id: P15586
gene_symbol: GNS
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  GNS (N-acetylglucosamine-6-sulfatase; EC 3.1.6.14, also called glucosamine-6-sulfatase/G6S)
  is a lysosomal exo-sulfatase that hydrolytically removes the 6-O-sulfate group from terminal
  N-acetyl-D-glucosamine-6-sulfate residues during the stepwise exolytic degradation of the
  glycosaminoglycans heparan sulfate and keratan sulfate. Like other members of the sulfatase
  family, it depends on a catalytic C-alpha-formylglycine residue generated from an active-site
  cysteine by the formylglycine-generating enzyme SUMF1, and it binds a catalytic Ca2+ ion. The
  mature enzyme is synthesized as a glycosylated precursor with a cleavable signal peptide and
  acts in the lysosomal lumen at acidic pH. Loss of GNS activity causes mucopolysaccharidosis
  type IIID (Sanfilippo syndrome D), an autosomal-recessive lysosomal storage disorder marked by
  heparan sulfate accumulation and progressive central nervous system degeneration.
alternative_products:
- name: '1'
  id: P15586-1
- name: '2'
  id: P15586-2
  sequence_note: VSP_056486
existing_annotations:
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation placing the active enzyme in the lysosome. This matches the
      UniProt subcellular location and the well-established role of GNS as an acid hydrolase acting
      in lysosomal glycosaminoglycan degradation. Core localization; accept.
    action: ACCEPT
    reason: >-
      GNS is a lysosomal sulfatase; UniProt records subcellular location Lysosome and its function
      is defined by lysosomal degradation of heparan/keratan sulfate.
    supported_by:
    - reference_id: file:human/GNS/GNS-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome."
    - reference_id: PMID:1463457
      supporting_text: >-
        Glucosamine-6-sulphatase is an exo-hydrolase required for the lysosomal degradation of
        heparan sulphate and keratan sulphate.
- term:
    id: GO:0030200
    label: heparan sulfate proteoglycan catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation to heparan sulfate catabolism, consistent with the enzyme's
      defined role in the stepwise exolytic degradation of heparan sulfate. Core biological process;
      accept.
    action: ACCEPT
    reason: >-
      GNS removes the 6-sulfate from terminal GlcNAc-6-sulfate residues, a required step in
      lysosomal heparan sulfate degradation; its deficiency causes lysosomal storage of heparan
      sulfate (MPS IIID).
    supported_by:
    - reference_id: PMID:1463457
      supporting_text: >-
        Deficiency of glucosamine-6-sulphatase activity leads to the lysosomal storage of the
        glycosaminoglycan, heparan sulphate
- term:
    id: GO:0008449
    label: N-acetylglucosamine-6-sulfatase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) annotation to the exact molecular function of GNS. This is the core
      catalytic activity, independently supported by direct enzymology; accept.
    action: ACCEPT
    reason: >-
      The GO term definition (hydrolysis of the 6-sulfate group of GlcNAc-6-sulfate units of
      heparan and keratan sulfate) matches the experimentally established activity (EC 3.1.6.14).
    supported_by:
    - reference_id: file:human/GNS/GNS-uniprot.txt
      supporting_text: "Hydrolyzes 6-sulfate groups in N-acetyl-d-glucosaminide units"
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation (combined IEA methods / UniProt-SubCell) to lysosome, agreeing with the
      curated UniProt subcellular location. Accept.
    action: ACCEPT
    reason: >-
      Redundant with the IBA lysosome annotation and with UniProt's curated Lysosome location; the
      IEA mapping is correct.
    supported_by:
    - reference_id: file:human/GNS/GNS-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome."
