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4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid 2-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate + H2O
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid 2-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-GlcUA + GlcN-2-N-sulfate-6-O-sulfate
more than 95% cleavage
-
-
?
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid 2-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-IdoUA-(beta-1,4)-GlcNAc-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-3-O-sulfate-6-O-sulfate + H2O
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid 2-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-IdoUA-(beta-1,4)-GlcNAc-6-O-sulfate-(alpha-1,4)-GlcUA + GlcN-2-N-sulfate-3-O-sulfate-6-O-sulfate
26% cleavage
-
-
?
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid 2-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-IdoUA-(beta-1,4)-GlcNAc-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate + H2O
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid 2-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-IdoUA-(beta-1,4)-GlcNAc-6-O-sulfate-(alpha-1,4)-GlcUA + GlcN-2-N-sulfate-6-O-sulfate
85% cleavage
-
-
?
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate + H2O
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-GlcUA + GlcN-2-N-sulfate-6-O-sulfate
40% cleavage
-
-
?
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate + H2O
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-GlcUA + GlcN-2-N-sulfate-6-O-sulfate
more than 95% cleavage
-
-
?
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-(beta-1,4)-GlcNAc-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-3-O-sulfate + H2O
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-(beta-1,4)-GlcNAc-6-O-sulfate-(alpha-1,4)-GlcUA + GlcN-2-N-sulfate-3-O-sulfate
21% cleavage
-
-
?
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-2-O-sulfate-(beta-1,4)-GlcN-2-N-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate + H2O
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-2-O-sulfate-(beta-1,4)-GlcN-2-N-sulfate-(alpha-1,4)-GlcUA + GlcN-2-N-sulfate-6-O-sulfate
44% cleavage
-
-
?
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-2-O-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate + H2O
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-2-O-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-GlcUA + GlcN-2-N-sulfate-6-O-sulfate
more than 95% cleavage
-
-
?
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-2-O-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-IdoUA-(beta-1,4)-GlcNAc-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate + H2O
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-2-O-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-IdoUA-(beta-1,4)-GlcNAc-6-O-sulfate-(alpha-1,4)-GlcUA + GlcN-2-N-sulfate
59% cleavage
-
-
?
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-2-O-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-IdoUA-(beta-1,4)-GlcNAc-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-3-O-sulfate + H2O
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-2-O-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-IdoUA-(beta-1,4)-GlcNAc-6-O-sulfate-(alpha-1,4)-GlcUA + GlcN-2-N-sulfate-3-O-sulfate
60% cleavage
-
-
?
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-2-O-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-IdoUA-2-O-sulfate-(beta-1,4)-GlcNAc-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate + H2O
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-2-O-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-IdoUA-2-O-sulfate-(beta-1,4)-GlcNAc-(alpha-1,4)-GlcUA + GlcN-2-N-sulfate-6-O-sulfate
30% cleavage
-
-
?
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-2-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate + H2O
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-2-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-GlcUA + GlcN-2-N-sulfate-6-O-sulfate
56% cleavage
-
-
?
extracellular matrix + H2O
?
-
-
-
-
?
fondaparinux + H2O
2N-sulfo-6-O-sulfo-alpha-D-GlcN-(1->4)-beta-GlcA + a trisaccharide
fondaparinux + H2O
?
-
-
-
-
?
heparan sulfate + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
catalytic mechanism that involves two conserved acidic residues, a putative proton donor at Glu225 and a nucleophile at Glu343
-
-
?
heparan sulfate proteoglycan + H2O
?
heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
heparan sulfate proteolycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
-
-
-
?
heparan sulphate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
-
-
?
heparansulfate proteoglycan + H2O
?
-
-
-
?
heparin octasaccharide + H2O
?
cleavage of the single beta-D-glucuronidic linkage in a heparin-derived octasaccharide with high affinity for antithrombin
-
-
?
heparin sulfate + H2O
?
cleavage to 5000 Da oligosaccharides
-
-
?
insulin-like growth factor 2 receptor + H2O
?
-
-
-
?
low density receptor-related protein-1 + H2O
?
-
-
-
?
methyl 2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranosyl-(1,4)-beta-D-glucopyranuronosyl-(1,4)-2-deoxy-3,6-di-O-sulfo-2-(sulfoamino)-D-glucopyranosyl-(1,4)-2-O-sulfo-alpha-L-idopyranuronosyl-(1,4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranoside + H2O
4-O-[2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranosyl]-D-glucopyranuronic acid + methyl 2-deoxy-3,6-di-O-sulfo-2-(sulfoamino)-D-glucopyranosyl-(1,4)-2-O-sulfo-alpha-L-idopyranuronosyl-(1,4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranoside
i.e. fondaparinux
-
-
?
sulfated PG545 + H2O
?
-
-
-
-
?
sulfated trisaccharide from PG545 + H2O
?
-
-
-
-
?
[GlcAbeta(1,4)GlcNSO3H-3SO3Halpha(1,4)]m-GlcAbeta(1,4)GlcNSO3H-3SO3Halpha(1,4)-[GlcAbeta(1,4)GlcNSO3H-3SO3H]n + H2O
[GlcAbeta(1,4)GlcNSO3H-3SO3Halpha(1,4)]m-GlcA + GlcNSO3H-3SO3Halpha(1,4)-[GlcAbeta(1,4)GlcNSO3H-3SO3H]n
both N- and O-sulfations (either 6-O-sulfation or 3-O-sulfation) are required for the cleavage by heparanase. Structural moiety recognized by heparanase includes a GlcA unit and GlcNS unit carrying O-sulfations. The enzyme proves to be promiscuous in the aspect of the type and location of O-sulfation required for recognition
-
-
?
[GlcAbeta(1,4)GlcNSO3H-6SO3Halpha(1,4)]m-GlcAbeta(1,4)GlcNSO3H-6SO3Halpha(1,4)-[GlcAbeta(1,4)GlcNSO3H-6SO3H]n + H2O
[GlcAbeta(1,4)GlcNSO3H-6SO3Halpha(1,4)]m-GlcA + GlcNSO3H-6SO3Halpha(1,4)-[GlcAbeta(1,4)GlcNSO3H-3SO3H]n
both N- and O-sulfations (either 6-O-sulfation or 3-O-sulfation) are required for the cleavage by heparanase. Structural moiety recognized by heparanase includes a GlcA unit and GlcNS unit carrying O-sulfations. The enzyme proves to be promiscuous in the aspect of the type and location of O-sulfation required for recognition
-
-
?
[GlcAbeta(1,4)GlcNSO3Halpha(1,4)]m-GlcAbeta(1,4)GlcNSO3Halpha(1,4)-[GlcAbeta(1,4)GlcNSO3H]n + H2O
[GlcAbeta(1,4)-GlcNSO3Halpha(1,4)]m-GlcA + GlcNSO3Halpha(1,4)-[GlcAbeta(1,4)GlcNSO3H]n
heparanase does not cleave the linkage of GlcA2S-GlcNS but rather cleaves the linkage of GlcA-GlcNS nearby
-
-
?
additional information
?
-
fondaparinux + H2O
2N-sulfo-6-O-sulfo-alpha-D-GlcN-(1->4)-beta-GlcA + a trisaccharide
-
-
-
?
fondaparinux + H2O
2N-sulfo-6-O-sulfo-alpha-D-GlcN-(1->4)-beta-GlcA + a trisaccharide
-
a pentasaccharide substrate, heparanase is a retaining glycosidase, NMR spectroscopic analysis, overview
-
-
?
heparan sulfate + H2O
?
-
-
-
-
?
heparan sulfate + H2O
?
-
enzyme BpHep is specific for heparan sulfate
-
-
?
heparan sulfate + H2O
?
-
-
-
?
heparan sulfate + H2O
?
-
-
-
-
?
heparan sulfate + H2O
?
-
-
-
?
heparan sulfate + H2O
?
-
-
-
-
?
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
-
-
?
heparan sulfate + H2O
?
-
heparanase is a strict endo-beta-glucuronidase with no exolytic glucuronidase activity. The enzyme only cleaves the glycosidic bond in the middle of the substrate. Heparan sulfate is a polysaccharide that has the disaccharide repeating unit of glucuronic acid or iduronic acid and glucosamine. Certain parts of heparan sulfate are occupied by the repeating disaccharide of -GlcA-GlcNAc-, known as the lowly sulfated domain. Other parts of HS are dominated by the highly sulfated disaccharide repeating unit of GlcA-GlcNS3S6S-IdoA2SGlcNS6S-, known as highly sulfated domain, overview
-
-
?
heparan sulfate + H2O
?
