id: P35475
gene_symbol: IDUA
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  IDUA encodes alpha-L-iduronidase, a lysosomal exo-glycosidase (glycosyl hydrolase
  family 39; EC 3.2.1.76) that hydrolyses terminal, non-reducing alpha-L-iduronic
  acid residues from the glycosaminoglycans heparan sulfate and dermatan sulfate.
  It is one of the sequential enzymes of lysosomal glycosaminoglycan catabolism,
  acting by a retaining double-displacement mechanism (nucleophile Glu299, general
  acid/base Glu182); an N-glycan attached to Asn372 forms part of the substrate-binding
  pocket and is required for full activity. The enzyme is a monomer that is trafficked
  to and acts within the lysosomal lumen. Loss of IDUA activity blocks GAG degradation
  and causes lysosomal accumulation and urinary excretion of heparan sulfate and
  dermatan sulfate, producing mucopolysaccharidosis type I, which spans a clinical
  spectrum from severe (Hurler syndrome) through intermediate (Hurler-Scheie) to
  attenuated (Scheie syndrome).
alternative_products:
- name: '1'
  id: P35475-1
- name: '2'
  id: P35475-2
  sequence_note: VSP_057029, VSP_057030
existing_annotations:
- term:
    id: GO:0003940
    label: L-iduronidase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) assignment of the defining catalytic activity of IDUA,
      L-iduronidase activity. This is the core molecular function of the gene and
      is concordant with direct experimental structural/biochemical evidence.
    action: ACCEPT
    reason: >-
      L-iduronidase activity is the well-established core function of IDUA, confirmed
      by crystal structures and enzyme kinetics of the human enzyme. The IBA call is
      consistent with the manual experimental annotations.
    supported_by:
    - reference_id: PMID:24036510
      supporting_text: >-
        IDUA participates in the stepwise degradation of the glycosaminoglycans
        (GAGs) heparan sulphate and dermatan sulphate, by removing a single
        α-L-iduronyl residue from the non-reducing ends of these complex
        polysaccharides.
    - reference_id: file:human/IDUA/IDUA-uniprot.txt
      supporting_text: 'RecName: Full=Alpha-L-iduronidase;'
- term:
    id: GO:0003940
    label: L-iduronidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic (multi-method IEA) assignment of L-iduronidase activity, mapped in
      part from EC 3.2.1.76. Correct and identical to the experimentally supported
      core molecular function.
    action: ACCEPT
    reason: >-
      Redundant with the experimentally supported GO:0003940 annotations; the EC
      3.2.1.76 mapping is exactly the enzyme's activity.
    supported_by:
    - reference_id: file:human/IDUA/IDUA-uniprot.txt
      supporting_text: EC=3.2.1.76;
- term:
    id: GO:0004553
    label: hydrolase activity, hydrolyzing O-glycosyl compounds
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro-derived (IPR000514, Glyco_hydro_39) mapping to the general parent term
      for O-glycosyl hydrolases. Correct but less informative than the specific
      L-iduronidase activity term.
    action: KEEP_AS_NON_CORE
    reason: >-
      IDUA is a glycoside hydrolase family 39 member and does hydrolyse O-glycosyl
      (alpha-L-iduronosidic) linkages, so the term is not wrong, but it is a broad
      grouping term subsumed by the specific GO:0003940 L-iduronidase activity. Kept
      as non-core rather than treated as the representative molecular function.
    supported_by:
    - reference_id: file:human/IDUA/IDUA-uniprot.txt
      supporting_text: Belongs to the glycosyl hydrolase 39 family.
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UniProt Subcellular-Location keyword mapping placing IDUA in the lysosome. This
      is the correct and physiologically relevant compartment for the enzyme.
    action: ACCEPT
    reason: >-
      IDUA is a mannose-6-phosphate-targeted lysosomal hydrolase; lysosomal
      localization is central to its function and is asserted by UniProt with
      literature support.
    supported_by:
    - reference_id: file:human/IDUA/IDUA-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Lysosome'
- term:
    id: GO:0005975
    label: carbohydrate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro-derived high-level biological-process term. IDUA does participate in
      carbohydrate metabolism, but this is a very broad grouping term subsumed by the
      specific glycosaminoglycan catabolic annotations.
    action: KEEP_AS_NON_CORE
    reason: >-
      Not incorrect, but far too general; the informative processes are heparan
      sulfate and dermatan sulfate catabolism. Retained as non-core.
    supported_by:
    - reference_id: PMID:24036510
      supporting_text: >-
        IDUA participates in the stepwise degradation of the glycosaminoglycans
        (GAGs) heparan sulphate and dermatan sulphate, by removing a single
        α-L-iduronyl residue from the non-reducing ends of these complex
        polysaccharides.
