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Literature summary for 3.2.1.166 extracted from
- Structural characterization of human heparanase reveals insights into substrate recognition (2015), Nat. Struct. Mol. Biol., 22, 1016-1022 .
Cloned(Commentary)
| Cloned (Comment) | Organism |
|---|---|
| single gene, recombinant expression in Spodoptera frugiperda cells via baculovrius transfection method. The two subunits cotranslationally fold into mature heterodimeric HPSE, bypassing the 65 kDa proenzyme form and ensuring expression of only active enzyme | Homo sapiens |
Crystallization (Commentary)
| Crystallization (Comment) | Organism |
|---|---|
| purified recombinant heterodimeric wild-type apo-enzyme, X-ray diffraction structure determiantion and analysis at 1.75 A resolution | Homo sapiens |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| PI-88 | - |
Homo sapiens |  |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| cell surface | HPSE can be trafficked to the cell surface or released into the extracellular matrix in order to effect breakdown of extracellular pools of heparan sulfate | Homo sapiens | 9986 | - |
| endosome | late | Homo sapiens | 5768 | - |
| extracellular | HPSE can be trafficked to the cell surface or released into the extracellular matrix in order to effect breakdown of extracellular pools of heparan sulfate | Homo sapiens | - |
- |
| lysosome | - |
Homo sapiens | 5764 | - |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| heparan sulfate + H2O | Homo sapiens | - |
? | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | Q9Y251 | - |
- |
Posttranslational Modification
| Posttranslational Modification | Comment | Organism |
|---|---|---|
| glycoprotein | enzyme HPSE contains 6 putative N-glycosylation sites, all residing on the 50 kDa subunit. N-linked GlcNAcs (corresponding to N-glycan trees trimmed by endoglycosidase (Endo)H during protein preparation) are found in the apo-HPSE structure at Asn162, Asn200, Asn217, Asn238 and Asn459. Additionally a core alpha1->6 linked fucose is located on the GlcNAc linked to Asn459. No noticeable density corresponding to GlcNAc is observed at the N-glycosylation site Asn178, suggesting this position may not be well N-glycosylated during baculoviral expression, or that N-GlcNAc here is not compatible with crystal packing | Homo sapiens |
| proteolytic modification | an endo-acting binding cleft is exposed by proteolytic activation of latent proenzyme, proHPSE. Enzyme HPSE is initially translated as a pre-proenzyme, containing a signal sequence spanning Met1-Ala35. Cleavage of this signal sequence by signal peptidase leaves an inactive 65 kDa proHPSE, which must undergo further processing for activity. Proteolytic removal by cathepsin L of a linker spanning Ser110-Gln157 liberates an N-terminal 8 kDa subunit and a C-terminal 50 kDa subunit, which remain associated as a non-covalent heterodimer in mature active HPSE29 | Homo sapiens |
Purification (Commentary)
| Purification (Comment) | Organism |
|---|---|
| recombinant enzyme from insect cells | Homo sapiens |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| heparan sulfate + H2O | - |
Homo sapiens | ? | - |
? | |
| heparan sulfate + H2O | enzyme HPSE catalyzes hydrolysis of internal GlcUA(beta1->4)GlcNS linkages in heparan sulfate, with net retention of anomeric configuration. HPSE breakdown of HS is not indiscriminate, but instead is restricted to a small subset of GlcUAs reflecting a requirement for specific N- and O-sulfation patterns on neighboring sugars | Homo sapiens | ? | - |
? | |
| additional information | oligosaccharide complexes map the substrate-binding and sulfate recognition motifs. Analysis of the structural basis of HPSE substrate interactions, overview. HPSE interaction induces distortion of the substrate chain | Homo sapiens | ? | - |
? | |
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| heterodimer | 1 * 8000 + 1 * 50000, mature enzyme, SDS-PAGE | Homo sapiens |
| monomer | 1 * 65000, inactive proenzyme, SDS-PAGE | Homo sapiens |
| More | tertiary structure of enzyme HPSE, overview. The domain architecture of HPSE comprises a (beta/alpha)8 domain flanked by a smaller beta-sandwich domain. Both 8 kDa and 50 kDa subunits are structurally involved in both domains: the 8 kDa subunit contributes one beta-sheet to the beta-sandwich, and the 1st beta-alpha-beta fold of the (beta/alpha)8 domain, with the remaining folds contributed by the 50 kDa subunit | Homo sapiens |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| endo-beta-glucuronidase | - |
Homo sapiens |
| HPSE | - |
Homo sapiens |
General Information
| General Information | Comment | Organism |
|---|---|---|
| evolution | the enzyme belongs to the glycoxadside hydrolase family 79, GH79 | Homo sapiens |
| malfunction | whilst controlled HPSE activity plays an important role in physiological processing of the extracellular matrix, aberrant HPSE expression is associated with inflammation and cancerous growth. The proliferative advantages conferred by HPSE lead to its upregulation by tumors in a variety of tissues, and HPSE overexpression correlates strongly with metastasis and worsened clinical prognoses | Homo sapiens |
| physiological function | enzyme HPSE present in late endosomes and lysosomes performs an essential housekeeping role in catabolic processing of internalized heparan sulfate proteoglycans (HSPGs). HPSE mediated breakdown of heparan sulfate in the extracellular matrix has several effects on the behavior of nearby cells. Weakening of structural heparan sulfate networks in the extracellular matrix and basement membranes directly facilitates cell motility and extravasation into surrounding tissues. Latent pools of growth factors stored by heparan sulfate are released upon breakdown by HPSE, promoting increased cell proliferation, motility and angiogenesis. Heparan sulfate fragments generated by HPSE activity can also activate downstream signaling cascades. Whilst controlled HPSE activity plays an important role in physiological processing of the extracellular matrix, aberrant HPSE expression is associated with inflammation and cancerous growth. The proliferative advantages conferred by HPSE lead to its upregulation by tumors in a variety of tissues, and HPSE overexpression correlates strongly with metastasis and worsened clinical prognoses | Homo sapiens |
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