-
isolated from Escherichia coli K5 strain. heparanase is a strict endo-beta-glucuronidase with no exolytic glucuronidase activity. The enzyme only cleaves the glycosidic bond in the middle of the substrate. Second, heparanase not only cleaves the linkages of -GlcA-GlcNS6S-, but also degrades the linkage of -GlcA-GlcNAc6S. Third, the enzyme does not uniformly cleave the linkages of -GlcA-GlcNS6S-. Depending on the trisaccharide sequence at the nonreducing end of the nonasaccharide substrates, heparanase is able to choose to cleave the subsequent nonreducing end linkage of -GlcA-GlcNS6S- in the substrate or leave it intact. This unique observation suggests that heparanase displays two cleavage modes: consecutive cleavage and gapped cleavage. In the consecutive mode, heparanase cleaves the nonreducing trisaccharide at Step 1 digestion, and then cleaves the linkage between Residues 5 and 6 at Step 2 digestion. In the gapped cleavage, heparanase also cleaves the trisaccharide from the nonreducing end at Step 1 digestion, and then cleaves the linkage between Residues 7 and 9
-
-
?
heparan sulfate + H2O
?
-
-
-
?
heparan sulfate proteoglycan + H2O
?
-
-
-
-
?
heparan sulfate proteoglycan + H2O
?
-
-
-
-
?
heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
-
-
-
?
heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
HPSE may play a role in ovulation
-
-
?
heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
cleavage of the beta-1,4-glycosidic bond between a D-glucuronate and a D-glucosamine in heparan sulfate. Cleavage to short chains of 6000-8000 Da. 2-O-sulfate groups are not required for C1A heparanase to recognize and degrade the substrate
-
-
?
heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
heparan sulphate fragments generated are dependent on the pH of the reaction. at pH 6.5, both enzymes generate 9000 Da products, while at pH 5.5 the shorter 6000 Da glycosaminoglycans are produced
-
-
?
heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
-
-
-
?
heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
the heparanase enzyme may play a role in cell migration occurring both at the very early stages of embryogenesis and later on in morphogenesis of the cardiovascular and nervous systems
-
-
?
heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
-
-
-
?
heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
-
-
?
heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
-
-
-
?
heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
-
-
?
heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
heparanase 1 has multiple physiologic functions in the epidermis. It plays an important role in epidermal differentiation, possibly by modulating the liberation of heparan sulfate bound (growth) factors. In the stratum corneum, the endoglycosidase activity of heparanase 1 might be indispensable and represent the first step in the desquamation process and in Langerhans cells, its catalytic activity is required for the trans-tissue migration of these cells
-
-
?
heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
heparanase cleaves the heparan sulfate glycosaminoglycans from proteoglycan core proteins and degrades them to small oligosaccharides. Inside cells, the enzyme is important for the normal catabolism of heparan sulfate proteoglycans, generating glycosaminoglycan fragments that are then transported to lysosomes and completely degraded. When secreted, heparanase degrades basement membrane heparan sulfate glycosaminoglycans at sites of injury or inflammation, allowing extravasion of immune cells into nonvascular spaces and releasing factors that regulate cell proliferation and angiogenesis. At physiological pH the enzyme binds to the extracellular matrix of cell surface heparan sulfate proteolycan but is inactive. When the pH is lowered, which could occur at sites of inflammation or matrix damage, the bound enzyme becomes active and cleaves the heparan sulfate proteoglycan it is bound to
-
-
?
heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
role for heparanase-1 in tissue morphogenesis, regeneration and repair during embryonic development and in the adult. Heparanase-1 may contribute to these processes by its effects on remodelling of extracellular matrix, cell migration, adhesion and proliferation. Heparanase-1 contributes to tumour growth by supporting cell survival under stress conditions
-
-
?
heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
cleavage to 5000 Da oligosaccharides
-
-
?
heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
the average molecular mass of the degradation products is determined to be 2000030000 Da
-
-
?
heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
the enzyme is an endo-beta-D-glucuronidase producing glucuronic acid or an iduronic acid at the newly formed reducing terminus. Heparanase-1 cuts macromolecular heparin into fragments of 500020000 Da. Infrequent enzyme cleavage sites may be due to either the recognition of a single, unusual modification in the heparin/HS chains or the requirement of a specific extended carbohydrate sequence for the cleavage
-
-
?
heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
-
-
-
?
heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
heparanase results in release of low-molecular-weight-labeled degradation fragments. The degradation products of heparan sulfate are 5- to 6fold smaller than intact HS side chains
-
-
?
heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
heparanase results in release of low-molecular-weight-labeled degradation fragments. The degradation products of heparan sulfate are 5- to 6fold smaller than intact HS side chains
-
-
?
heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
-
-
-
?
heparin + H2O
?
-
-
-
?
heparin + H2O
?
heparanase cleaves macromolecular heparin at multiple sites. Heparanase primarily cleaves target structures distinct from the antithrombin-binding sequence
-
-
?
syndecan-1 + H2O
?
-
-
-
-
?
syndecan-1 + H2O
?
-
-
-
?
syndecan-1 + H2O
?
-
heparanase promotes the activity of this mitogenic protein by removing the heparan sulfate chains from syndecan-1 leaving the deglycanated heparan sulfate proteoglycans as the active receptor for lacritin
-
-
?
additional information
?
-
-
activity assays using fluorescein isothiocyanate (FITC)-labeled glycosaminoglycans. NMR spectroscopic study of enzyme cleavage site specificity, overview
-
-
?
additional information
?
-
a capsular polysaccharide from Escherichia coli K5, with the same (-GlcUA-(beta-1,4)-GlcNAc-(alpha-1,4)-)n structure as the unmodified backbone of heparan sulfate, resists heparanase degradation in its native state as well as after chemical N-deacetylation/N-sulfation or partial enzymatic C-5 epimerization of beta-D-GlcUA to alpha-L-idopyranuronic acid. By contrast, a chemically O-sulfated (but still N-acetylated) K5 derivative is susceptible to heparanase cleavage. O-Sulfate groups, but not N-sulfate or alpha-L-idopyranuronic acid residues are essential for substrate recognition by the heparanase. Selective O-desulfation of the heparin octasaccharide implicates a 2-O-sulfate group on a hexuronic acid residue located two monosaccharide units from the cleavage site, toward the reducing end
-
-
?
additional information
?
-
-
a capsular polysaccharide from Escherichia coli K5, with the same (-GlcUA-(beta-1,4)-GlcNAc-(alpha-1,4)-)n structure as the unmodified backbone of heparan sulfate, resists heparanase degradation in its native state as well as after chemical N-deacetylation/N-sulfation or partial enzymatic C-5 epimerization of beta-D-GlcUA to alpha-L-idopyranuronic acid. By contrast, a chemically O-sulfated (but still N-acetylated) K5 derivative is susceptible to heparanase cleavage. O-Sulfate groups, but not N-sulfate or alpha-L-idopyranuronic acid residues are essential for substrate recognition by the heparanase. Selective O-desulfation of the heparin octasaccharide implicates a 2-O-sulfate group on a hexuronic acid residue located two monosaccharide units from the cleavage site, toward the reducing end
-
-
?
additional information
?
-
endo-beta-D-glucuronidase activity of the heparanase is dependent on the size and high sulfation of the oligosaccharide substrates. The GlcN-2-N-sulfate residue on reducing side of the target GlcUA is an essential but not sufficient requirement. The GlcN-3-sulfate residue on the reducing side of the target GlcUA exhibits a promoting effect in a relatively low sulfated sequence but an inhibitory effect in a highly sulfated sequence. The 6-O-sulfated group on the nonreducing side GlcN residue of the target GlcUA is an important but not absolute requirement. A iduronic acid-2-sulfate residue located two sugar residues away from the target GlcUA residue toward the reducing side is not an absolute requirement
-
-
?
additional information
?
-
-
endo-beta-D-glucuronidase activity of the heparanase is dependent on the size and high sulfation of the oligosaccharide substrates. The GlcN-2-N-sulfate residue on reducing side of the target GlcUA is an essential but not sufficient requirement. The GlcN-3-sulfate residue on the reducing side of the target GlcUA exhibits a promoting effect in a relatively low sulfated sequence but an inhibitory effect in a highly sulfated sequence. The 6-O-sulfated group on the nonreducing side GlcN residue of the target GlcUA is an important but not absolute requirement. A iduronic acid-2-sulfate residue located two sugar residues away from the target GlcUA residue toward the reducing side is not an absolute requirement
-
-
?
additional information
?
-
the substrate that carries the repeating unit of IdoA2S-GlcNS is completely resistant to the heparanase digestion. The polysaccharide with repeating units of GlcA-GlcNAc6S is not a a substrate. No activity with heparosan
-
-
?
additional information
?
-
the enzyme specifically cleaves the glycol-bond between D-glucuronic acid and N-sulfo glucosamine units leaving 4000-5000 Da stubs attached to the core protein
-
-
?
additional information
?
