id: P22304
gene_symbol: IDS
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  IDS (iduronate 2-sulfatase) is a lysosomal sulfatase (EC 3.1.6.13) that catalyses
  a step in the stepwise exolytic degradation of the glycosaminoglycans heparan sulfate
  and dermatan sulfate. It hydrolytically removes the 2-O-sulfate group from terminal,
  non-reducing-end L-iduronate-2-sulfate (2-O-sulfo-alpha-L-iduronic acid) residues,
  exposing iduronate for the next enzyme in the pathway (alpha-L-iduronidase, IDUA).
  Like all eukaryotic sulfatases, its catalytic activity depends on a Calpha-formylglycine
  (3-oxoalanine, FGly) residue generated post-translationally at Cys84 in the endoplasmic
  reticulum by the formylglycine-generating enzyme (FGE/SUMF1), and it binds one active-site
  Ca2+ ion per subunit. The enzyme is synthesized as an ER precursor, N-glycosylated and
  proteolytically processed to a mature form, and traffics to the lysosome/lysosomal lumen
  where it acts. Deficiency of IDS causes mucopolysaccharidosis type II (Hunter syndrome),
  an X-linked lysosomal storage disease with tissue accumulation of heparan and dermatan
  sulfate.
alternative_products:
- name: 1 (Long)
  id: P22304-1
- name: 2 (Short)
  id: P22304-2
  sequence_note: VSP_006301, VSP_006302
- name: '3'
  id: P22304-3
  sequence_note: VSP_039116, VSP_039117
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) assertion that IDS is active in the lysosome. This is the
      well-established site of action of IDS and is consistent with experimental
      localization and the lysosomal GAG degradation pathway.
    action: ACCEPT
    reason: >-
      IDS is a lysosomal GAG-degrading sulfatase. UniProt records SUBCELLULAR LOCATION
      Lysosome, and IDS acts in the lysosomal degradation of dermatan/heparan sulfate.
      Core cellular location.
    supported_by:
    - reference_id: file:human/IDS/IDS-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
    - reference_id: PMID:28593992
      supporting_text: "their degradation and recycling in the lysosome is"
- term:
    id: GO:0004423
    label: iduronate-2-sulfatase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) assertion of the defining molecular function of IDS,
      iduronate-2-sulfatase activity (EC 3.1.6.13). This is the exact GOA term and
      the core molecular function.
    action: ACCEPT
    reason: >-
      This is the biochemically defined activity of IDS: hydrolysis of the 2-sulfate
      group from L-iduronate-2-sulfate residues of dermatan/heparan sulfate. Strongly
      supported by direct enzymology and crystal structure.
    supported_by:
    - reference_id: PMID:28593992
      supporting_text: "IDS belongs to the sulfatase family of enzymes and catalyses hydrolysis of the C2-sulfate ester bond at the non-reducing end of 2-O-sulfo-α-L-iduronic acid residues in dermatan sulfate and heparan sulfate."
- term:
    id: GO:0004423
    label: iduronate-2-sulfatase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic (InterPro/ARBA + EC 3.1.6.13) assertion of iduronate-2-sulfatase
      activity. Correct and consistent with the experimental and phylogenetic annotations.
    action: ACCEPT
    reason: >-
      IEA mapping from the IDS InterPro family (IPR035874) and EC 3.1.6.13 to the exact,
      correct molecular function term. Core molecular function.
    supported_by:
    - reference_id: file:human/IDS/IDS-uniprot.txt
      supporting_text: "Reaction=Hydrolysis of the 2-sulfate groups of the L-iduronate 2-"
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Electronic assertion of lysosomal localization, consistent with UniProt SubCell
      and experimental data.
    action: ACCEPT
    reason: >-
      IEA lysosome annotation agrees with UniProt SUBCELLULAR LOCATION and IDA evidence.