- term:
    id: GO:0030200
    label: heparan sulfate proteoglycan catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA electronic assignment of heparan sulfate proteoglycan catabolism, one of
      the two core degradative pathways in which IDUA acts. Well supported by
      experimental and structural evidence.
    action: ACCEPT
    reason: >-
      IDUA removes terminal alpha-L-iduronate from heparan sulfate during its stepwise
      lysosomal degradation; loss of IDUA blocks HS breakdown (HS accumulation in
      Idua-deficient mice).
    supported_by:
    - reference_id: PMID:24036510
      supporting_text: >-
        IDUA participates in the stepwise degradation of the glycosaminoglycans
        (GAGs) heparan sulphate and dermatan sulphate, by removing a single
        α-L-iduronyl residue from the non-reducing ends of these complex
        polysaccharides.
    - reference_id: PMID:21873421
      supporting_text: >-
        representing the terminal iduronic acid residue capping the non-reducing end
        of the HS chain, where no further degradation can occur in the absence of Idua.
- term:
    id: GO:0030209
    label: dermatan sulfate proteoglycan catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA electronic assignment of dermatan sulfate proteoglycan catabolism, the
      second core degradative pathway of IDUA. Duplicated by an experimental IDA
      annotation below.
    action: ACCEPT
    reason: >-
      IDUA hydrolyses the unsulfated alpha-L-iduronosidic linkages of dermatan sulfate
      (this is its defining EC 3.2.1.76 reaction); a core biological process.
    supported_by:
    - reference_id: file:human/IDUA/IDUA-uniprot.txt
      supporting_text: Hydrolysis of unsulfated alpha-L-iduronosidic linkages in
    - reference_id: PMID:24036510
      supporting_text: >-
        IDUA participates in the stepwise degradation of the glycosaminoglycans
        (GAGs) heparan sulphate and dermatan sulphate, by removing a single
        α-L-iduronyl residue from the non-reducing ends of these complex
        polysaccharides.
- term:
    id: GO:0030211
    label: heparin proteoglycan catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA electronic assignment of heparin proteoglycan catabolism. Heparin is a
      highly sulfated relative of heparan sulfate bearing the same
      alpha-L-iduronosidic linkages, on which IDUA acts. Supported experimentally by
      the Idua-knockout mouse (below) and retained consistent with that IMP.
    action: ACCEPT
    reason: >-
      Heparin shares the alpha-L-iduronosidic linkages of heparan sulfate, and the
      Idua-deficient mouse demonstrates that terminal iduronate removal from these
      chains requires IDUA. Kept consistent with the IMP annotation to the same term.
    supported_by:
    - reference_id: PMID:21873421
      supporting_text: >-
        representing the terminal iduronic acid residue capping the non-reducing end
        of the HS chain, where no further degradation can occur in the absence of Idua.
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: >-
      ARBA electronic assignment of lysosomal lumen localization. This is the precise
      compartment in which IDUA carries out GAG degradation and is well supported.
    action: ACCEPT
    reason: >-
      IDUA is a soluble lysosomal hydrolase acting in the acidic lumen; the more
      specific lumen term is preferable to the generic lysosome term and is retained
      as a core localization.
    supported_by:
    - reference_id: file:human/IDUA/IDUA-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Lysosome'
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Electronic annotation transferred from the rat ortholog (D3ZE16) via Ensembl
      Compara. There is no evidence that IDUA, a soluble lysosomal glycosidase, acts
      as a signaling receptor ligand.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      IDUA is a lysosomal hydrolase with no established signaling-ligand role; this is
      an uninformative binding term propagated electronically from an ortholog and is
      not supported by the human literature or structural/functional characterization.