-
-
heparanase is an endo-beta-glucuronidase that cleaves heparan sulfate and facilitates the passage of migrating cells through extracellular matrices, particularly basement membranes, as well as releasing heparan sulfate-bound growth factors from the extracellular matrices, whereby the released growth factors also aid wound healing and angiogenesis
-
-
?
additional information
?
-
-
heparanase is an endo-beta-glucuronidase that cleaves heparan sulfate side chains of proteoglycans in basement membranes and the extracellular matrix
-
-
?
additional information
?
-
-
heparanase is an endo-glycosidase that cleaves the heparan sulfate polymers at a limited number of sites within the chain releasing smaller fragments of 10-20 sugar units from heparan sulfate proteoglycan complexes
-
-
?
additional information
?
-
the enzyme is an endo-beta-glucuronidase that cleaves heparan sulfate proteoglycans in the extracellular matrix and basement membrane, releasing heparin/heparan sulfate oligosaccharides of appreciable size
-
-
?
additional information
?
-
-
the enzyme is an endo-beta-glucuronidase that cleaves heparan sulfate proteoglycans in the extracellular matrix and basement membrane, releasing heparin/heparan sulfate oligosaccharides of appreciable size
-
-
?
additional information
?
-
6-O-sulfo heparosan and N-sulfo heparosan are resistant to cleavage by heparanase
-
-
?
additional information
?
-
-
6-O-sulfo heparosan and N-sulfo heparosan are resistant to cleavage by heparanase
-
-
?
additional information
?
-
-
the enzyme hydrolyses the glycosidic bond between the (1->4)-alpha-GlcA and the 2-N-sulfo-3,6-di-O-sulfo-(1->4)-alpha-D-GlcN
-
-
?
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
-
-
?
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
-
-
?
additional information
?
-
heparanase, but not proheparanase, interacts directly with antithrombin in a non-covalent manner resulting in the activation of antithrombin. Complex formation and activity analysis, overview. The activation of Pro41Leu, Arg47Cys, Lys114Ala and Lys125Ala antithrombin mutants by heparanase is impaired
-
-
?
additional information
?
-
development of two heparanase activity assays to cover a whole range of applications, overview. The first is a fast and easy method based on commercial homogenous substrate, fondaparinux and usage of a fluorescent redox marker, resazurin. Resazurin reduction reaction at pH 5.5 and 45°C. The second method is a quantitative assay based on biotinylated heparan sulfate that uses an easier technique to immobilize the substrate in a 96-well plate via protamine sulfate. Biotinylated heparan sulfate is immobilized. The enzymatic assay is performed using chimeric recombinant heparanase at different concentrations. In sequence, the immobilized biotinylated heparan sulfate that is not digested by recombinant heparanase is bound to streptavidin conjugated with europium. Fluorescence is measured using a time-resolved fluorometer. Both methods have high sensitivity and can be used to detect heparanase activity
-
-
?
additional information
?
-
fondaparinux assay method
-
-
?
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
-
-
?
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
-
-
?
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(((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(1H-benzo[d]imidazole-2,5-diyl))bis(acetyl))bis(azanediyl))bis-(methylene))diboronic acid
-
(((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis(azanediyl))bis(3-methylbutane-1,1-diyl))diboronic acid
-
(((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis(azanediyl))bis-(methylene))diboronic acid
-
(2E)-N-(3,4-dichlorophenyl)-3-[3-fluoro-4-[5-(2-oxopropyl)-1,3-benzoxazol-2-yl]phenyl]prop-2-enamide
-
-
(3R,5S)-8-nonyl-9-oxo-1,6-dioxaspiro[4.4]non-7-ene-2,2,3-tricarboxylic acid
-
-
(3S,4S,5R,6R)-4,5-dihydroxy-6-[(trifluoroacetyl)amino]piperidine-3-carboxylic acid
-
-
(3S,4S,5R,6R)-6-(acetylamino)-4,5-dihydroxypiperidine-3-carboxylic acid
-
-
(5R)-3-heptadecanoyl-5-(hydroxymethyl)-4-methoxyfuran-2(5H)-one
-
-
(5R)-4-(benzyloxy)-3-heptadecanoyl-5-(hydroxymethyl)furan-2(5H)-one
-
-
(5S)-8-nonyl-9-oxo-1,6-dioxaspiro[4.4]non-7-ene-2,2,3-tricarboxylic acid
-
-
(IdoA2S-GlcNS)n
polysaccharide containing IdoA2S-GlcNS repeating unit, inhibits the activity of heparanase
1,3-bis(1-(5,6-dimethylbenzo[d]oxazol-2-yl)piperidin-4-yl)urea
-
1,3-bis(4-(5,6-dimethylbenzo[d]oxazol-2-yl)-2-fluorophenyl)urea
-
1,3-bis(4-(5,6-dimethylbenzo[d]oxazol-2-yl)phenyl)urea
-
1,3-bis[4-(1H-benzimidazol-2-yl)phenyl]urea
-
-
1,3-bis[4-(5,6-dimethyl-1H-benzimidazol-2-yl)phenyl]urea
1-[2-([3-[(7-chloroquinolin-4-yl)amino]-5-(hydroxymethyl)benzyl]amino)prop-2-en-1-yl]piperidin-4-ol
-
-
1-[3-[(7-chloroquinolin-4-yl)amino]-5-([[3-(piperidin-1-yl)prop-1-en-2-yl]amino]methyl)benzyl]piperidin-4-ol
-
-
2,2'-((((carbonylbis(azanediyl))bis(4,1-phenylenesulfonyl))bis-(azanediyl))bis(3,1-phenylene))diacetic acid
-
2,2'-((((Iminomethylene)bis(azanediyl))bis(4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))diacetic acid
-
2,2'-(((4,4'-(2-hydroxypropane-1,3-diyl)bis(benzoyl))bis-(azanediyl))bis(3,1-phenylene))diacetic acid
-
2,2'-(((4,4'-(2-oxopropane-1,3-diyl)bis(benzoyl))bis-(azanediyl))bis(3,1-phenylene))diacetic acid
-
2,2'-(((4,4'-(carbonylbis(azanediyl))bis(benzoyl))bis(azanediyl))-bis(3,1-phenylene))diacetic acid
-
2,2'-(((4,4'-(carbonylbis(azanediyl))bis(benzoyl))bis(azanediyl))-bis(4-hydroxy-3,1-phenylene))diacetic acid
-
2,2'-(((4,4'-(thiocarbonylbis(azanediyl))bis(3-fluorobenzoyl))bis-(azanediyl))bis(3,1-phenylene))diacetic acid
-
2,2'-(((carbonylbis(azanediyl))bis(3,1-phenylene))bis(benzo[d]-oxazole-2,5-diyl))diacetic acid
-
2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(1H-benzo[d]imidazole-2,5-diyl))diacetic acid
-
2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))bis(N-isopentylacetamide)
-
2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))diacetic acid
causes inhibition of the proliferation of human CME-1 synovial sarcoma cells
2,2'-(((carbonylbis(azanediyl))bis(4,1-phenylene))bis(benzo[d]-oxazole-2,5-diyl))diacetic acid
-
2,2'-(((carbonylbis(azanediyl))bis(piperidine-4,1-diyl))bis(benzo-[d]oxazole-2,5-diyl))diacetic acid
-
2,2'-(((thiocarbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))-bis(1H-benzo[d]imidazole-2,5-diyl))diacetic acid
-
2,2'-(((thiocarbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))-bis(benzo[d]oxazole-2,5-diyl))diacetic acid
-
2,2'-(((thiocarbonylbis(azanediyl))bis(4,1-phenylene))bis(benzo-[d]oxazole-2,5-diyl))diacetic acid
-
2,2'-((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(1H-benzo[d]imidazole-2,5-diyl))bis(acetyl))bis-(azanediyl))bis(3-phenylpropanoic acid)
-
2,2'-((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis-(azanediyl))bis(3-phenylpropanoic acid)
-
2,2'-((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis-(azanediyl))diacetic acid
-
2,2'-((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis-(azanediyl))dipropionic acid
-
2,2'-((2,2'-(((thiocarbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis-(azanediyl))diacetic acid
-
2-(3-(4-(3-(4-((5-(carboxymethyl)-2-hydroxyphenyl)carbamoyl)-phenyl)-2-hydroxypropyl)-3-hydroxybenzamido)phenyl)acetic acid
-
2-[(3-[4-[3-(4-chloro-2-cyclohexylphenoxy)-5-nitrophenoxy]phenyl]propanoyl)amino]ethanesulfonic acid
-
-
2-[2-methoxy-5-(5-phenyl-1,3-benzoxazol-2-yl)-4-(propylamino)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid
-
-
2-[3-(1,3-benzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-indene-5-carboxylic acid
-
-
2-[3-[5-(4-chlorophenyl)-1,3-benzoxazol-2-yl]-4-(propylamino)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid
-
-
2-[3-[5-(4-fluorophenyl)-1,3-benzoxazol-2-yl]-4-(propylamino)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid
-
-
2-[4-[4-(6-amino-1H-benzimidazol-2-yl)phenoxy]phenyl]-1H-benzimidazol-5-amine
-
-
3,3'-((4,4'-(carbonylbis(azanediyl))bis(benzoyl))bis(azanediyl))-dibenzoic acid
-
3-heptadecanoyl-4-hydroxy-5-(hydroxymethyl)furan-2(5H)-one
-
-
3-[(7-chloroquinolin-4-yl)amino]-N-[2-(dimethylamino)ethyl]-5-([[3-(piperidin-1-yl)prop-1-en-2-yl]amino]methyl)benzamide