      Core cellular location.
    supported_by:
    - reference_id: file:human/IDS/IDS-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: >-
      Electronic (ARBA) assertion of lysosomal lumen localization. IDS is a soluble
      lysosomal enzyme that acts in the lumen, so this more specific compartment is
      appropriate.
    action: ACCEPT
    reason: >-
      IDS is a soluble luminal lysosomal hydrolase; lysosomal lumen is a correct,
      more specific cellular component. Core cellular location.
    supported_by:
    - reference_id: file:human/IDS/IDS-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:1901136
    label: carbohydrate derivative catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      Electronic (ARBA) assertion that IDS is involved in carbohydrate derivative
      catabolism. Not wrong, but this is a very high-level parent of the informative
      glycosaminoglycan / heparan sulfate / dermatan sulfate catabolic terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Correct in essence but uninformatively general. The informative process terms for
      IDS are glycosaminoglycan catabolic process (GO:0006027, already annotated by IDA)
      and the heparan/dermatan sulfate catabolic subprocesses. Kept but flagged as
      over-general rather than removed, since it is a true (electronic) superclass.
    supported_by:
    - reference_id: PMID:2122463
      supporting_text: "Iduronate 2-sulfatase (IDS, EC 3.1.6.13) is required for the lysosomal"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15962010
  qualifier: enables
  review:
    summary: >-
      IntAct IPI capturing a physical interaction between IDS and SUMF2 (UniProtKB:Q8NBJ7).
      SUMF2 is an ER paralogue of the formylglycine-generating enzyme SUMF1 that stably
      associates with sulfatases and modulates SUMF1-mediated activation. This is a
      regulatory ER interaction, not a core molecular function, and the bare protein
      binding term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare GO:0005515 protein binding conveys no specific molecular function. The
      underlying SUMF2 interaction is real but peripheral (regulation of sulfatase
      maturation/activation in the ER). Per curation policy, kept and flagged as an
      over-annotation rather than removed.
    supported_by:
    - reference_id: PMID:15962010
      supporting_text: "SUMF2 was able to stably associate with IDS and with SGSH alone or in a"
    - reference_id: PMID:15962010
      supporting_text: "SUMF2 colocalizes with SUMF1 within the"
- term:
    id: GO:0004423
    label: iduronate-2-sulfatase activity
  evidence_type: EXP
  original_reference_id: PMID:11731225
  qualifier: enables
  review:
    summary: >-
      Experimental (transient expression / activity assay) evidence for
      iduronate-2-sulfatase activity, from characterization of MPS II mutations that
      reduce IDS activity. Supports the core molecular function.
    action: ACCEPT
    reason: >-
      Direct experimental measurement of IDS enzyme activity (wild-type versus disease
      mutants) in expression studies. Exact, correct core molecular function term.
    supported_by:
    - reference_id: PMID:11731225
      supporting_text: "recessive lysosomal storage disorder caused by the deficiency of the enzyme"
- term:
    id: GO:0004423
    label: iduronate-2-sulfatase activity
  evidence_type: EXP
  original_reference_id: PMID:28593992
  qualifier: enables
  review:
    summary: >-
      Experimental evidence for iduronate-2-sulfatase activity from the crystal structure
      paper, which measured specific activity of purified IDS on the fluorogenic
      iduronide-2-sulfate substrate and characterized the active site. Core molecular
      function.
    action: ACCEPT
    reason: >-
      IDS was assayed as catalytically active (specific activity ~36 umol/h/mg on
      MU-alpha-L-iduronide-2-sulfate) and its active site and mechanism were defined.
      Exact, correct core molecular function.
    supported_by:
    - reference_id: PMID:28593992
      supporting_text: "IDS belongs to the sulfatase family of enzymes and catalyses hydrolysis of the C2-sulfate ester bond at the non-reducing end of 2-O-sulfo-α-L-iduronic acid residues in dermatan sulfate and heparan sulfate."
