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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005764 lysosome | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: file:human/IDS/IDS-uniprot.txt SUBCELLULAR LOCATION: Lysosome PMID:28593992 their degradation and recycling in the lysosome is |
| GO:0004423 iduronate-2-sulfatase activity | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:28593992 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-Ξ±-L-iduronic acid residues in dermatan sulfate and heparan sulfate. |
| GO:0004423 iduronate-2-sulfatase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (InterPro/ARBA + EC 3.1.6.13) assertion of iduronate-2-sulfatase activity. Correct and consistent with the experimental and phylogenetic annotations. 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. Supporting Evidence: file:human/IDS/IDS-uniprot.txt Reaction=Hydrolysis of the 2-sulfate groups of the L-iduronate 2- |
| GO:0005764 lysosome | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assertion of lysosomal localization, consistent with UniProt SubCell and experimental data. Reason: IEA lysosome annotation agrees with UniProt SUBCELLULAR LOCATION and IDA evidence. Core cellular location. Supporting Evidence: file:human/IDS/IDS-uniprot.txt SUBCELLULAR LOCATION: Lysosome |
| GO:0043202 lysosomal lumen | IEA GO_REF:0000117 | ACCEPT | 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. Reason: IDS is a soluble luminal lysosomal hydrolase; lysosomal lumen is a correct, more specific cellular component. Core cellular location. Supporting Evidence: file:human/IDS/IDS-uniprot.txt SUBCELLULAR LOCATION: Lysosome |
| GO:1901136 carbohydrate derivative catabolic process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:2122463 Iduronate 2-sulfatase (IDS, EC 3.1.6.13) is required for the lysosomal |
| GO:0005515 protein binding | IPI PMID:15962010 Sulphatase activities are regulated by the interaction of su... | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:15962010 SUMF2 was able to stably associate with IDS and with SGSH alone or in a PMID:15962010 SUMF2 colocalizes with SUMF1 within the |
| GO:0004423 iduronate-2-sulfatase activity | EXP PMID:11731225 The effect of four mutations on the expression of iduronate-... | ACCEPT | 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. Reason: Direct experimental measurement of IDS enzyme activity (wild-type versus disease mutants) in expression studies. Exact, correct core molecular function term. Supporting Evidence: PMID:11731225 recessive lysosomal storage disorder caused by the deficiency of the enzyme |
| GO:0004423 iduronate-2-sulfatase activity | EXP PMID:28593992 Insights into Hunter syndrome from the structure of iduronat... | ACCEPT | 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. 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. Supporting Evidence: PMID:28593992 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-Ξ±-L-iduronic acid residues in dermatan sulfate and heparan sulfate. |
| GO:0005509 calcium ion binding | IDA PMID:28593992 Insights into Hunter syndrome from the structure of iduronat... | ACCEPT | 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. 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). Supporting Evidence: PMID:28593992 Extra electron density for a metal ion was observed next to the modified FGS residue. file:human/IDS/IDS-uniprot.txt Note=Binds 1 Ca(2+) ion per subunit. |
| GO:0006027 glycosaminoglycan catabolic process | IDA PMID:28593992 Insights into Hunter syndrome from the structure of iduronat... | ACCEPT | 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. 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. Supporting Evidence: PMID:28593992 required for the step-wise degradation and recycling of complex glycosaminoglycans |
| GO:0004423 iduronate-2-sulfatase activity | IDA PMID:10838181 Expression of five iduronate-2-sulfatase site-directed mutat... | ACCEPT | 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. 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. Supporting Evidence: PMID:10838181 Substitution of arginine with histidine residue resulted in 13.7% residual PMID:10838181 belongs to the CXPSR pentapeptide conserved in all human sulfatases |
| GO:0005764 lysosome | IDA PMID:10838181 Expression of five iduronate-2-sulfatase site-directed mutat... | ACCEPT | 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. Reason: Directly demonstrated lysosomal localization/trafficking of IDS. Consistent with UniProt SubCell and IBA/IEA annotations. Core cellular location. Supporting Evidence: PMID:10838181 subcellular fractionation demonstrated poor transport to lysosomes file:human/IDS/IDS-uniprot.txt SUBCELLULAR LOCATION: Lysosome |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-2262743 | ACCEPT | Summary: Reactome TAS (defective IDS reaction) placing IDS in the lysosomal lumen. IDS is a soluble luminal lysosomal hydrolase, so this compartment is correct. Reason: IDS acts as a soluble enzyme in the lysosomal lumen; the more specific lumen term is appropriate. Core cellular location. Supporting Evidence: file:human/IDS/IDS-uniprot.txt SUBCELLULAR LOCATION: Lysosome |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-9036046 | ACCEPT | Summary: Reactome TAS (defective IDS in heparan sulfate degradation) placing IDS in the lysosomal lumen. Correct compartment for this soluble hydrolase. Reason: Duplicate lysosomal lumen assertion from a distinct Reactome reaction; correct and consistent. Core cellular location. Supporting Evidence: file:human/IDS/IDS-uniprot.txt SUBCELLULAR LOCATION: Lysosome |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-1678650 | ACCEPT | Summary: Reactome TAS (IDS hydrolyses heparan sulfate) placing IDS in the lysosomal lumen, the site of heparan sulfate degradation. Reason: Correct luminal lysosomal location, from a Reactome heparan sulfate degradation reaction. Core cellular location. Supporting Evidence: file:human/IDS/IDS-uniprot.txt SUBCELLULAR LOCATION: Lysosome |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-1793182 | ACCEPT | Summary: Reactome TAS (IDS hydrolyses dermatan sulfate) placing IDS in the lysosomal lumen, the site of dermatan sulfate degradation. Reason: Correct luminal lysosomal location, from a Reactome dermatan sulfate degradation reaction. Core cellular location. Supporting Evidence: file:human/IDS/IDS-uniprot.txt SUBCELLULAR LOCATION: Lysosome |
| GO:0004423 iduronate-2-sulfatase activity | TAS PMID:2122463 Hunter syndrome: isolation of an iduronate-2-sulfatase cDNA ... | ACCEPT | 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. Reason: Foundational reference establishing IDS identity and enzymatic role. Exact, correct core molecular function term. Supporting Evidence: PMID:2122463 Iduronate 2-sulfatase (IDS, EC 3.1.6.13) is required for the lysosomal |
| GO:0030200 heparan sulfate proteoglycan catabolic process | IEA file:human/IDS/IDS-uniprot.txt | NEW | 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. 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. Supporting Evidence: PMID:28593992 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-Ξ±-L-iduronic acid residues in dermatan sulfate and heparan sulfate. file:human/IDS/IDS-uniprot.txt GO:0030200; P:heparan sulfate proteoglycan catabolic process |
| GO:0030209 dermatan sulfate proteoglycan catabolic process | IEA file:human/IDS/IDS-uniprot.txt | NEW | 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. 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. Supporting Evidence: PMID:28593992 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-Ξ±-L-iduronic acid residues in dermatan sulfate and heparan sulfate. file:human/IDS/IDS-uniprot.txt GO:0030209; P:dermatan sulfate proteoglycan catabolic process |
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