-
-
3-[(7-chloroquinolin-4-yl)amino]-N-[2-(morpholin-4-yl)ethyl]-5-([[3-(piperidin-1-yl)prop-1-en-2-yl]amino]methyl)benzamide
-
-
4-[(4-carboxy-3-hydroxy-5-methylphenoxy)carbonyl]-3-hydroxy-5-pentadecylphenyl beta-D-glucopyranosiduronic acid
-
-
4-[(4-carboxy-3-hydroxy-5-methylphenoxy)carbonyl]-3-hydroxy-5-pentadecylphenyl methyl beta-D-glucopyranosiduronate
-
-
4-[(7-chloroquinolin-4-yl)amino]-2-(pyrrolidin-1-ylmethyl)phenol
-
-
4-[(7-chloroquinolin-4-yl)amino]phenol
-
-
4-[[5-(3,6-dibromo-9H-fluoren-9-yl)-4-hydroxy-2-(2-phenylethyl)pentanethioyl]amino]benzenesulfonic acid
-
-
5-bromo-2-hydroxy-N-[(E)-(3-[2-[(4-methylphenyl)amino]-2-oxoethyl]-2-oxo-2,3-dihydro-1H-inden-1-ylidene)methyl]benzamide
-
-
5-[2-[4-([4-[(3-bromo-4-methoxybenzoyl)amino]benzyl]amino)-3-fluorophenyl]-1H-benzimidazol-5-yl]-4-oxopentanoic acid
i.e. SST0871AA1
5-[3-(2-methylidenenonadecyl)-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]-2-phenoxybenzenesulfonic acid
-
-
7-chloro-N-[3-([[3-(piperidin-1-yl)prop-1-en-2-yl]amino]methyl)-5-([[3-(piperidin-1-yl)prop-1-en-2-yl]oxy]methyl)phenyl]quinolin-4-amine
-
-
7-chloro-N-[3-[(diethylamino)methyl]-4-(morpholin-4-yl)phenyl]quinolin-4-amine
-
-
7-chloro-N-[4-(furan-2-yl)-3-(pyrrolidin-1-ylmethyl)phenyl]quinolin-4-amine
-
-
7-chloro-N-[4-ethoxy-3-(pyrrolidin-1-ylmethyl)phenyl]quinolin-4-amine
-
-
amodiaquine
-
an antimalarial drug
basic fibroblast growth factor
-
-
-
defibrotide
a polydisperse oligonucleotide isolated from porcine mucosa that has multiple biological effects including inhibition of heparanase gene expression and enzymatic activity
-
heparanase inhibitor PI-88
a mixture of highly sulfated, monophosphorylated mannose oligosaccharides, derived from the extracellular phosphomannan of the yeast Pichia holstii, with potential antiangiogenic activity
-
laminarin sulfate
-
0.01 mM, complete inhibition
-
low molecular weight heparin
-
-
-
Lys-Lys-Asp-Cys
0.025 mM or above
M402
-
a glycol-split heparin compound similar to SST0001 yet smaller in molecular mass
maltohexaose sulfate
with at least 3 sulfate groups per internal sugar and up to four sulfates in the terminal sugar residues, docking sstudy and binding structure, overview
muparfostat
formally PI-88, a phosphomannopentaose
N'-[3-[(7-chloroquinolin-4-yl)amino]-5-([[3-(piperidin-1-yl)prop-1-en-2-yl]amino]methyl)benzyl]-N,N-dimethylethane-1,2-diamine
-
-
N-[4-([[4-(1H-benzimidazol-2-yl)phenyl]amino]methyl)phenyl]-3-bromo-4-methoxybenzamide
-
-
N-[4-([[5-(1H-benzimidazol-2-yl)pyridin-2-yl]amino]methyl)phenyl]-3-bromo-4-methoxybenzamide
-
-
N-[4-bromo-3-[(diethylamino)methyl]phenyl]-7-chloroquinolin-4-amine
-
-
necuparanib
formally M402, an N-sulfated glycol-split heparin of 6 kDa, shows efficacy in metastasis models
-
oligomannurarate sulfate
the heparanase inhibitor simultaneously targets basic fibroblast growth factor, combats tumor angiogenesis and metastasis. The inhibitor is a promising candidate agent for cancer therapy
-
oligomannurarate sulphate
-
oligomanurarate sulfate
-
JG3, a marine-derived oligosaccharide and a heparanase inhibitor
PG545 cholestanol aglycon
-
the cholestanol aglycon of PG545 significantly increased affinity for heparanase and also modified the inhibition mode, parabolic competition
PG545 trisaccharide derivative
-
-
sodium octyl 2-deoxy-2-(sulfonatoamino)-alpha-D-glucopyranoside
-
-
sodium octyl 4-O-[2-deoxy-2-(sulfoamino)-alpha-D-glucopyranosyl]-beta-D-glucopyranosiduronate
-
specific inhibition
sodium octyl beta-D-glucopyranosiduronate
-
-
sulfated PG545
-
competitive inhibition
sulfated trisaccharide from PG545
-
partial competitive inhibition
[2-(2-carboxybenzoyl)-6-(phenylsulfanyl)phenyl](hydroxy)oxoammonium
-
-
[2-(4-[[(2E)-3-(4-bromophenyl)prop-2-enoyl]amino]phenyl)-1,3-benzoxazol-5-yl]acetic acid
-
[2-[4-([4-[(3-bromo-4-methoxybenzoyl)amino]benzyl]amino)-3-fluorophenyl]-1H-benzimidazol-5-yl]acetic acid
i.e. SST0867AA1
[3-[(7-chloroquinolin-4-yl)amino]-5-([[3-(morpholin-4-yl)prop-1-en-2-yl]amino]methyl)phenyl]methanol
-
-
[3-[(7-chloroquinolin-4-yl)amino]-5-([[3-(piperidin-1-yl)prop-1-en-2-yl]amino]methyl)phenyl](morpholin-4-yl)methanone
-
-
[4-(5-[2-chloro-4-[(4-chlorobenzoyl)amino]phenyl]furan-2-yl)-1,3-thiazol-2-yl]acetic acid
-
-
[4-[5-(2,4-dichlorophenyl)furan-2-yl]-1,3-oxazol-2-yl]acetic acid
-
-
[4-[5-(4-[[(2E)-3-(4-bromophenyl)prop-2-enoyl]amino]-2-chlorophenyl)furan-2-yl]-1,3-thiazol-2-yl]acetic acid
-
-
1,3-bis[4-(5,6-dimethyl-1H-benzimidazol-2-yl)phenyl]urea
-
-
1,3-bis[4-(5,6-dimethyl-1H-benzimidazol-2-yl)phenyl]urea
-
heparin
-
-
heparin
commercial heparin is a powerful inhibitor of heparanase action toward antithrombin-binding oligosaccharides
heparin
heparin-binding domains HBD-1 and HBD-2 in heparanase, structure overview. The optimal length of a heparin chain required to bridge HBD-1 and HBD-2 for the effective inhibition is known to be an octadecasaccharide, whereas heparin tetrasaccharides and hexasaccharides as well as N-acetylated heparins (N-acetylation higher than 50%) are poor inhibitors of heparanase
heparin
IC50 is 0.001 mg/ml
PG545
-
a heparan sulfate mimetic tetrasaccharide, competitive inhibition
PG545
-
a synthetic, potent competitive inhibitor of heparanase with significant anti-tumor, anti-angiogenic, and anti-metastatic activity in a variety of animal models
PG545
a fully sulfated synthetic tetrasaccharide functionalized with a cholestanyl aglycon
PI-88
-
competitive inhibitor of heparanase
PI-88
-
inhibits primary tumor growth of invasive rat mammary adenocarcinoma, metastasis, and reduced vascularity of these tumors while demonstrating significant anti-tumor activity in the pancreatic neuroendocrine RIP2-Tag2 model and in models of leukemia
roneparstat
-
is an N-acetylated, glycol-splitheparin,which inhibits heparanase, downregulates HGF, VEGF, and MMP-9 expression and suppresses angiogene-sis. Roneparstat also diminishes heparanase-induced shedding of syndecan-1, which is known to be a potent promoter of myeloma
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
SST0001
-
-
SST0001
N-acetylated, glycol-split heparin
suramin
-
-
additional information
no inhibition by basic fibroblast growth factor
-
additional information
the PG500 series of heparan sulfate mimetics potently block the enzymatic activity of heparanase (fully sulfated, single entity oligosaccharides attached to a lipophilic moiety, which have been optimized for drug development)
-
additional information
a simple, accurate, and robust biochemical assay for heparanase activity that uses a commercially available homogeneous substrate (fondaparinux) with a single enzymatic cleavage point and, thus, does not have the problems associated with using heparan sulfate-based assays. The assay is suitable for testing heparanase inhibitors and could easily be adapted for use in high-throughput screening applications
-
additional information
polysacchride with repeating disaccharide units of GlcA-GlcNAc or polysaccharide with repeating units of GlcA-GlcNAc6S do not inhibit activity of heparanase
-
additional information
-
the full-length heparanase 2c protein inhibits heparanase enzymatic activity, likely due to its high affinity to heparin and heparan sulfate and its ability to associate physically with heparanase
-
additional information
-
screening of a virtual inhibitor library composed of 27 known heparanase inhibitors and a commercial collection of drugs and drug-like compounds, overview. A subset of fourteen 4-arylaminoquinolines from a global set of 249 analogues of amodiaquine is selected based on the application of in silico models, a QSAR solubility prediction model and a chemical diversity analysis. Some of these compounds displayed binding affinities in the micromolar range. Structure-activity relationships around the amodiaquine scaffold, overview
-
additional information
the natural heparan sulfate-heparanase interactions are used as a template for the design of heparan sulfate-mimicking glycopolymers, e.g. saccharide-functionalized neo-glycopolymers, which retain the key biological properties of the natural polysaccharides, synthesis and mass spectrometric identification, detailed overview. A glycopolymer with 12 repeating units is determined to be the most potent inhibitor and to have tight-binding characteristics. This glycopolymer also lacks anticoagulant activity. Inhibition of heparanase by HS mimicking monomers and neo-glycopolymers using TR-FRET assay