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IDA
  original_reference_id: PMID:28593992
  qualifier: enables
  review:
    summary: >-
      IDA (crystal structure, PDB 5FQL) showing a single active-site Ca2+ ion coordinated
      near the catalytic formylglycine and metal-binding aspartates. This structural
      calcium is required for active-site stabilization / sulfate-ester formation.
    action: ACCEPT
    reason: >-
      Directly demonstrated by the 2.3 A crystal structure: one Ca2+ per subunit in the
      active site. This is a genuine metal-binding property that underpins catalysis;
      retained (supporting rather than the headline core function).
    supported_by:
    - reference_id: PMID:28593992
      supporting_text: "Extra electron density for a metal ion was observed next to the modified FGS residue."
    - reference_id: file:human/IDS/IDS-uniprot.txt
      supporting_text: "Note=Binds 1 Ca(2+) ion per subunit."
- term:
    id: GO:0006027
    label: glycosaminoglycan catabolic process
  evidence_type: IDA
  original_reference_id: PMID:28593992
  qualifier: involved_in
  review:
    summary: >-
      IDA that IDS participates in glycosaminoglycan catabolism. IDS removes the 2-sulfate
      from L-iduronate-2-sulfate residues as a required step in the stepwise lysosomal
      degradation of the GAGs heparan sulfate and dermatan sulfate. Core biological process.
    action: ACCEPT
    reason: >-
      IDS is required for the stepwise (exolytic) lysosomal degradation of heparan and
      dermatan sulfate; loss of activity causes GAG accumulation (Hunter syndrome). The
      GAG catabolic process is the correct, appropriately specific core BP.
    supported_by:
    - reference_id: PMID:28593992
      supporting_text: "required for the step-wise degradation and recycling of complex glycosaminoglycans"
- term:
    id: GO:0004423
    label: iduronate-2-sulfatase activity
  evidence_type: IDA
  original_reference_id: PMID:10838181
  qualifier: enables
  review:
    summary: >-
      IDA for iduronate-2-sulfatase activity from site-directed mutagenesis / expression
      studies that measured residual enzyme activity of IDS variants (e.g. R88H retained
      ~13.7% activity; R88P abolished activity). Core molecular function.
    action: ACCEPT
    reason: >-
      Direct measurement of IDS enzyme activity for wild-type and active-site (CxPSR/R88)
      mutants, tying activity to the formylglycine-modification motif. Exact, correct core
      molecular function.
    supported_by:
    - reference_id: PMID:10838181
      supporting_text: "Substitution of arginine with histidine residue resulted in 13.7% residual"
    - reference_id: PMID:10838181
      supporting_text: "belongs to the CXPSR pentapeptide conserved in all human sulfatases"
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IDA
  original_reference_id: PMID:10838181
  qualifier: located_in
  review:
    summary: >-
      IDA for lysosomal localization from subcellular fractionation of IDS expressed in
      COS cells (wild-type IDS transported to lysosomes; several MPS II mutants showed
      poor lysosomal transport). Core cellular location.
    action: ACCEPT
    reason: >-
      Directly demonstrated lysosomal localization/trafficking of IDS. Consistent with
      UniProt SubCell and IBA/IEA annotations. Core cellular location.
    supported_by:
    - reference_id: PMID:10838181
      supporting_text: "subcellular fractionation demonstrated poor transport to lysosomes"
    - reference_id: file:human/IDS/IDS-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2262743
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS (defective IDS reaction) placing IDS in the lysosomal lumen. IDS is a
      soluble luminal lysosomal hydrolase, so this compartment is correct.
    action: ACCEPT
    reason: >-
      IDS acts as a soluble enzyme in the lysosomal lumen; the more specific lumen term is
      appropriate. Core cellular location.
    supported_by:
    - reference_id: file:human/IDS/IDS-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9036046
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS (defective IDS in heparan sulfate degradation) placing IDS in the
      lysosomal lumen. Correct compartment for this soluble hydrolase.
    action: ACCEPT
    reason: >-
      Duplicate lysosomal lumen assertion from a distinct Reactome reaction; correct and
      consistent. Core cellular location.
    supported_by:
    - reference_id: file:human/IDS/IDS-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1678650
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS (IDS hydrolyses heparan sulfate) placing IDS in the lysosomal lumen,
      the site of heparan sulfate degradation.