- term:
    id: GO:0008449
    label: N-acetylglucosamine-6-sulfatase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic annotation to the specific sulfatase activity, transferred from InterPro/EC
      (EC:3.1.6.14) and orthologs. Correct and matches the experimentally verified activity; accept.
    action: ACCEPT
    reason: >-
      The InterPro family (IPR012251, GlcNAc_6-SO4ase) and EC 3.1.6.14 map precisely to GO:0008449;
      consistent with direct enzymology.
    supported_by:
    - reference_id: PMID:1463457
      supporting_text: >-
        We have isolated human cDNA clones and derived amino acid sequence coding for the entire
        glucosamine-6-sulphatase protein
- term:
    id: GO:0030203
    label: glycosaminoglycan metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO electronic annotation to the broad glycosaminoglycan metabolic parent. Not wrong,
      but less informative than the specific heparan/keratan sulfate catabolic terms already
      annotated. Keep as non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      This is a high-level metabolic parent; the specific catabolic processes (heparan sulfate,
      keratan sulfate, glycosaminoglycan catabolic process) capture the function more precisely and
      are retained as core.
    supported_by:
    - reference_id: PMID:3689315
      supporting_text: >-
        Forms A and B both desulphate substrates derived from keratan sulphate and heparin.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17474147
  qualifier: enables
  review:
    summary: >-
      IPI annotation to bare "protein binding" from a high-throughput SH3-domain peptide-array
      screen (NCK1 SH3 domain, UniProtKB:P16333). "Protein binding" is uninformative about GNS's
      molecular function, and the interaction derives from a proteome-wide peptide-array method
      rather than a validated functional complex. Retained but flagged as over-annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation guidelines, bare "protein binding" IPIs add no functional information; this one
      comes from a systematic SH3 peptide-array screen. There is no evidence that NCK1 binding is
      part of GNS's biological function, so it is marked as over-annotated rather than removed.
    supported_by:
    - reference_id: PMID:17474147
      supporting_text: >-
        A group of 12 Src homology (SH) 3 domains from eight human proteins (Swiss-Prot ID: SRC,
        PLCG1, P85A, NCK1, GRB2, FYN, CRK) were used to screen a peptide target array
- term:
    id: GO:0005539
    label: glycosaminoglycan binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Electronic annotation (Ensembl ortholog transfer) to glycosaminoglycan binding. GNS acts on
      GAG substrates (heparan/keratan sulfate), so substrate binding is plausible, but as a binding
      term it is subsumed by the catalytic activity and does not add core functional information.
      Keep as non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      Binding of the GAG substrate is inherent to the enzyme's catalytic activity (GO:0008449); the
      standalone binding term is not independently informative of GNS's core function.
    supported_by:
    - reference_id: PMID:3689315
      supporting_text: >-
        Aglycone structures that influence substrate binding and/or enzyme activity
- term:
    id: GO:0030200
    label: heparan sulfate proteoglycan catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation redundant with the IBA and IDA annotations to heparan sulfate
      catabolism. Correct core biological process; accept.
    action: ACCEPT
    reason: >-
      Consistent with the experimentally supported role of GNS in lysosomal heparan sulfate
      degradation.
    supported_by:
    - reference_id: PMID:1463457
      supporting_text: >-
        an exo-hydrolase required for the lysosomal degradation of heparan sulphate and keratan
        sulphate
- term:
    id: GO:0042340
    label: keratan sulfate proteoglycan catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation (Ensembl ortholog transfer) to keratan sulfate catabolism. GNS also
      desulfates keratan-sulfate-derived substrates, so this process is a genuine part of its
      function. Accept as core.
    action: ACCEPT
    reason: >-
      UniProt FUNCTION and EC 3.1.6.14 both name keratan sulfate as a substrate, and direct
      enzymology shows desulfation of keratan-sulfate-derived substrates.
    supported_by:
    - reference_id: file:human/GNS/GNS-uniprot.txt
      supporting_text: "of heparin sulfate and keratan sulfate."
    - reference_id: PMID:3689315
      supporting_text: >-
        Forms A and B both desulphate substrates derived from keratan sulphate and heparin.