-
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
-
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
-
additional information
symmetrical benzazolyl derivatives show potent anti-heparanase activity, synthesis, and molecular docking studies, overview. The anti-metastatic potential of compounds 2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))diacetic acid, 2,2'-((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis-(azanediyl))diacetic acid, and 2,2'-((2,2'-(((thiocarbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis-(azanediyl))diacetic acid, proves the inhibition of the expression of proangiogenic factors in tumor cells. Molecular modeling of inhibitor binding and mechanism
-
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0.01
(((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(1H-benzo[d]imidazole-2,5-diyl))bis(acetyl))bis(azanediyl))bis-(methylene))diboronic acid
Homo sapiens
above, pH 5.0 37°C, recombinant enzyme
0.00487 - 0.01
(((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis(azanediyl))bis(3-methylbutane-1,1-diyl))diboronic acid
0.00001
(((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis(azanediyl))bis-(methylene))diboronic acid
Homo sapiens
pH 5.0 37°C, recombinant enzyme
0.01
1,3-bis(1-(5,6-dimethylbenzo[d]oxazol-2-yl)piperidin-4-yl)urea
Homo sapiens
above, pH 5.0 37°C, recombinant enzyme
0.01
1,3-bis(4-(5,6-dimethylbenzo[d]oxazol-2-yl)-2-fluorophenyl)urea
Homo sapiens
above, pH 5.0 37°C, recombinant enzyme
0.01
1,3-bis(4-(5,6-dimethylbenzo[d]oxazol-2-yl)phenyl)urea
Homo sapiens
above, pH 5.0 37°C, recombinant enzyme
0.00056
1,3-bis[4-(5,6-dimethyl-1H-benzimidazol-2-yl)phenyl]urea
Homo sapiens
pH 5.0 37°C, recombinant enzyme
0.01
2,2'-((((carbonylbis(azanediyl))bis(4,1-phenylenesulfonyl))bis-(azanediyl))bis(3,1-phenylene))diacetic acid
Homo sapiens
above, pH 5.0 37°C, recombinant enzyme
0.00602
2,2'-((((Iminomethylene)bis(azanediyl))bis(4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))diacetic acid
Homo sapiens
pH 5.0 37°C, recombinant enzyme
0.01
2,2'-(((4,4'-(2-hydroxypropane-1,3-diyl)bis(benzoyl))bis-(azanediyl))bis(3,1-phenylene))diacetic acid
Homo sapiens
above, pH 5.0 37°C, recombinant enzyme
0.01
2,2'-(((4,4'-(2-oxopropane-1,3-diyl)bis(benzoyl))bis-(azanediyl))bis(3,1-phenylene))diacetic acid
Homo sapiens
above, pH 5.0 37°C, recombinant enzyme
0.00176
2,2'-(((4,4'-(carbonylbis(azanediyl))bis(benzoyl))bis(azanediyl))-bis(3,1-phenylene))diacetic acid
Homo sapiens
pH 5.0 37°C, recombinant enzyme
0.00273
2,2'-(((4,4'-(carbonylbis(azanediyl))bis(benzoyl))bis(azanediyl))-bis(4-hydroxy-3,1-phenylene))diacetic acid
Homo sapiens
pH 5.0 37°C, recombinant enzyme
0.00261
2,2'-(((4,4'-(thiocarbonylbis(azanediyl))bis(3-fluorobenzoyl))bis-(azanediyl))bis(3,1-phenylene))diacetic acid
Homo sapiens
pH 5.0 37°C, recombinant enzyme
0.01
2,2'-(((carbonylbis(azanediyl))bis(3,1-phenylene))bis(benzo[d]-oxazole-2,5-diyl))diacetic acid
Homo sapiens
above, pH 5.0 37°C, recombinant enzyme
0.00098
2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(1H-benzo[d]imidazole-2,5-diyl))diacetic acid
Homo sapiens
pH 5.0 37°C, recombinant enzyme
0.01
2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))bis(N-isopentylacetamide)
Homo sapiens
above, pH 5.0 37°C, recombinant enzyme
0.00018
2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))diacetic acid
Homo sapiens
pH 5.0 37°C, recombinant enzyme
0.0032
2,2'-(((carbonylbis(azanediyl))bis(4,1-phenylene))bis(benzo[d]-oxazole-2,5-diyl))diacetic acid
Homo sapiens
pH 5.0 37°C, recombinant enzyme
0.01
2,2'-(((carbonylbis(azanediyl))bis(piperidine-4,1-diyl))bis(benzo-[d]oxazole-2,5-diyl))diacetic acid
Homo sapiens
above, pH 5.0 37°C, recombinant enzyme
0.00099
2,2'-(((thiocarbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))-bis(1H-benzo[d]imidazole-2,5-diyl))diacetic acid
Homo sapiens
pH 5.0 37°C, recombinant enzyme
0.0014
2,2'-(((thiocarbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))-bis(benzo[d]oxazole-2,5-diyl))diacetic acid
Homo sapiens
pH 5.0 37°C, recombinant enzyme
0.00181
2,2'-(((thiocarbonylbis(azanediyl))bis(4,1-phenylene))bis(benzo-[d]oxazole-2,5-diyl))diacetic acid
Homo sapiens
pH 5.0 37°C, recombinant enzyme
0.00082 - 0.01
2,2'-((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(1H-benzo[d]imidazole-2,5-diyl))bis(acetyl))bis-(azanediyl))bis(3-phenylpropanoic acid)
0.00072
2,2'-((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis-(azanediyl))bis(3-phenylpropanoic acid)
Homo sapiens
pH 5.0 37°C, recombinant enzyme
0.00045
2,2'-((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis-(azanediyl))diacetic acid
Homo sapiens
pH 5.0 37°C, recombinant enzyme
0.00037
2,2'-((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis-(azanediyl))dipropionic acid
Homo sapiens
pH 5.0 37°C, recombinant enzyme
0.00008
2,2'-((2,2'-(((thiocarbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis-(azanediyl))diacetic acid
Homo sapiens
pH 5.0 37°C, recombinant enzyme
0.01
2-(3-(4-(3-(4-((5-(carboxymethyl)-2-hydroxyphenyl)carbamoyl)-phenyl)-2-hydroxypropyl)-3-hydroxybenzamido)phenyl)acetic acid
Homo sapiens
above, pH 5.0 37°C, recombinant enzyme
0.00917
3,3'-((4,4'-(carbonylbis(azanediyl))bis(benzoyl))bis(azanediyl))-dibenzoic acid
Homo sapiens
pH 5.0 37°C, recombinant enzyme
0.00064
5-[2-[4-([4-[(3-bromo-4-methoxybenzoyl)amino]benzyl]amino)-3-fluorophenyl]-1H-benzimidazol-5-yl]-4-oxopentanoic acid
Homo sapiens
pH 5.0 37°C, recombinant enzyme
0.000025
heparanase inhibitor PI-88
Homo sapiens
pH 5.0, 37°C
-
0.00005
laminarin sulfate
Mus musculus
-
-
-
0.012
PG545
Homo sapiens
-
pH 5.0, 37°C
0.000003
roneparstat
Homo sapiens
pH and temperature not specified in the publication
6
sodium octyl 2-deoxy-2-(sulfonatoamino)-alpha-D-glucopyranoside
Homo sapiens
-
pH and temperature not specified in the publication
1.4
sodium octyl 4-O-[2-deoxy-2-(sulfoamino)-alpha-D-glucopyranosyl]-beta-D-glucopyranosiduronate
Homo sapiens
-
pH and temperature not specified in the publication
0.000005
SST0001
Homo sapiens
pH 5.0 37°C, recombinant enzyme
0.416
sulfated PG545
Homo sapiens
-
pH 5.0, 37°C
4.82
sulfated trisaccharide from PG545
Homo sapiens
-
pH 5.0, 37°C
0.05
suramin
Mus musculus
-
-
0.00042
[2-(4-[[(2E)-3-(4-bromophenyl)prop-2-enoyl]amino]phenyl)-1,3-benzoxazol-5-yl]acetic acid
Homo sapiens
pH 5.0 37°C, recombinant enzyme
0.00286
[2-[4-([4-[(3-bromo-4-methoxybenzoyl)amino]benzyl]amino)-3-fluorophenyl]-1H-benzimidazol-5-yl]acetic acid
Homo sapiens
pH 5.0 37°C, recombinant enzyme
additional information
additional information
-
0.00487
(((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis(azanediyl))bis(3-methylbutane-1,1-diyl))diboronic acid
Homo sapiens
pH 5.0 37°C, recombinant enzyme
0.01
(((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis-(benzo[d]oxazole-2,5-diyl))bis(acetyl))bis(azanediyl))bis(3-methylbutane-1,1-diyl))diboronic acid
Homo sapiens
above, pH 5.0 37°C, recombinant enzyme
0.00082
2,2'-((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(1H-benzo[d]imidazole-2,5-diyl))bis(acetyl))bis-(azanediyl))bis(3-phenylpropanoic acid)
Homo sapiens
pH 5.0 37°C, recombinant enzyme
0.01
2,2'-((2,2'-(((carbonylbis(azanediyl))bis(3-fluoro-4,1-phenylene))bis(1H-benzo[d]imidazole-2,5-diyl))bis(acetyl))bis-(azanediyl))bis(3-phenylpropanoic acid)
Homo sapiens
above, pH 5.0 37°C, recombinant enzyme
0.00002
heparin
Homo sapiens
heparanase action toward antithrombin-binding oligosaccharides
0.001
heparin
Mus musculus
-
-
additional information
additional information
Homo sapiens
-
dissociation constants, overview
-
additional information
additional information
Homo sapiens
IC50 values of heparan sulfate-mimicking glycopolymers, overview
-
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metabolism
-
key enzymes sulfatases and heparanase of the pathway actively influence cancer cell proliferation, signaling, invasion, and metastasis