    action: ACCEPT
    reason: >-
      Correct luminal lysosomal location, from a Reactome heparan sulfate degradation
      reaction. Core cellular location.
    supported_by:
    - reference_id: file:human/IDS/IDS-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1793182
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS (IDS hydrolyses dermatan sulfate) placing IDS in the lysosomal lumen,
      the site of dermatan sulfate degradation.
    action: ACCEPT
    reason: >-
      Correct luminal lysosomal location, from a Reactome dermatan sulfate degradation
      reaction. Core cellular location.
    supported_by:
    - reference_id: file:human/IDS/IDS-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0004423
    label: iduronate-2-sulfatase activity
  evidence_type: TAS
  original_reference_id: PMID:2122463
  qualifier: enables
  review:
    summary: >-
      TAS for iduronate-2-sulfatase activity from the original IDS cDNA cloning paper,
      which identified IDS (EC 3.1.6.13) as the enzyme required for lysosomal degradation
      of heparan and dermatan sulfate. Core molecular function.
    action: ACCEPT
    reason: >-
      Foundational reference establishing IDS identity and enzymatic role. Exact, correct
      core molecular function term.
    supported_by:
    - reference_id: PMID:2122463
      supporting_text: "Iduronate 2-sulfatase (IDS, EC 3.1.6.13) is required for the lysosomal"
- term:
    id: GO:0030200
    label: heparan sulfate proteoglycan catabolic process
  evidence_type: IEA
  original_reference_id: file:human/IDS/IDS-uniprot.txt
  qualifier: involved_in
  review:
    summary: >-
      IDS removes the 2-O-sulfate from L-iduronate-2-sulfate residues in heparan sulfate,
      an obligatory step in its stepwise lysosomal degradation. UniProt records this
      process (GO:0030200) as an Ensembl-projected annotation; added here as NEW to
      capture the specific heparan sulfate catabolic role, which is more informative than
      the generic glycosaminoglycan/carbohydrate-derivative catabolic terms.
    action: NEW
    reason: >-
      Heparan sulfate is one of the two physiological IDS substrates; loss of IDS causes
      heparan sulfate accumulation in Hunter syndrome. This specific catabolic process is
      supported by the enzyme's mechanism and by Reactome HS-GAG degradation reactions.
    supported_by:
    - reference_id: PMID:28593992
      supporting_text: "IDS belongs to the sulfatase family of enzymes and catalyses hydrolysis of the C2-sulfate ester bond at the non-reducing end of 2-O-sulfo-α-L-iduronic acid residues in dermatan sulfate and heparan sulfate."
    - reference_id: file:human/IDS/IDS-uniprot.txt
      supporting_text: "GO:0030200; P:heparan sulfate proteoglycan catabolic process"
- term:
    id: GO:0030209
    label: dermatan sulfate proteoglycan catabolic process
  evidence_type: IEA
  original_reference_id: file:human/IDS/IDS-uniprot.txt
  qualifier: involved_in
  review:
    summary: >-
      IDS removes the 2-O-sulfate from L-iduronate-2-sulfate residues in dermatan sulfate,
      an obligatory step in its stepwise lysosomal degradation. UniProt records this
      process (GO:0030209) as an Ensembl-projected annotation; added here as NEW to
      capture the specific dermatan sulfate catabolic role.
    action: NEW
    reason: >-
      Dermatan sulfate is the second physiological IDS substrate; loss of IDS causes
      dermatan sulfate accumulation in Hunter syndrome. This specific catabolic process is
      supported by the enzyme's mechanism and by Reactome CS/DS degradation reactions.
    supported_by:
    - reference_id: PMID:28593992
      supporting_text: "IDS belongs to the sulfatase family of enzymes and catalyses hydrolysis of the C2-sulfate ester bond at the non-reducing end of 2-O-sulfo-α-L-iduronic acid residues in dermatan sulfate and heparan sulfate."