- term:
    id: GO:0043199
    label: sulfate binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Electronic annotation (Ensembl ortholog transfer) to sulfate binding. Sulfate is the product
      moiety released by GNS and sulfate/phosphate ions are potent product inhibitors, so sulfate
      contact is expected, but the term is not independently informative of the core function.
      Keep as non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      Sulfate interaction is a facet of the catalytic mechanism (product/inhibitor binding) rather
      than a distinct core molecular function; subsumed by GO:0008449.
    supported_by:
    - reference_id: PMID:3689315
      supporting_text: >-
        Sulphate and phosphate ions are potent inhibitors of enzyme activity.
- term:
    id: GO:0008449
    label: N-acetylglucosamine-6-sulfatase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2263495
  qualifier: enables
  review:
    summary: >-
      TAS annotation (Reactome) to the specific sulfatase activity, in the context of the keratan
      sulfate degradation / MPS IIID pathway. Core molecular function; accept.
    action: ACCEPT
    reason: >-
      Reactome represents the curated pathway role of GNS cleaving sulfate from GlcNAc-6-sulfate
      units; consistent with all other lines of evidence.
    supported_by:
    - reference_id: PMID:3689315
      supporting_text: >-
        Enzyme activity is highly specific towards glucosamine 6-sulphate or glucose 6-sulphate
        residues.
- term:
    id: GO:0008449
    label: N-acetylglucosamine-6-sulfatase activity
  evidence_type: EXP
  original_reference_id: PMID:1463457
  qualifier: enables
  review:
    summary: >-
      Experimental (EXP) annotation from the cloning/characterization paper that established the
      catalytic activity (EC 3.1.6.14) and the full-length human sequence. This is the primary
      experimental support for the core molecular function; accept.
    action: ACCEPT
    reason: >-
      Direct demonstration of catalytic activity and derivation of the entire glucosamine-6-
      sulphatase coding sequence; the definitive experimental evidence for GO:0008449.
    supported_by:
    - reference_id: PMID:1463457
      supporting_text: >-
        Glucosamine-6-sulphatase is an exo-hydrolase required for the lysosomal degradation of
        heparan sulphate and keratan sulphate.
- term:
    id: GO:0008449
    label: N-acetylglucosamine-6-sulfatase activity
  evidence_type: IDA
  original_reference_id: PMID:15595925
  qualifier: enables
  review:
    summary: >-
      IDA annotation from purification of the enzyme from human neutrophil granules and its
      identification as N-acetylglucosamine-6-sulphatase (EC 3.1.6.14) with confirmed activity
      toward N-acetylglucosamine-6-sulphate. Direct experimental support for the core activity;
      accept.
    action: ACCEPT
    reason: >-
      The purified 75 kDa neutrophil protein was identified by MS and its identity confirmed by
      enzymatic activity toward the GlcNAc-6-sulphate substrate, directly demonstrating GO:0008449.
    supported_by:
    - reference_id: PMID:15595925
      supporting_text: >-
        identified the protein to be N-acetylglucosamine-6-sulphatase (EC 3.1.6.14). The identity of
        the protein was confirmed by demostrating enzymatic activity towards the substrate
        N-acetylglucosamine 6-sulphate.
- term:
    id: GO:0030200
    label: heparan sulfate proteoglycan catabolic process
  evidence_type: IDA
  original_reference_id: PMID:15595925
  qualifier: involved_in
  review:
    summary: >-
      IDA annotation to heparan sulfate catabolism from the neutrophil-enzyme study, which showed
      O-desulphation activity toward heparan-sulphate-derived saccharides. Consistent with the core
      catabolic role; accept.
    action: ACCEPT
    reason: >-
      The purified enzyme desulfated heparan-sulphate-derived saccharides, directly linking its
      activity to heparan sulfate degradation.
    supported_by:
    - reference_id: PMID:15595925
      supporting_text: >-
        The enzyme also showed O-desulphation activity towards heparan sulphate-derived saccharides.