    supported_by:
    - reference_id: file:human/IDUA/IDUA-uniprot.txt
      supporting_text: >-
        Lysosomal hydrolase responsible for the degradation of the
- term:
    id: GO:0006027
    label: glycosaminoglycan catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl-transferred annotation to the parent glycosaminoglycan catabolic process
      term. This correctly captures IDUA's role in GAG breakdown and is the immediate
      parent of the HS and DS catabolic annotations.
    action: ACCEPT
    reason: >-
      IDUA is a bona fide GAG-degrading lysosomal exo-glycosidase; the term is correct,
      if broader than the HS/DS-specific terms.
    supported_by:
    - reference_id: PMID:24036510
      supporting_text: >-
        IDUA participates in the stepwise degradation of the glycosaminoglycans
        (GAGs) heparan sulphate and dermatan sulphate, by removing a single
        α-L-iduronyl residue from the non-reducing ends of these complex
        polysaccharides.
- term:
    id: GO:0030200
    label: heparan sulfate proteoglycan catabolic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2024096
  qualifier: involved_in
  review:
    summary: >-
      Reactome traceable-author annotation placing IDUA in the HS-GAG degradation
      pathway. Concordant with the experimentally supported role in heparan sulfate
      catabolism.
    action: ACCEPT
    reason: >-
      Reactome curates IDUA as a step in lysosomal heparan sulfate degradation,
      consistent with the enzyme's characterized activity.
    supported_by:
    - reference_id: Reactome:R-HSA-1678716
      supporting_text: >-
        The lysosomal enzyme alpha-L-iduronidase (IDUA) cleaves the terminal L-iduronic
        acid residue from either heparan sulfate or dermatan sulfate chains of
        proteoglycans
- term:
    id: GO:0030209
    label: dermatan sulfate proteoglycan catabolic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1793186
  qualifier: involved_in
  review:
    summary: >-
      Reactome traceable-author annotation placing IDUA in dermatan sulfate
      degradation (hydrolysis of the unsulfated alpha-L-iduronosidic link in DS).
      Concordant with the enzyme's EC 3.2.1.76 reaction.
    action: ACCEPT
    reason: >-
      Curated Reactome pathway step matching IDUA's defining catalytic reaction on
      dermatan sulfate.
    supported_by:
    - reference_id: Reactome:R-HSA-1793186
      supporting_text: >-
        The lysosomal enzyme alpha-L-iduronidase (IDUA) hydrolyzes the nonreducing
        terminal iduronide glycosidic bond in heparan sulfate and dermatan sulfate
- term:
    id: GO:0003940
    label: L-iduronidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1678716
  qualifier: enables
  review:
    summary: >-
      Reactome traceable-author assertion of L-iduronidase activity (cleavage of
      terminal L-iduronate from HS chains). Core molecular function.
    action: ACCEPT
    reason: >-
      Restates the enzyme's defining catalytic activity within a curated reaction.
    supported_by:
    - reference_id: Reactome:R-HSA-1678716
      supporting_text: >-
        The lysosomal enzyme alpha-L-iduronidase (IDUA) cleaves the terminal L-iduronic
        acid residue from either heparan sulfate or dermatan sulfate chains of
        proteoglycans
- term:
    id: GO:0003940
    label: L-iduronidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1793186
  qualifier: enables
  review:
    summary: >-
      Reactome traceable-author assertion of L-iduronidase activity (hydrolysis of the
      unsulfated alpha-L-iduronosidic link in DS). Core molecular function.
    action: ACCEPT
    reason: >-
      Restates the enzyme's defining catalytic activity within a curated dermatan
      sulfate reaction.
    supported_by:
    - reference_id: Reactome:R-HSA-1793186
      supporting_text: >-
        The lysosomal enzyme alpha-L-iduronidase (IDUA) hydrolyzes the nonreducing
        terminal iduronide glycosidic bond in heparan sulfate and dermatan sulfate
- term:
    id: GO:0003940
    label: L-iduronidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2090037
  qualifier: enables
  review:
    summary: >-
      Reactome traceable-author assertion of L-iduronidase activity within a heparan
      sulfate chain hydrolysis reaction. Core molecular function.
    action: ACCEPT
    reason: >-
      Duplicate curated assertion of the enzyme's defining catalytic activity.
