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Literature summary for 3.2.1.166 extracted from
- Heparanase from basic research to therapeutic applications in cancer and inflammation (2016), Drug Resist. Updat., 29, 54-75 .
Application
| Application | Comment | Organism |
|---|---|---|
| diagnostics | upregulation of heparanase expression correlates with increased tumor size, tumor angiogenesis, enhanced metastasis and poor prognosis. Heparanase expressed by tumor cells, innate immune cells, activated endothelial cells as well as other cells of the tumor microenvironment is a master regulator of the aggressive phenotype of cancer and an important contributor to the poor outcome of cancer patients | Homo sapiens |
| drug development | heparanase inhibitors used in tandem with chemotherapeutic drugs overcome initial chemoresistance, providing a strong rationale for applying anti-heparanase therapy in combination with conventional anti-cancer drugs. Heparin-like compounds that inhibit heparanase activity are being evaluated in clinical trials for various types of cancer. Heparanase expressed by tumor cells, innate immune cells, activated endothelial cells as well as other cells of the tumor microenvironment is a prime target for therapy | Homo sapiens |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| defibrotide | a polydisperse oligonucleotide isolated from porcine mucosa that has multiple biological effects including inhibition of heparanase gene expression and enzymatic activity | Homo sapiens | |
| additional information | heparanase inhibitors used in tandem with chemotherapeutic drugs overcome initial chemoresistance. Heparin-like compounds that inhibit heparanase activity are being evaluated in clinical trials for various types of cancer. Heparanase-inhibiting small molecules are developed based on the recently resolved crystal structure of the heparanase protein. Heparanase neutralizing monoclonal antibodies have been generated and found effective in preclinical cancer models | Homo sapiens | |
| muparfostat | formally PI-88, a phosphomannopentaose | Homo sapiens |  |
| necuparanib | formally M402, an N-sulfated glycol-split heparin of 6 kDa, shows efficacy in metastasis models | Homo sapiens | |
| PG545 | a fully sulfated synthetic tetrasaccharide functionalized with a cholestanyl aglycon | Homo sapiens | |
| roneparstat | SST0001, an N-acetylated glycol-split heparin and a potent inhibitor of heparanase, consists of a chemically modified heparin (reduced oxidized N-acetylated heparin) that is non-anticoagulant and is not degraded by the enzyme. In a model of dexamethasone resistant MM, the combination of Roneparstat with dexamethasone inhibits tumor growth. Roneparstat dramatically reduces tumor growth in bone when used in combination with either bortezomib or melphalan | Homo sapiens | |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| endosome | late endosomes | Homo sapiens | 5768 | - |
| 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 | - |
? | - |
? | |
| additional information | Homo sapiens | heparanase interacts with syndecans by virtue of the typical high affinity that exists between an enzyme and its substrate. This high affinity interaction directs rapid and efficient cellular uptake of the heparanase-syndecan complex | ? | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | Q9Y251 | - |
- |
Posttranslational Modification
| Posttranslational Modification | Comment | Organism |
|---|---|---|
| proteolytic modification | heparanase is initially translated as a preproenzyme containing a signal sequence spanning Met1-Ala35. Cleavage of this signal sequence by signal peptidase yields an inactive 65-kDa pro-heparanase, 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 noncovalent heterodimer in mature active heparanase. Processing of heparanase is mediated by syndecan 1 cytoplasmic domain and involves syntenin and alpha-actinin. Heparanase uptake is regarded a pre-requisite for the delivery of latent 65 kDa heparanase to lysosomes and its subsequent proteolytic processing and activation into 8 and 50 kDa protein subunits | Homo sapiens |
Reaction
| Reaction | Comment | Organism | Reaction ID |
|---|---|---|---|
| endohydrolysis of (1->4)-beta-D-glycosidic bonds of heparan sulfate chains in heparan sulfate proteoglycan | mode of action, overview | Homo sapiens |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| carcinoma cell | - |
Homo sapiens | - |
| colon | heparanase expression is up-regulated in the colon of patients suffering from Crohn's disease and ulcerative colitis | Homo sapiens | - |
| lung | - |
Homo sapiens | - |
| lung | heparanase induction is found in biopsies of human inflammatory lung disease | Homo sapiens | - |
| macrophage | - |
Homo sapiens | - |
| additional information | heparanase expression is enhanced in almost all cancers examined including various carcinomas, sarcomas and hematological malignancies | Homo sapiens | - |
| additional information | tumor cell | Homo sapiens | - |
| myeloma cell | heparanase gene expression increases dramatically in myeloma patients following chemotherapy | Homo sapiens | - |
| neutrophil | - |
Homo sapiens | - |
| pancreas | - |
Homo sapiens | - |
| pancreatic ductal adenocarcinoma cell | - |
Homo sapiens | - |
| synovia | heparanase expression is up-regulated in the synovial fluid and tissue of patients suffering from rheumatoid arthritis, but not in unaffected individuals | Homo sapiens | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| heparan sulfate + H2O | - |
Homo sapiens | ? | - |
? | |