- term:
    id: GO:0042582
    label: azurophil granule
  evidence_type: IDA
  original_reference_id: PMID:15595925
  qualifier: located_in
  review:
    summary: >-
      IDA annotation locating GNS to azurophil (primary) granules of human neutrophils, based on
      subcellular fractionation showing activity mainly in primary-granule fractions. This is a
      genuine, experimentally supported neutrophil-specific location, but secondary to the core
      lysosomal compartment where GNS performs GAG catabolism. Keep as non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      Azurophil (primary) granules are a specialized neutrophil location; the annotation is valid
      but represents a cell-type-specific compartment rather than the canonical lysosomal site of
      GNS's core catabolic function.
    supported_by:
    - reference_id: PMID:15595925
      supporting_text: >-
        Subcellular fractionation of neutrophil organelles showed the presence of enzymatic activity
        mainly in the same fractions as primary granules.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798751
  qualifier: located_in
  review:
    summary: >-
      TAS annotation (Reactome neutrophil-degranulation pathway) placing GNS in the extracellular
      region upon exocytosis of azurophil granule contents. Consistent with the biochemical
      observation that GNS is released from neutrophils; a secondary, context-dependent location.
      Keep as non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reflects release of granule contents during neutrophil degranulation; not the compartment of
      GNS's core lysosomal catabolic function.
    supported_by:
    - reference_id: PMID:15595925
      supporting_text: >-
        PMA treatment of the neutrophils induced release of the enzyme, indicating its matrix
        protein nature.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6800434
  qualifier: located_in
  review:
    summary: >-
      TAS annotation (Reactome ficolin-rich granule exocytosis pathway) placing GNS in the
      extracellular region upon degranulation. Same rationale as the other extracellular-region
      annotation; secondary location. Keep as non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      Context-dependent extracellular localization following granule exocytosis; not the core
      lysosomal compartment.
    supported_by:
    - reference_id: PMID:15595925
      supporting_text: >-
        PMA treatment of the neutrophils induced release of the enzyme, indicating its matrix
        protein nature.
- term:
    id: GO:0035578
    label: azurophil granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798751
  qualifier: located_in
  review:
    summary: >-
      TAS annotation (Reactome) to azurophil granule lumen, consistent with the experimental
      demonstration that GNS is a soluble matrix protein of neutrophil primary granules. Secondary,
      cell-type-specific location. Keep as non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      Corroborated by biochemistry (matrix protein of primary granules) but represents a
      specialized neutrophil compartment rather than the core lysosomal site.
    supported_by:
    - reference_id: PMID:15595925
      supporting_text: >-
        indicating its matrix protein nature
- term:
    id: GO:1904813
    label: ficolin-1-rich granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6800434
  qualifier: located_in
  review:
    summary: >-
      TAS annotation (Reactome) to ficolin-1-rich granule lumen, from the neutrophil-degranulation
      curation. A specialized neutrophil granule subtype; secondary location. Keep as non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      Neutrophil-granule-subtype location derived from pathway curation; not the core lysosomal
      compartment for GAG catabolism.
    supported_by:
    - reference_id: PMID:15595925
      supporting_text: >-
        Subcellular fractionation of neutrophil organelles showed the presence of enzymatic activity
        mainly in the same fractions as primary granules.
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2263495
  qualifier: located_in
  review:
    summary: >-
      TAS annotation (Reactome) to the lysosomal lumen, the compartment where GNS performs GlcNAc-6-
      sulfate desulfation during GAG catabolism. Core localization; accept.
    action: ACCEPT
    reason: >-
      GNS is a soluble luminal lysosomal hydrolase; the lysosomal lumen is its functional
      compartment.
    supported_by:
    - reference_id: file:human/GNS/GNS-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome."