evolution
-
the enzyme belongs to the clan A glycoside hydrolase family 79, GH79
evolution
-
the enzyme belongs to the glycoside hydrolase family 79, GH79
evolution
the enzyme belongs to the glycoside hydrolase family 79, GH79
evolution
the enzyme belongs to the glycoxadside hydrolase family 79, GH79
evolution
-
the enzyme belongs to the glycoxadside hydrolase family 79, GH79, from GH clan A
malfunction
stable knockdown of HPA expression decreases the in vitro invasive, metastatic and angiogenetic capabilities of gastric cancer cells
malfunction
-
heparanase knockdown impairs neurite outgrowth induced by nerve growth factor
malfunction
-
heparanase variant T5 overexpression results in increased cell proliferation and larger colonies in soft agar, mediated by Src activation
malfunction
-
enhanced growth/aggressiveness of numerous cancer cell types following overexpression of heparanase and inhibition of the tumorigenic/metastatic abilities of cancer cells following heparanase gene silencing
malfunction
-
enzymatically inactive heparanase: mutated heparanase designated M343 fails to stimulate exosome secretion, whereas mutant M225 has a mild stimulatory effect
malfunction
-
enzyme inhibition decreases the release of IL-1beta and TNF-alpha significantly, but does not change the mRNA levels of IL-1beta and TNF-alpha significantly in Astragalus membranaceus extract-treated macrophages
malfunction
-
in siRNA treated T-cells, the repressing H3K9ac activation mark is reduced, with transcriptional repression of the CD69, IFNalpha and IL-2 genes and a concomitant decrease in H3K4me1 levels, accumulation of H3K4m2, not H3K4m3
malfunction
-
the lack of heparanase or its inhibition prevents the increased synthesis of TGF-beta by tubular cells in response to pro-fibrotic stimuli such as FGF-2, advanced glycosylation end products and albumin overload. TGF-beta induces an autocrine loop to sustain its signal, whereas the lack of the enzyme partially interferes with this autocrine loop
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
malfunction
macrophages from heparanase-knockout (Hpa-KO) mice express lower levels of cytokines (e.g. TNFalpha, interleukin 1-beta) and exhibit lower motility and phagocytic capacities. Inoculation of control monocytes togetherwith Lewis lung carcinoma (LLC) cells into Hpa-KO mice results in nearly complete inhibition of tumor growth. In striking contrast, inoculating LLC cells together with monocytes isolated from Hpa-KO mice does not affect tumor growth, indicating that heparanase is critically required for activation and function of macrophages
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
physiological function
histidine-rich glycoprotein interferes with heparanase binding to cell surface receptors, particularly heparan sulfate proteoglycans. Thus, the interaction between histidine-rich glycoprotein and heparanase can potentially regulate the role of heparanase in a variety of physiological and pathological conditions
physiological function
-
biologically active interleukin-2 is released from the surface of endothelial cells and smooth muscle cells lining blood vessels by heparanase
physiological function
-
heparanase activity correlates with the metastatic potential of tumor-derived cells. Heparanase activity is implicated in neovascularization, inflammation and autoimmunity, involving the migration of vascular endothelial cells and activated cells of the immune system. Heparan sulfate cleavage by heparanase is required for structural remodeling of the extracellular matrix. Inactive heparanase facilitates adhesion and migration of primary endothelial cells and promotes phosphorylation of signaling molecules such as Akt and Src, facilitating gene transcription (i.e. vascular endothelial growth factor) and phosphorylation of selected Src substrates (i.e. endothelial growth factor receptor). Heparanase upregulates both the expression and shedding of syndecan-1 from the surface of myeloma cells
physiological function
-
heparanase is constantly overexpressed and activated throughout ulcerative colitis. Heparanase powers a chronic inflammatory circuit that promotes colitis-associated tumorigenesis. Heparanase overexpression markedly increases the incidence and severity of colitis-associated colonic tumors. Heparanase overexpression directly affects macrophage recruitment and activation
physiological function
-
heparanase over-expression results in reduced hepatic clearance of postprandial lipoproteins and higher levels of fasting and postprandial serum triglycerides. Heparanase over-expression also induces formation of fatty streaks in the aorta
physiological function
-
heparanase plays a dual role in driving hepatocyte growth factor signaling by enhancing hepatocyte growth factor expression and activity. Heparanase mediates enhanced syndecan-1 shedding. Although heparanase enzyme activity is required for enhanced syndecan-1 shedding, the active enzyme is not required for enhanced hepatocyte growth factor synthesis
physiological function
-
heparanase promotes the nerve growth factor-induced neuritogenesis via MAPK p38 pathway
physiological function
-
heparanase upregulates Th2 cytokines resulting in inhibition of the inflammatory lesion of experimental autoimmune encephalitis. Heparanase inhibits mitogen-induced splenocyte proliferation and mixed lymophocyte reaction through modulation of their repertoire of cytokines indicated by a marked increase in the levels of interleukin-4, interleukin-6 and interleukin-10, and a parallel decrease in interleukin-12 and tissue necrosis factor-alpha
physiological function
-
heparanase variant T5 activates Src and facilitates cell proliferation and enhances myeloma xenograft development
physiological function
heparanase/MAPK1 signaling up regulates MMP9 and uPAR causing temporary loss of cell surface syndecan-1. Heparanase also activates AKT, P38, RAC1, PKC, and Src, thereby stimulating syndecan clustering, cell adhesion and tumorigenicity. Chronically elevated heparanase augments heparan sulfate 6-O-sulfation of syndecan-1, increases affinity for FGF1 and 2, and associates with tumor angiogenesis and metastatic potential
physiological function
-
over-expression of heparanase is responsible for heparan sulfate reduction via its endoglycosidase activity and its capacity to regulate the heparan sulfate-proteoglycans core protein. Heparanase regulates the gene expression of syndecan-1. The enzyme is relevant to the progression of diabetic nephropathytake and takes part in several processes, e.g. extracellular-matrix remodeling and cell-cell crosstalk, via its heparan sulfate endoglycosidase activity and capacity to regulate the expression of the heparan sulfate-proteoglycan syndecan-1
physiological function
-
each cell has a dynamic control over the exact sequence of heparan sulfate and can change the way they respond to growth factors by altering the structure of the heparan sulfate on their surfaces. To accommodate those structural variations in heparan sulfate, heparanase adapts itself to recognize the overall structure of heparan sulfate, especially those highly sulfated domains in heparan sulfate.The substrate specificity plays a critical role in dissecting the biological functions of heparanase and heparan sulfate. Heparanase is capable of varying its substrate specificities depending on the saccharide structures around the cleavage site, overview. Potential regulating role of the surrounding saccharide sequences in controlling the cleavage site and the degradation extent by the enzyme
physiological function
-
heparanase is a key enzyme involved in the dissemination of metastatic cancer cells
physiological function
-
heparanase is a key player in renal fibrosis by regulating TGF-beta expression and activity, overview. Heparanase is an endo-beta-D-glucuronidase that cleaves heparan-sulfate thus regulating the bioavailability of growth factors (FGF-2, TGF-beta). The enzyme controls FGF-2-induced epithelial-mesenchymal transition in tubular cells and is necessary for the development of diabetic nephropathy in mice.