    - reference_id: file:human/IDS/IDS-uniprot.txt
      supporting_text: "GO:0030209; P:dermatan sulfate proteoglycan catabolic process"
core_functions:
- description: >-
    Lysosomal iduronate-2-sulfatase: hydrolytically removes the 2-O-sulfate group from
    terminal, non-reducing-end L-iduronate-2-sulfate residues of heparan sulfate and
    dermatan sulfate, a required step in the stepwise lysosomal catabolism of these
    glycosaminoglycans. Catalysis depends on the active-site Calpha-formylglycine (from
    Cys84, generated by SUMF1/FGE) and a bound Ca2+ ion.
  molecular_function:
    id: GO:0004423
    label: iduronate-2-sulfatase activity
  directly_involved_in:
  - id: GO:0030200
    label: heparan sulfate proteoglycan catabolic process
  - id: GO:0030209
    label: dermatan sulfate proteoglycan catabolic process
  locations:
  - id: GO:0005764
    label: lysosome
  - id: GO:0043202
    label: lysosomal lumen
  supported_by:
  - reference_id: PMID:28593992
    supporting_text: "IDS belongs to the sulfatase family of enzymes and catalyses hydrolysis of the C2-sulfate ester bond at the non-reducing end of 2-O-sulfo-α-L-iduronic acid residues in dermatan sulfate and heparan sulfate."
  - reference_id: file:human/IDS/IDS-uniprot.txt
    supporting_text: "Lysosomal enzyme involved in the degradation pathway of"
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  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/IDS/IDS-uniprot.txt
  title: UniProtKB entry P22304 (IDS_HUMAN)
  findings: []
- id: PMID:10838181
  title: Expression of five iduronate-2-sulfatase site-directed mutations.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only in cache; supports IDS iduronate-2-sulfatase activity (residual
      activity of R88H/R88P mutants), the CXPSR formylglycine motif, and poor lysosomal
      transport of mutants. PubMed-verified title.
- id: PMID:11731225
  title: The effect of four mutations on the expression of iduronate-2-sulfatase in
    mucopolysaccharidosis type II.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only in cache; transient-expression/activity study of IDS MPS II mutations,
      supporting the iduronate-2-sulfatase activity annotation. PubMed-verified title.
- id: PMID:15962010
  title: Sulphatase activities are regulated by the interaction of sulphatase-modifying
    factor 1 with SUMF2.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Full text available; source of the IDS-SUMF2 (Q8NBJ7) IntAct IPI. SUMF2 stably
      associates with IDS and modulates SUMF1/FGE-mediated sulfatase activation in the ER.
      Supports a real but peripheral interaction; the protein binding term is uninformative.
- id: PMID:2122463
  title: 'Hunter syndrome: isolation of an iduronate-2-sulfatase cDNA clone and analysis
    of patient DNA.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Original IDS cDNA cloning paper; establishes IDS (EC 3.1.6.13) as required for
      lysosomal degradation of heparan and dermatan sulfate, and defines the precursor
      processing. PubMed-verified title.
- id: PMID:28593992
  title: Insights into Hunter syndrome from the structure of iduronate-2-sulfatase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text available; crystal structure (PDB 5FQL) of human IDS. Defines the
      catalytic mechanism (formylglycine at Cys84, active-site Ca2+), specific activity
      on iduronide-2-sulfate substrate, and role in stepwise GAG (HS/DS) degradation.
      Primary support for the MF, calcium binding, and GAG catabolism annotations.
- id: Reactome:R-HSA-1678650
  title: IDS hydrolyses Heparan sulfate chain(5)
  findings: []
- id: Reactome:R-HSA-1793182
  title: IDS hydrolyses dermatan sulfate (Chebi:63517 chain)
  findings: []
- id: Reactome:R-HSA-2262743
  title: Defective IDS does not hydrolyse dermatan sulfate (Chebi:63517 chain)
  findings: []
- id: Reactome:R-HSA-9036046
  title: Defective IDS does not hydrolyse Heparan sulfate chain(5)
  findings: []