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: >-
      High-throughput (HDA) detection of GNS in exosomes purified from expressed prostatic
      secretions in urine, from a shotgun proteomics survey of ~900 proteins. This reflects presence
      in a secreted vesicle fraction rather than a core functional location. Keep as non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      Large-scale proteomic detection in an exosome preparation; consistent with GNS being a
      soluble, secretable hydrolase but not indicative of its core catabolic site.
    supported_by:
    - reference_id: PMID:23533145
      supporting_text: >-
        In pooled EPS-urine exosome samples, ~900 proteins were detected.
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1638032
  qualifier: located_in
  review:
    summary: >-
      TAS annotation (Reactome keratan sulfate degradation reaction) to lysosomal lumen. Redundant
      with the other lysosomal-lumen annotation and consistent with GNS's core compartment; accept.
    action: ACCEPT
    reason: >-
      GNS acts as a soluble luminal lysosomal enzyme; lysosomal lumen is the correct core location.
    supported_by:
    - reference_id: file:human/GNS/GNS-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome."
- term:
    id: GO:0008484
    label: sulfuric ester hydrolase activity
  evidence_type: IDA
  original_reference_id: PMID:15962010
  qualifier: enables
  review:
    summary: >-
      IDA annotation to the broad "sulfuric ester hydrolase activity" parent, from a study of
      SUMF1/SUMF2 regulation in which GNS was among the sulphatases assayed. GNS's specific activity
      is N-acetylglucosamine-6-sulfatase (GO:0008449), a child of this term, so the annotation
      should be made more specific.
    action: MODIFY
    reason: >-
      GO:0008484 is the sulfatase-family parent; the specific, experimentally established activity
      of GNS is GO:0008449. Replace with the specific term. The SUMF1/SUMF2 study confirms GNS is a
      formylglycine-dependent sulphatase whose activity is modulated by SUMF1.
    proposed_replacement_terms:
    - id: GO:0008449
      label: N-acetylglucosamine-6-sulfatase activity
    supported_by:
    - reference_id: PMID:15962010
      supporting_text: >-
        we transfected Cos7 cells with several sulphatase cDNAs ( ARSA , ARSC , ARSF , IDS , SGSH ,
        GALNS , GNS )
    - reference_id: file:human/GNS/GNS-uniprot.txt
      supporting_text: "critical for catalytic activity"
- term:
    id: GO:0006027
    label: glycosaminoglycan catabolic process
  evidence_type: TAS
  original_reference_id: PMID:3689315
  qualifier: involved_in
  review:
    summary: >-
      TAS annotation to glycosaminoglycan catabolic process, from the detailed catalytic-properties
      study establishing GNS as a highly specific exo-sulfatase acting on heparin/heparan- and
      keratan-sulfate-derived substrates. Core biological process (parent of the heparan/keratan
      catabolic terms); accept.
    action: ACCEPT
    reason: >-
      GNS is an exo-enzyme in the stepwise catabolism of glycosaminoglycans; this parent term is
      appropriate and directly supported by the enzymology.
    supported_by:
    - reference_id: PMID:3689315
      supporting_text: >-
        Both forms A and B are exo-enzymes, since activity towards internal sulphate ester bonds was
        not observed.
- term:
    id: GO:0008449
    label: N-acetylglucosamine-6-sulfatase activity
  evidence_type: TAS
  original_reference_id: PMID:3689315
  qualifier: enables
  review:
    summary: >-
      TAS annotation to the specific molecular function from the catalytic-properties study, which
      determined kinetic parameters against physiological-substrate analogues and showed high
      specificity for glucosamine-6-sulphate residues. Core activity; accept.
    action: ACCEPT
    reason: >-
      Detailed enzymology directly supports GO:0008449: high specificity for GlcNAc-6-sulphate /
      glucose-6-sulphate residues with catalytic efficiency greatly enhanced on physiological-like
      substrates.
    supported_by:
    - reference_id: PMID:3689315
      supporting_text: >-
        Enzyme activity is highly specific towards glucosamine 6-sulphate or glucose 6-sulphate
        residues.