physiological function
-
heparanase is an endoglycosidase that specifically degrades heparan sulfate, one of the main components of the extracellular matrix. Heparanase is implicated in cancer processes such as tumour formation, angiogenesis and metastasis
physiological function
-
heparanase is the only known mammalian glycosidase capable of cleaving heparan sulfate chains. The expression of this enzyme is associated with tumor development because of its ability to degrade extracellular matrix and promote cell invasion
physiological function
-
heparanase is the sole mammalian endoglycosidase that cleaves heparan sulfate, the key polysaccharide of the ECM and basement membranes. Heparan sulfate is a ubiquitous macromolecule associated with the cell surface and extracellular matrix of a wide range of tissues and organs. Heparanase is preferentially expressed in human psoriatic lesions. The enzyme has the capacity to promote cancer progression. Enzyme involvement of heparanase in the pathogenesis of psoriasis and a role for the enzyme in facilitating abnormal interactions between immune and epithelial cell subsets of the affected skin
physiological function
-
heparanase regulates secretion, composition, and function of tumor cell-derived exosomes. The enzyme expression is up-regulated as tumors become more aggressive and is associated with enhanced tumor growth, angiogenesis, and metastasis. Heparanase enzyme activity is required for robust enhancement of exosome secretion because enzymatically inactive forms of heparanase, even when present in high amounts, do not dramatically increase exosome secretion. Heparanase also impacts exosome protein cargo as reflected by higher levels of syndecan-1, VEGF, and hepatocyte growth factor in exosomes secreted by heparanase-high expressing cells as compared with heparanase-low expressing cells. Exosomes from heparanase-high cells stimulate spreading of tumor cells on fibronectin and invasion of endothelial cells through extracellular matrix better than do exosomes secreted by heparanase-low cells
physiological function
-
heparanase, the sole mammalian endoglycosidase degrading heparan sulfate, is causally involved in cancer metastasis, angiogenesis, inflammation and kidney dysfunction. Involvement of heparanase in atherosclerosis and other vessel wall pathologies, overview. Heparanase promotes thrombosis after vascular injury and contributes to a pro-coagulant state in human carotid atherosclerosis. Heparanase emerges as a regulator of vulnerable lesion development and potential target for therapeutic intervention in atherosclerosis and related vessel wall complications. The enzyme plays a direct role of heparanase in tumor metastasis. heparanase promotes gene expression (i.e., VEGF, tissue factor, HGF, RANKL, TNFalpha) and signaling pathways (i.e., phosphorylation of Akt, Src, Erk, EGF-receptor, insulin receptor) of which some are mediated by its C-terminus domain, devoid of heparanase enzymatic activity. Heparanase activates macrophages via Toll-like receptor similar to the marked increase of TNFalpha and IL-1 following addition of heparanase to monocytes isolated from human peripheral blood. Molecular mechanism underlying cytokine induction by heparanase, overview. Heparanase alters arterial structure and repair following endovascular stenting. The enzyme is a potent regulator of vascular remodeling, both on the level of paracrine regulation of vascular homeostasis and as an effector molecule in vascular response to injury
physiological function
-
human heparanase is a heparan sulfate degrading enzyme located in the extracellular matrix playing a decisive role in angiogenesis and tumor metastasis
physiological function
-
nuclear heparanase controls transcription of a distinct cohort of T-cell inducible genes. Since heparanase associates with active chromatin marks and RNAP II, the activated enzyme plays a role in gene transcription. The endoglycosidase heparanase enters the nucleus of T lymphocytes and modulates H3 methylation at actively transcribed genes via the interplay with key chromatin modifying enzymes. Chromatin-bound heparanase is a prerequisite for the transcription of a subset of inducible immune response genes in activated T-cells. The actions of heparanase seem to influence gene transcription by associating with the demethylase LSD1, preventing recruitment of the methylase MLL and thereby modifying histone H3 methylation patterns. Heparanase belongs to an emerging class of proteins that play an important role in regulating transcription in addition to their well-recognized extra-nuclear functions
physiological function
-
role of heparanase in the modification of heparan sulfate proteoglycans within the tumour microenvironment, overview. Involvement of heparanase in the metastatic extravasation of tumor cells and invasion of immune cells
physiological function
-
the enzyme degrades side chains of heparan sulfate. Versatile role of heparanase in inflammation, detailed overview. In light of the potential tissue damage as a consequence of inappropriate cleavage of heparan sulfate, under physiological conditions heparanase is tightly regulated. Along with posttranslational proteolytic processing regulation of heparanase gene transcription represents an important control mechanism. Role for heparanase located within the cell nuclei in regulating expression of genes involved in shaping of inflammatory phenotype in endothelial and T cells. Key role of heparan sulfate in glycocalyx structure during acute inflammatory lung injury heparanase-mediated degradation and loss of pulmonary endothelial glycocalyx facilitating neutrophil recruitment. The enzyme is involved in colon inflammatory bowel disease through exposure of the endothelial surface and increased availability of adhesion molecules
physiological function
-
the enzyme induces development of psoriasiform skin inflammation in mice. Enzymatic cleavage of heparan sulfate by heparanase profoundly affects a variety of pathophysiological processes, including inflammation, where heparanase activity is often associated with extracellular matrix remodeling, immunocyte activation,and release of chemokines anchored within the extracellular matrix network and cell surface. Heparanase of epidermal origin appears to facilitate abnormal activation of skin-infiltrating macrophages, thus generating psoriasis-like inflammation conditions, characterized by induction of STAT 3, enhanced NF-kappaB signaling, elevated expression of TNF-alpha and increased vascularization. Enzyme involvement of heparanase in the pathogenesis of psoriasis and a role for the enzyme in facilitating abnormal interactions between immune and epithelial cell subsets of the affected skin
physiological function
the enzyme is an endo-beta-glucuronidase associated with cell invasion in cancer metastasis, angiogenesis and inflammation. Cleaving heparan sulfate and releasing heparin/heparan sulfate oligosaccharides, the enzyme causes the release of growth factors, which accelerate tumor growth and metastasis
physiological function
-
the enzyme is implicated in several diverse pathological processes associated with extracellular matrix degradation such as metastasis, inflammation and angiogenesis
physiological function
-
the enzyme is involved in the process of tumor metastasis
physiological function
-
the enzyme may be a key regulator of migration and immune response mediator in macrophages. The enzyme is an endo-beta-glucuronidase that cleaves heparan sulfate at specific intra-chain sites, is strongly implicated in dissemination of metastatic tumor cells. When mouse macrophages are stimulated with lipopolysaccharide in the absence or presence of active enzyme, the enzyme strongly sensitizes macrophages activated by lipopolysaccharide in vitro, as indicated by a marked increase in TNF-alpha, IL-6, and IL-12 p35 [5,6]. Furthermore, induction of the enzyme in several inflammatory conditions occurs and is associated with degradation of heparan sulfate, remodeling of the extracellular matrix, facilitating the inflammatory cell migration towards the injury sites and releasing of chemokines anchored within the extracellular matrix network and cell surfaces
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
physiological function
heparanase is a mammalian endo-beta-glucuronidase with importance in various pathological, e.g. carcinogenesis, and non-pathological events. Despite tumor development heparanase can also modulate inflammatory processes, scarring, tissue repair, and tissue regeneration
physiological function
heparanase is an endo-beta-glucuronidase that cleaves heparan sulfate (HS) side chains presumably at sites of low sulfation. Heparanase is critically required for activation and function of macrophages. Heparanase activates Erk, p38, and JNK signaling in macrophages by a linear cascade, leading to increased c-Fos levels and induction of cytokine expression in a manner that apparently does not require heparanase enzymatic activity. Heparanase is a key mediator of macrophage activation and function in tumorigenesis and cross-talk with the tumor microenvironment. Heparanase from the tumor microenvironment supports tumor growth. Mutant Hpa-KO macrophages do not attenuate tumor growth
physiological function
heparanase is an endoglycosidase that participates in morphogenesis, tissue repair, heparan sulphates turnover and immune response processes. It is overexpressed in tumor cells favoring the metastasis as it penetrates the endothelial layer that lines blood vessels and facilitates the metastasis by degradation of heparan sulphate proteoglycans of the extracellular matrix. Heparanase may also affect the hemostatic system in a non-enzymatic manner, up-regulating the expression of tissue factor, which is the initiator of blood coagulation, and dissociating tissue factor pathway inhibitor on the cell surface membrane of endothelial and tumor cells, thus resulting in a procoagulant state. Heparanase activates antithrombin through the binding to its heparin binding site. Activation of antithrombin, which is the most important endogenous anticoagulant, mainly accelerates factor Xa inhibition, supporting an allosteric activation effect. Heparanase may exert a non-enzymatic function interaction