| additional information | heparanase interacts with syndecans by virtue of the typical high affinity that exists between an enzyme and its substrate. This high affinity interaction directs rapid and efficient cellular uptake of the heparanase-syndecan complex | Homo sapiens | ? | - |
? | |
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| heterodimer | the enzyme is formed by an N-terminal 8-kDa subunit and a C-terminal 50-kDa subunit, which remain associated as a noncovalent heterodimer in mature active heparanase | Homo sapiens |
Ki Value [mM]
| Ki Value [mM] | Ki Value maximum [mM] | Inhibitor | Comment | Organism | Structure |
|---|---|---|---|---|---|
| 0.000006 | - |
PG545 | pH and temperature not specified in the publication | Homo sapiens | |
IC50 Value
| IC50 Value | IC50 Value Maximum | Comment | Organism | Inhibitor | Structure |
|---|---|---|---|---|---|
| 0.000003 | - |
pH and temperature not specified in the publication | Homo sapiens | roneparstat | |
Expression
| Organism | Comment | Expression |
|---|---|---|
| Homo sapiens | heparanase expression is enhanced in almost all cancers examined including various carcinomas, sarcomas and hematological malignancies. Upregulation of heparanase expression correlates with increased tumor size, tumor angiogenesis, enhanced metastasis and poor prognosis. Heparanase is upregulated in response to chemotherapy in cancer patients and the surviving cells acquire chemoresistance, attributed, at least in part, to autophagy | up |
General Information
| General Information | Comment | Organism |
|---|---|---|
| malfunction | knockdown of heparanase or treatments of tumor-bearing mice with heparanase-inhibiting compounds, markedly attenuate tumor progression further underscoring the potential of anti-heparanase therapy for multiple types of cancer. Heparanase neutralizing monoclonal antibodies block myeloma and lymphoma tumor growth and dissemination. This is attributable to a combined effect on the tumor cells and/or cells of the tumor microenvironment. Heparanase inhibitors used in tandem with chemotherapeutic drugs overcome initial chemoresistance. Blocking heparanase diminishes drug resistance in myeloma | Homo sapiens |
| additional information | processing of heparanase is mediated by syndecan 1 cytoplasmic domain and involves syntenin and alpha-actinin. Heparanase interacts with syndecans by virtue of the typical high affinity that exists between an enzyme and its substrate. This high affinity interaction directs rapid and efficient cellular uptake of the heparanase-syndecan complex | Homo sapiens |
| physiological function | heparanase, the sole heparan sulfate degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, angiogenesis and metastasis. Heparanase regulates gene expression, activates cells of the innate immune system, promotes the formation of exosomes and autophagosomes, and stimulates signal transduction pathways via enzymatic and non-enzymatic activities. These effects dynamically impact multiple regulatory pathways that together drive inflammatory responses, tumor survival, growth, dissemination and drug resistance, but in the same time, may fulfill some normal functions associated, for example, with vesicular traffic lysosomal-based secretion, stress response, and heparan sulfate turnover. Upregulation of heparanase expression correlates with increased tumor size, tumor angiogenesis, enhanced metastasis and poor prognosis. Much of the impact of heparanase on tumor progression is related to its function in mediating tumor-host crosstalk, priming the tumor microenvironment to better support tumor growth, metastasis and chemoresistance. Heparanase regulates gene expression, activates cells of the innate immune system, promotes the formation of exosomes and autophagosomes, and stimulates signal transduction pathways via enzymatic and non-enzymatic activities. These effects dynamically impact multiple regulatory pathways that together drive inflammatory responses, tumor survival, growth, dissemination and drug resistance, but in the same time, may fulfill some normal functions associated, for example, with vesicular traffic lysosomal-based secretion, stress response, and heparan sulfate turnover. Heparanase expressed by tumor cells, innate immune cells, activated endothelial cells as well as other cells of the tumor microenvironment is a master regulator of the aggressive phenotype of cancer. Heparanase present in late endosomes and lysosomes plays an essential housekeeping role in catabolic processing of internalized heparan sulfate proteoglycans (HSPGs), which contribute to the structural integrity, self-assembly and insolubility of the extracellular matrix (ECM) and basement membrane, thus intimately modulating cell-ECM interactions. The enzyme is involved in hematologic malignancies, e.g. multiple myeloma, overview. Heparanase enhances myeloma progression via CXCL10 down regulation. Heparan sulfate-rich glycocalyx has to be removed by lung expressed heparanase in order for neutrophils to entrap in the pulmonary vasculature in response to lipopolysacchride (LPS) septic signals. Heparanase is critical for neutrophil entry to lungs exposed to tobacco smoke. No role for lung heparanase in neutrophil infiltration to lungs exposed to intranasal LPS or in neutrophil emigration from blood to the inflamed skin or peritoneal cavity. Heparanase effects on macrophages in chronic inflammation, inflammation-associated cancer, and anti-inflammatory activity, as well as coupling aseptic inflammation and tumorigenesis. Heparanase regulates secretion, composition, and function of tumor cell-derived exosomes. Recombinant heparanase promotes TNFalpha production by macrophages. Impact of heparanase on gene expression, cell signaling and angiogenesis | Homo sapiens |
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