core_functions:
- description: >-
    Lysosomal N-acetylglucosamine-6-sulfatase (EC 3.1.6.14) that hydrolytically removes the 6-O-
    sulfate group from terminal N-acetyl-D-glucosamine-6-sulfate residues, a required exolytic step
    in the lysosomal catabolism of heparan sulfate and keratan sulfate.
  molecular_function:
    id: GO:0008449
    label: N-acetylglucosamine-6-sulfatase activity
  directly_involved_in:
  - id: GO:0030200
    label: heparan sulfate proteoglycan catabolic process
  locations:
  - id: GO:0043202
    label: lysosomal lumen
  supported_by:
  - reference_id: PMID:1463457
    supporting_text: >-
      Glucosamine-6-sulphatase is an exo-hydrolase required for the lysosomal degradation of heparan
      sulphate and keratan sulphate.
  - reference_id: file:human/GNS/GNS-uniprot.txt
    supporting_text: "Hydrolyzes 6-sulfate groups in N-acetyl-d-glucosaminide units"
- description: >-
    The same lysosomal sulfatase also acts in keratan sulfate catabolism, desulfating GlcNAc-6-
    sulfate residues of keratan-sulfate-derived substrates.
  molecular_function:
    id: GO:0008449
    label: N-acetylglucosamine-6-sulfatase activity
  directly_involved_in:
  - id: GO:0042340
    label: keratan sulfate proteoglycan catabolic process
  locations:
  - id: GO:0005764
    label: lysosome
  supported_by:
  - reference_id: PMID:3689315
    supporting_text: >-
      Forms A and B both desulphate substrates derived from keratan sulphate and heparin.
  - reference_id: file:human/GNS/GNS-uniprot.txt
    supporting_text: "of heparin sulfate and keratan sulfate."
proposed_new_terms: []
suggested_questions:
- question: >-
    Does GNS have any non-lysosomal physiological role in extracellular glycosaminoglycan
    remodeling, given its presence and O-desulphation activity in neutrophil primary granules and
    its release upon degranulation?
suggested_experiments:
- description: >-
    Structure-guided characterization of the formylglycine-dependent active site (Cys91 -> FGly,
    Ca2+ coordination) to map how MPS IIID missense variants (e.g. S94I, K340R, G418E) disrupt
    catalysis or protein stability.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:1463457
  title: A cDNA clone for human glucosamine-6-sulphatase reveals differences between
    arylsulphatases and non-arylsulphatases.
  findings:
  - statement: >-
      GNS (glucosamine-6-sulphatase) is a lysosomal exo-hydrolase required for degradation of
      heparan sulphate and keratan sulphate; its deficiency causes MPS IIID with lysosomal storage
      of heparan sulphate. The full 552-aa precursor with a 36-aa leader was cloned and its
      catalytic activity (EC 3.1.6.14) established.
    supporting_text: >-
      Glucosamine-6-sulphatase is an exo-hydrolase required for the lysosomal degradation of heparan
      sulphate and keratan sulphate.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Primary cloning/characterization paper; directly establishes the core molecular function and
      biological role. Source of the UniProt EC 3.1.6.14 and FUNCTION evidence.
- id: PMID:15595925
  title: Purification of a 75 kDa protein from the organelle matrix of human neutrophils
    and identification as N-acetylglucosamine-6-sulphatase.
  findings:
  - statement: >-
      A 75 kDa neutrophil granule-matrix protein was purified and identified by MS as
      N-acetylglucosamine-6-sulphatase (EC 3.1.6.14), with confirmed activity toward
      N-acetylglucosamine-6-sulphate and O-desulphation of heparan-sulphate-derived saccharides;
      it localizes to primary (azurophil) granules and is released on PMA stimulation.
    supporting_text: >-
      identified the protein to be N-acetylglucosamine-6-sulphatase (EC 3.1.6.14). The identity of
      the protein was confirmed by demostrating enzymatic activity towards the substrate
      N-acetylglucosamine 6-sulphate.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Provides direct (IDA) support for the molecular function, heparan sulfate catabolic process,
      and the neutrophil primary-granule / secreted locations.