    supported_by:
    - reference_id: Reactome:R-HSA-1678716
      supporting_text: >-
        The lysosomal enzyme alpha-L-iduronidase (IDUA) cleaves the terminal L-iduronic
        acid residue from either heparan sulfate or dermatan sulfate chains of
        proteoglycans
- term:
    id: GO:0003940
    label: L-iduronidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2206299
  qualifier: enables
  review:
    summary: >-
      Reactome traceable-author assertion of L-iduronidase activity (associated with a
      defective-IDUA/disease reaction). Core molecular function.
    action: ACCEPT
    reason: >-
      Duplicate curated assertion of the enzyme's defining catalytic activity in the
      MPS I disease context.
    supported_by:
    - reference_id: Reactome:R-HSA-1678716
      supporting_text: >-
        The lysosomal enzyme alpha-L-iduronidase (IDUA) cleaves the terminal L-iduronic
        acid residue from either heparan sulfate or dermatan sulfate chains of
        proteoglycans
- term:
    id: GO:0003940
    label: L-iduronidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9036037
  qualifier: enables
  review:
    summary: >-
      Reactome traceable-author assertion of L-iduronidase activity within a
      heparan-sulfate-chain reaction. Core molecular function.
    action: ACCEPT
    reason: >-
      Duplicate curated assertion of the enzyme's defining catalytic activity.
    supported_by:
    - reference_id: Reactome:R-HSA-1678716
      supporting_text: >-
        The lysosomal enzyme alpha-L-iduronidase (IDUA) cleaves the terminal L-iduronic
        acid residue from either heparan sulfate or dermatan sulfate chains of
        proteoglycans
- term:
    id: GO:0003940
    label: L-iduronidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9036041
  qualifier: enables
  review:
    summary: >-
      Reactome traceable-author assertion of L-iduronidase activity (associated with
      the defective-IDUA dermatan sulfate reaction). Core molecular function.
    action: ACCEPT
    reason: >-
      Duplicate curated assertion of the enzyme's defining catalytic activity.
    supported_by:
    - reference_id: Reactome:R-HSA-1793186
      supporting_text: >-
        The lysosomal enzyme alpha-L-iduronidase (IDUA) hydrolyzes the nonreducing
        terminal iduronide glycosidic bond in heparan sulfate and dermatan sulfate
- term:
    id: GO:0003940
    label: L-iduronidase activity
  evidence_type: EXP
  original_reference_id: PMID:23959878
  qualifier: enables
  review:
    summary: >-
      Experimental (EXP) assignment of L-iduronidase activity from a structural/kinetic
      study of human IDUA that determined the crystal structure with iduronate bound
      and characterized catalysis, including the role of the Asn372 N-glycan.
    action: ACCEPT
    reason: >-
      Direct experimental determination of the enzyme's catalytic activity in humans;
      this is the strongest evidence for the core molecular function.
    supported_by:
    - reference_id: PMID:23959878
      supporting_text: >-
        human α-l-iduronidase (hIDUA), of which a dysfunction causes accumulation of
        dermatan/heparan sulfate leading to mucopolysaccharidosis type I, uses its own
        N-glycan as a substrate binding and catalytic module.
- term:
    id: GO:0030211
    label: heparin proteoglycan catabolic process
  evidence_type: IMP
  original_reference_id: PMID:21873421
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      IMP annotation from a murine Idua-knockout study showing accumulation of heparan
      sulfate with a terminal iduronate-capped disaccharide, demonstrating that Idua is
      required for degradation of iduronate-containing heparan sulfate/heparin chains.
    action: ACCEPT
    reason: >-
      Loss of Idua in mice blocks removal of terminal iduronate from HS/heparin,
      causing pathological accumulation; strong genetic evidence for IDUA's role in
      catabolism of iduronate-bearing HS/heparin. Retained (heparin is closely related
      to HS, and the phenotype is directly demonstrated).
    supported_by:
    - reference_id: PMID:21873421
      supporting_text: >-
        representing the terminal iduronic acid residue capping the non-reducing end
        of the HS chain, where no further degradation can occur in the absence of Idua.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: >-
      High-throughput mass-spectrometry detection of IDUA among ~900 proteins in
      exosomes isolated from expressed prostatic secretions in urine. This reflects
      presence of the secretory/lysosomal protein in extracellular vesicles rather
      than a distinct functional site.
    action: KEEP_AS_NON_CORE
    reason: >-
      A proteomics survey placed IDUA in urinary exosomes; lysosomal/secretory
      hydrolases are commonly recovered in extracellular vesicles. This is a valid
      detection but not the enzyme's primary functional location, so it is retained as
      non-core.
    supported_by:
    - reference_id: PMID:23533145
      supporting_text: >-
        In pooled EPS-urine exosome samples, ~900 proteins were detected.
