmacological chaperone provides
    insight into Gaucher disease.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Crystal structure of GCase; supports lysosomal-membrane-associated localization and active-site biology.
- id: PMID:17897319
  title: Integral and associated lysosomal membrane proteins.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Lysosomal membrane proteomics; supports GBA lysosomal-membrane localization (HDA).
- id: PMID:18022370
  title: LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting
    of beta-glucocerebrosidase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Landmark paper identifying LIMP-2/SCARB2 as the M6P-independent trafficking receptor for GCase;
      grounds the ER/Golgi/TGN transit and lysosomal localization annotations.
- id: PMID:19279008
  title: 'Acid beta-glucosidase 1 counteracts p38delta-dependent induction of interleukin-6:
    possible role for ceramide as an anti-inflammatory lipid.'
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Supports downstream ceramide-mediated signalling (IL-6/p38/MAPK) roles in MCF-7 cells; these are
      indirect, non-core physiological effects of GBA-generated ceramide.
- id: PMID:19279011
  title: Involvement of acid beta-glucosidase 1 in the salvage pathway of ceramide
    formation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes that GBA1 hydrolyses GlcCer to lysosomal ceramide and feeds the PKC-activated ceramide
      salvage pathway; supports the core hydrolase activity and the non-core ceramide/sphingosine terms.
- id: PMID:21098288
  title: Decreased glucocerebrosidase activity in Gaucher disease parallels quantitative
    enzyme loss due to abnormal interaction with TCP1 and c-Cbl.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Underlies the TCP1 'protein binding' IPI; relates to GCase folding/quality control, not core function.
- id: PMID:21700325
  title: Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic
    loop in synucleinopathies.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Loss of GCase compromises lysosomal degradation and accumulates alpha-synuclein; supports core
      activity/process and the Parkinson-disease link.
- id: PMID:22659419
  title: Beta-glucosidase 1 (GBA1) is a second bile acid β-glucosidase in addition
    to β-glucosidase 2 (GBA2). Study in β-glucosidase deficient mice and humans.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Shows GBA1 hydrolyses glucosylceramide (main substrate) and also bile-acid-beta-glucoside; supports
      core glucosylceramidase and broad beta-glucosidase activities.
- 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: High-throughput exosome proteomics; source of the non-core extracellular-exosome HDA localization.
- id: PMID:23580063
  title: Loss of β-glucocerebrosidase activity does not affect alpha-synuclein levels
    or lysosomal function in neuronal cells.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Pharmacological GCase inhibition study (assays beta-glucocerebrosidase activity); supports the core
      activity as the manipulated variable, though it reports no alpha-synuclein effect.
- id: PMID:24022302
  title: Functional analysis of 11 novel GBA alleles.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Variant functional analysis; supports core acid beta-glucosidase activity and glucosylceramide catabolism.
- id: PMID:24162852
  title: Structure of LIMP-2 provides functional insights with implications for SR-BI
    and CD36.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      LIMP-2 crystal structure showing where beta-glucocerebrosidase binds; underlies the LIMP-2 'protein binding'
      IPI (non-core trafficking interaction).
- id: PMID:24211208
  title: Cholesterol glucosylation is catalyzed by transglucosylation reaction of
    β-glucosidase 1.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Demonstrates GBA1 transglucosylation forming cholesteryl-glucoside; supports the non-core transglucosylase/
      glycolipid-biosynthetic and steryl-beta-glucosidase activities.
- id: PMID:25202012
  title: 'The LIMP-2/SCARB2 binding motif on acid β-glucosidase: basic and applied
    implications for Gaucher disease and associated neurodegenerative diseases.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Maps the 11-residue LIMP-2/SCARB2-binding motif on GCase; supports lysosomal localization (LIMP-2-dependent)
      and the scavenger-receptor-binding annotation.
- id: PMID:25456120
  title: iPSC-derived dopamine neurons reveal differences between monozygotic twins
    discordant for Parkinson's disease.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Source of the two supported NOT annotations (normal mitochondria and normal neurite outgrowth in GBA-N370S
      neurons) and the (over-annotated) neuronal-action-potential term.
- id: PMID:25584808
  title: Identification of miRNAs that modulate glucocerebrosidase activity in Gaucher
    disease cells.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: miRNA modulation of GCase activity in Gaucher cells; supports the core glucosylceramidase activity/process.
- id: PMID:26388395
  title: Mitochondrial dysfunction associated with glucocerebrosidase deficiency.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Review establishing GCase as a lysosomal sphingolipid-metabolism enzyme (GlcCer -> glucose + ceramide) and the
      indirect autophagy/mitochondrial consequences of its deficiency.
- id: PMID:26392287
  title: Glucocerebrosidase gene therapy prevents α-synucleinopathy of midbrain dopamine
    neurons.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      GCase gene therapy reduces alpha-synuclein in PD models; underlies the (over-annotated) lysosomal-protein-catabolism
      link, which is indirect.
- id: PMID:26724485
  title: 'Glucosylated cholesterol in mammalian cells and tissues: formation and degradation
    by multiple cellular β-glucosidases.'
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Shows GBA both synthesizes and degrades glucosylated cholesterol via transglucosylation, and restates the core
      role (GBA degrades GlcCer to ceramide and glucose in lysosomes, assisted by saposin C).
- id: PMID:27378698
  title: 'Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient
    cells: relevance to Parkinson disease.'
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Establishes that GCase deficiency impairs autophagic lysosome reformation/macroautophagy/mTOR; these are the basis
      for the several over-annotated autophagy/TOR/lysosome-organization terms.
- id: PMID:27789271
  title: Progranulin Recruits HSP70 to β-Glucocerebrosidase and Is Therapeutic Against
    Gaucher Disease.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Progranulin (GRN) binds GCase and recruits HSP70; underlies the GRN 'protein binding' IPI (non-core chaperone
      interaction).
- id: PMID:40159502
  title: Cryo-TEM structure of β-glucocerebrosidase in complex with its transporter
    LIMP-2.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Cryo-EM structure of the GCase-LIMP-2 complex; concisely restates GCase's core hydrolase activity and the
      ER->Golgi->lysosome trafficking route with LIMP-2.
- id: PMID:9201993
  title: Effect of saposins A and C on the enzymatic hydrolysis of liposomal glucosylceramide.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes saposin-A/C-dependent, anionic-phospholipid-dependent hydrolysis of liposomal glucosylceramide by
      glucosylceramidase; supports the core activity and its activator requirement.
- id: Reactome:R-HSA-1605591
  title: GBA1:SAPC hydrolyzes GlcCer
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reactome reaction capturing the saposin-C-dependent lysosomal hydrolysis of glucosylceramide by GBA1; matches the
      core function.