- id: PMID:15962010
  title: Sulphatase activities are regulated by the interaction of sulphatase-modifying
    factor 1 with SUMF2.
  findings:
  - statement: >-
      GNS is a formylglycine-dependent sulphatase; it was among the sulphatases whose activity is
      enhanced by SUMF1 (formylglycine-generating enzyme) and modulated by SUMF2. Supports the
      broad sulfuric-ester-hydrolase annotation, which is best refined to the specific
      GlcNAc-6-sulfatase activity.
    supporting_text: >-
      we transfected Cos7 cells with several sulphatase cDNAs ( ARSA , ARSC , ARSF , IDS , SGSH ,
      GALNS , GNS )
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      GNS is one of seven sulphatases co-transfected/assayed; supports the FGly/SUMF1 dependence of
      GNS activity but the paper's main focus is SUMF1/SUMF2 regulation, not GNS specifically.
- id: PMID:17474147
  title: Systematic identification of SH3 domain-mediated human protein-protein interactions
    by peptide array target screening.
  findings:
  - statement: >-
      GNS appears as a peptide-array hit for SH3 domains (including NCK1) in a proteome-wide
      screen. This underlies the bare "protein binding" IPI, which is uninformative about GNS's
      molecular function.
    supporting_text: >-
      A group of 12 Src homology (SH) 3 domains from eight human proteins (Swiss-Prot ID: SRC,
      PLCG1, P85A, NCK1, GRB2, FYN, CRK) were used to screen a peptide target array
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput SH3 peptide-array screen; citation is correct but supports only an
      uninformative "protein binding" annotation with no evidence of biological relevance to GNS.
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic
    secretions in urine.
  findings:
  - statement: >-
      GNS was detected among ~900 proteins in a shotgun-proteomics survey of urinary prostatic-
      secretion exosomes, underlying the extracellular-exosome location annotation.
    supporting_text: >-
      In pooled EPS-urine exosome samples, ~900 proteins were detected.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale exosome proteomics; supports only a non-core secreted-vesicle location.
- id: PMID:3689315
  title: Human liver N-acetylglucosamine-6-sulphate sulphatase. Catalytic properties.
  findings:
  - statement: >-
      Human liver GNS is a highly specific exo-sulfatase for glucosamine-6-sulphate / glucose-6-
      sulphate residues, desulfating keratan-sulphate- and heparin-derived substrates; it shows no
      activity toward internal sulphate ester bonds, and sulphate/phosphate ions are potent
      inhibitors.
    supporting_text: >-
      Both forms A and B are exo-enzymes, since activity towards internal sulphate ester bonds was
      not observed.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Detailed enzymology; supports the molecular function and the glycosaminoglycan catabolic
      process (exolytic mechanism).
- id: Reactome:R-HSA-1638032
  title: GNS:Ca2+ cleaves sulfate from GlcNAc-6-sulfate units of keratan sulfate
  findings: []
- id: Reactome:R-HSA-2263495
  title: Defective GNS does not hydrolyse 6-sulfate from GlcNAc6S
  findings: []
- id: Reactome:R-HSA-6798751
  title: Exocytosis of azurophil granule lumen proteins
  findings: []
- id: Reactome:R-HSA-6800434
  title: Exocytosis of ficolin-rich granule lumen proteins
  findings: []
- id: file:human/GNS/GNS-uniprot.txt
  title: UniProtKB entry P15586 (GNS_HUMAN)
  findings:
  - statement: >-
      UniProt records GNS as a lysosomal N-acetylglucosamine-6-sulfatase (EC 3.1.6.14) that
      hydrolyzes 6-sulfate groups of N-acetyl-D-glucosaminide units of heparan and keratan sulfate,
      requires a catalytic formylglycine (3-oxoalanine) residue, and whose deficiency causes MPS
      IIID.
    supporting_text: >-
      Hydrolyzes 6-sulfate groups in N-acetyl-d-glucosaminide units