- term:
    id: GO:0003940
    label: L-iduronidase activity
  evidence_type: IDA
  original_reference_id: PMID:24036510
  qualifier: enables
  review:
    summary: >-
      Direct assay (IDA) of L-iduronidase activity from the human IDUA crystal-structure
      and enzymology study that captured Michaelis and glycosyl-enzyme intermediate
      complexes with iduronate analogs and defined the retaining double-displacement
      mechanism.
    action: ACCEPT
    reason: >-
      Definitive experimental characterization of the enzyme's catalytic activity and
      mechanism; the primary evidence for the core molecular function.
    supported_by:
    - reference_id: PMID:24036510
      supporting_text: >-
        IDUA is an α-retaining glycoside hydrolase with strict substrate specificity
        for L-IdoA
- term:
    id: GO:0030209
    label: dermatan sulfate proteoglycan catabolic process
  evidence_type: IDA
  original_reference_id: PMID:24036510
  qualifier: involved_in
  review:
    summary: >-
      IDA annotation of dermatan sulfate proteoglycan catabolism from the structural
      and enzymological study showing IDUA removes alpha-L-iduronate from the
      non-reducing ends of dermatan sulfate (and heparan sulfate).
    action: ACCEPT
    reason: >-
      Experimentally grounded in IDUA's demonstrated action on dermatan sulfate; a core
      biological process.
    supported_by:
    - reference_id: PMID:24036510
      supporting_text: >-
        IDUA participates in the stepwise degradation of the glycosaminoglycans
        (GAGs) heparan sulphate and dermatan sulphate, by removing a single
        α-L-iduronyl residue from the non-reducing ends of these complex
        polysaccharides.
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2206299
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author localization of IDUA to the lysosomal lumen (disease
      reaction context). Correct core compartment.
    action: ACCEPT
    reason: >-
      Consistent with IDUA being a soluble lysosomal-lumen hydrolase.
    supported_by:
    - reference_id: Reactome:R-HSA-1678716
      supporting_text: The lysosomal enzyme alpha-L-iduronidase (IDUA)
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9036037
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author localization of IDUA to the lysosomal lumen (heparan
      sulfate reaction context). Correct core compartment.
    action: ACCEPT
    reason: >-
      Consistent with IDUA being a soluble lysosomal-lumen hydrolase.
    supported_by:
    - reference_id: Reactome:R-HSA-1678716
      supporting_text: The lysosomal enzyme alpha-L-iduronidase (IDUA)
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9036041
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author localization of IDUA to the lysosomal lumen (dermatan
      sulfate reaction context). Correct core compartment.
    action: ACCEPT
    reason: >-
      Consistent with IDUA being a soluble lysosomal-lumen hydrolase.
    supported_by:
    - reference_id: Reactome:R-HSA-1793186
      supporting_text: The lysosomal enzyme alpha-L-iduronidase (IDUA)
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1678716
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author localization of IDUA to the lysosomal lumen (HS chain
      cleavage reaction). Correct core compartment.
    action: ACCEPT
    reason: >-
      Consistent with IDUA being a soluble lysosomal-lumen hydrolase.
    supported_by:
    - reference_id: Reactome:R-HSA-1678716
      supporting_text: The lysosomal enzyme alpha-L-iduronidase (IDUA)
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1793186
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author localization of IDUA to the lysosomal lumen (DS link
      hydrolysis reaction). Correct core compartment.
    action: ACCEPT
    reason: >-
      Consistent with IDUA being a soluble lysosomal-lumen hydrolase.
    supported_by:
    - reference_id: Reactome:R-HSA-1793186
      supporting_text: The lysosomal enzyme alpha-L-iduronidase (IDUA)
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2090037
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author localization of IDUA to the lysosomal lumen (heparan
      sulfate chain reaction). Correct core compartment.
    action: ACCEPT
    reason: >-
      Consistent with IDUA being a soluble lysosomal-lumen hydrolase.
    supported_by:
    - reference_id: Reactome:R-HSA-1678716
      supporting_text: The lysosomal enzyme alpha-L-iduronidase (IDUA)
- term:
    id: GO:0003940
    label: L-iduronidase activity
  evidence_type: TAS
  original_reference_id: PMID:2470345
  qualifier: enables
  review:
    summary: >-
      Traceable-author annotation of L-iduronidase activity from the immunopurification
      and biochemical characterization of the human liver enzyme, which measured its
      activity toward heparan sulfate- and dermatan sulfate-derived substrates.
    action: ACCEPT
    reason: >-
      An early experimental characterization establishing the enzyme's catalytic
      activity on GAG-derived substrates; core molecular function.
    supported_by:
    - reference_id: PMID:2470345
      supporting_text: >-
        activities towards disaccharide substrates derived from two glycosaminoglycan
        sources, heparan sulphate and dermatan sulphate.
- term:
    id: GO:0005984
    label: disaccharide metabolic process
  evidence_type: TAS
  original_reference_id: PMID:2470345
  qualifier: involved_in
  review:
    summary: >-
      Traceable-author annotation of disaccharide metabolic process, derived from an
      in vitro assay in which the two enzyme forms were tested against GAG-derived
      disaccharide substrates. IDUA's physiological substrates are polymeric heparan
      sulfate and dermatan sulfate, not free disaccharides.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The disaccharide substrates were an experimental convenience for measuring
      activity; the in vivo role is exolytic removal of terminal iduronate from GAG
      polymers, captured by the glycosaminoglycan/HS/DS catabolic terms. This
      general metabolic-process term overstates a biological role in disaccharide
      metabolism.
    supported_by:
    - reference_id: PMID:2470345
      supporting_text: >-
        activities towards disaccharide substrates derived from two glycosaminoglycan
        sources, heparan sulphate and dermatan sulphate.
    - reference_id: PMID:24036510
      supporting_text: >-
        by removing a single α-L-iduronyl residue from the non-reducing ends of these
        complex polysaccharides.
core_functions:
- description: >-
    Hydrolysis of terminal, non-reducing alpha-L-iduronic acid residues from the
    glycosaminoglycans heparan sulfate and dermatan sulfate in the lysosomal lumen,
    a required exolytic step of lysosomal glycosaminoglycan catabolism.
  molecular_function:
    id: GO:0003940
    label: L-iduronidase activity
  directly_involved_in:
  - id: GO:0030200
    label: heparan sulfate proteoglycan catabolic process
  - id: GO:0030209
    label: dermatan sulfate proteoglycan catabolic process
  - id: GO:0006027
    label: glycosaminoglycan catabolic process
  locations:
  - id: GO:0043202
    label: lysosomal lumen
  - id: GO:0005764
    label: lysosome
  substrates:
  - id: CHEBI:28815
    label: heparan sulfate
  - id: CHEBI:18376
    label: dermatan sulfate
  supported_by:
  - reference_id: PMID:24036510
    supporting_text: >-
      IDUA participates in the stepwise degradation of the glycosaminoglycans
      (GAGs) heparan sulphate and dermatan sulphate, by removing a single
      α-L-iduronyl residue from the non-reducing ends of these complex
      polysaccharides.
  - reference_id: PMID:24036510
    supporting_text: >-
      IDUA is an α-retaining glycoside hydrolase with strict substrate specificity
      for L-IdoA
  - reference_id: file:human/IDUA/IDUA-uniprot.txt
    supporting_text: >-
      Lysosomal hydrolase responsible for the degradation of the
  - reference_id: file:human/IDUA/IDUA-uniprot.txt
    supporting_text: 'SUBCELLULAR LOCATION: Lysosome'
  - reference_id: Reactome:R-HSA-1678716
    supporting_text: >-
      The lysosomal enzyme alpha-L-iduronidase (IDUA) cleaves the terminal L-iduronic
      acid residue from either heparan sulfate or dermatan sulfate chains of
      proteoglycans
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:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:21873421
  title: Mucopolysaccharidosis type I, unique structure of accumulated heparan sulfate
    and increased N-sulfotransferase activity in mice lacking α-l-iduronidase.
  findings:
  - statement: >-
      Idua-deficient mice accumulate heparan sulfate bearing a terminal iduronate-capped
      disaccharide at the non-reducing end, where no further degradation can occur
      without Idua, confirming IDUA's role in heparan sulfate/heparin catabolism.
    supporting_text: >-
      representing the terminal iduronic acid residue capping the non-reducing end of
      the HS chain, where no further degradation can occur in the absence of Idua.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Murine Idua-knockout study directly demonstrating loss of terminal iduronate
      removal from heparan sulfate; supports the HS/heparin catabolic-process
      annotations.
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic
    secretions in urine.
  findings:
  - statement: >-
      IDUA was among ~900 proteins detected by shotgun proteomics of urinary
      prostatic-secretion exosomes, supporting its recovery in extracellular vesicles.
    supporting_text: In pooled EPS-urine exosome samples, ~900 proteins were detected.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput exosome proteomics; supports the extracellular-exosome
      localization annotation but is peripheral to IDUA's core lysosomal function.
- id: PMID:23959878
  title: Human α-L-iduronidase uses its own N-glycan as a substrate-binding and catalytic
    module.
  findings:
  - statement: >-
      Crystal structure and enzymology of human IDUA showing that the N-glycan at
      Asn372 forms part of the substrate-binding pocket and is required for full
      L-iduronidase activity.
    supporting_text: >-
      human α-l-iduronidase (hIDUA), of which a dysfunction causes accumulation of
      dermatan/heparan sulfate leading to mucopolysaccharidosis type I, uses its own
      N-glycan as a substrate binding and catalytic module.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Structural/kinetic characterization of human IDUA; strong experimental support
      for the core L-iduronidase activity.
- id: PMID:24036510
  title: Insights into mucopolysaccharidosis I from the structure and action of α-L-iduronidase.
  findings:
  - statement: >-
      Crystal structures of human IDUA bound to iduronate analogs define the catalytic
      mechanism (retaining double displacement; nucleophile Glu299, acid/base Glu182)
      and confirm exolytic removal of alpha-L-iduronate from heparan and dermatan
      sulfate.
    supporting_text: >-
      IDUA participates in the stepwise degradation of the glycosaminoglycans
      (GAGs) heparan sulphate and dermatan sulphate, by removing a single
      α-L-iduronyl residue from the non-reducing ends of these complex
      polysaccharides.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Definitive structural and mechanistic study of human IDUA; primary support for
      the molecular function and HS/DS catabolic processes.
- id: PMID:2470345
  title: Immunopurification and characterization of human alpha-L-iduronidase with
    the use of monoclonal antibodies.
  findings:
  - statement: >-
      Immunopurified human alpha-L-iduronidase from liver was active toward disaccharide
      substrates derived from both heparan sulfate and dermatan sulfate.
    supporting_text: >-
      activities towards disaccharide substrates derived from two glycosaminoglycan
      sources, heparan sulphate and dermatan sulphate.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Early biochemical characterization of the human enzyme; supports catalytic
      activity but its disaccharide-metabolic-process annotation reflects the assay
      substrate rather than the in vivo polymeric substrate.
- id: Reactome:R-HSA-1678716
  title: IDUA cleaves iduronate from HS chain
  findings: []
- id: Reactome:R-HSA-1793186
  title: IDUA hydrolyses the unsulfated alpha-L-iduronosidic link in DS
  findings: []
- id: Reactome:R-HSA-2024096
  title: HS-GAG degradation
  findings: []
- id: Reactome:R-HSA-2090037
  title: IDUA hydrolyses Heparan sulfate chain(6)
  findings: []
- id: Reactome:R-HSA-2206299
  title: Defective IDUA does not hydrolyse Heparan sulfate chain(6)
  findings: []
- id: Reactome:R-HSA-9036037
  title: Defective IDUA does not hydrolyse Heparan sulfate chain(1)
  findings: []
- id: Reactome:R-HSA-9036041
  title: Defective IDUA does not hydrolyse the unsulfated alpha-L-iduronosidic link
    in DS
  findings: []
- id: file:human/IDUA/IDUA-uniprot.txt
  title: UniProtKB entry P35475 (IDUA_HUMAN)
  findings: []