physiological function
heparanase is an enzyme which cleaves heparan sulfate (HS) polysaccharides of the extracellular matrix. It is a regulator of tumor behavior, plays a key role in kidney related diseases and autoimmune diabetes
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
physiological function
-
the enzyme degrades heparan sulfate (HS), a glycosaminoglycan (GAG), by hydrolysis of the beta-1,4-glycosidic linkage between glucuronic acid (GlcUA, G) and alpha-D-glucosamine (GlcN, N) residues. The overexpression of heparanase in cancers is well known and is associated with angiogenesis, inflammation and increased metastatic potential
physiological function
the upregulation of heparanase expression increases tumor size, angiogenesis, and metastasis, represents a validated target in the anti-cancer field
physiological function
the enzyme is involved in heparan sulfate biosynthesis
physiological function
-
the enzyme induces development of psoriasiform skin inflammation in mice. Enzymatic cleavage of heparan sulfate by heparanase profoundly affects a variety of pathophysiological processes, including inflammation, where heparanase activity is often associated with extracellular matrix remodeling, immunocyte activation,and release of chemokines anchored within the extracellular matrix network and cell surface. Heparanase of epidermal origin appears to facilitate abnormal activation of skin-infiltrating macrophages, thus generating psoriasis-like inflammation conditions, characterized by induction of STAT 3, enhanced NF-kappaB signaling, elevated expression of TNF-alpha and increased vascularization. Enzyme involvement of heparanase in the pathogenesis of psoriasis and a role for the enzyme in facilitating abnormal interactions between immune and epithelial cell subsets of the affected skin
-
additional information
-
endogenous heparanase forms a complex with RNAP II, histone H3 (a key nucleosome component) and the H3K9ac activation mark, in resting and activated T cells and with euchromatin
additional information
-
heparanase overexpressing transgenic mice in a model of 12-O-tetradecanoyl phorbol 12-myristate 13-acetate-induced cutaneous inflammation promotes development of mouse skin lesions that strongly recapitulate the human disease in terms of histomorphological appearance and molecularcellular characteristics
additional information
-
residues Glu225 and Glu343 are critical in its catalytic mechanism. Two heparan sulfate binding sites are formed by Lys158-Asp171 and Gln270-Lys280
additional information
-
sequence homology modeling indicates that heparanase contains a TIM barrel fold, which incorporates the two heparan sulfate-binding regions (residues 158-162 and 270-280) and the catalytic residues (Glu225 and Glu343) of the active site. The C-terminus of the protein forms a discrete domain, which has non-catalytic properties and is involved in a heparanase-mediated signaling function that is distinct from its enzymatic activity
additional information
the enzyme contains two glycosaminoglycan-binding domains. Computational analyses of the catalytic and heparin-binding sites and their interactions with glycosaminoglycans, docked structures are used to propose a model for substrates and conformer selectivity based on the dimensions of the active site, homology modelling, overview. Molecular dynamics simulations. Conformations of docked pentasaccharides in the binding site of heparanase
additional information
-
the enzyme contains two glycosaminoglycan-binding domains. Computational analyses of the catalytic and heparin-binding sites and their interactions with glycosaminoglycans, docked structures are used to propose a model for substrates and conformer selectivity based on the dimensions of the active site, homology modelling, overview. Molecular dynamics simulations. Conformations of docked pentasaccharides in the binding site of heparanase
additional information
-
three-dimensional sequence homology modelling, overview. Two essential acidic residues are Glu225 and Glu343, which are involved in the catalytic mechanism, acting as a proton donor and a nucleophile, respectively
additional information
-
NMR study of the endo cleavage mechanism of the heparanase, overview. Conserved active site regions, including a His-His-Tyr sequence. The BpHep residues Glu144 and Glu255 are predicted to be located at similar positions postulated for BhHep and are within loops between the beta-strands and alpha-helices, which is typical of TIM-barrel glycoside hydrolases, comparison to the human enzyme
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
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
additional information
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heparanase overexpressing transgenic mice in a model of 12-O-tetradecanoyl phorbol 12-myristate 13-acetate-induced cutaneous inflammation promotes development of mouse skin lesions that strongly recapitulate the human disease in terms of histomorphological appearance and molecularcellular characteristics
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Nannospalax galili, Nannospalax judaei (Q333X5)
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Miao, H.Q.; Navarro, E.; Patel, S.; Sargent, D.; Koo, H.; Wan, H.; Plata, A.; Zhou, Q.; Ludwig, D.; Bohlen, P.; Kussie, P.
Cloning, expression, and purification of mouse heparanase
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Mus musculus
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Miles, J.R.; Vallet, J.L.; Freking, B.A.; Nonneman, D.J.
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Homo sapiens (Q9Y251)
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Homo sapiens (Q9Y251), Homo sapiens
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Homo sapiens (Q9Y251), Homo sapiens
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Rattus norvegicus
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Mus musculus
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Role of heparanase on hepatic uptake of intestinal derived lipoprotein and fatty streak formation in mice
PLoS ONE
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Homo sapiens
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Homo sapiens
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Heparanase expression and localization in different types of human lung cancer
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Homo sapiens
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Heparanase is a key player in renal fibrosis by regulating TGF-beta expression and activity
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Homo sapiens
brenda
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Chemical shift assignments and secondary structure of the surrogate domain for drug discovery studies of human heparanase
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Homo sapiens
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Hit identification of novel heparanase inhibitors by structure- and ligand-based approaches
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Homo sapiens
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Homo sapiens
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Lerner, I.; Zcharia, E.; Neuman, T.; Hermano, E.; Rubinstein, A.M.; Vlodavsky, I.; Elkin, M.
Heparanase is preferentially expressed in human psoriatic lesions and induces development of psoriasiform skin inflammation in mice
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Homo sapiens, Mus musculus, Mus musculus BALB/c
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Homo sapiens
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Hammond, E.; Handley, P.; Dredge, K.; Bytheway, I.
Mechanisms of heparanase inhibition by the heparan sulfate mimetic PG545 and three structural analogues
FEBS Open Bio
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Homo sapiens
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Hammond, E.; Khurana, A.; Shridhar, V.; Dredge, K.
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Homo sapiens
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Gandhi, N.; Freeman, C.; Parish, C.; Mancera, R.
Computational analyses of the catalytic and heparin-binding sites and their interactions with glycosaminoglycans in glycoside hydrolase family 79 endo-D-glucuronidase (heparanase)
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22
35-55
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Homo sapiens (Q9Y251), Homo sapiens
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Thompson, C.A.; Purushothaman, A.; Ramani, V.C.; Vlodavsky, I.; Sanderson, R.D.
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Homo sapiens
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Mammalia
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Mammalia
brenda
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Homo sapiens
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Qin, Q.; Niu, J.; Wang, Z.; Xu, W.; Qiao, Z.; Gu, Y.
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Mus musculus
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The endoglycosidase heparanase enters the nucleus of T lymphocytes and modulates H3 methylation at actively transcribed genes via the interplay with key chromatin modifying enzymes
Transcription
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2012
Homo sapiens
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Melo, C.M.; Tersariol, I.L.; Nader, H.B.; Pinhal, M.A.; Lima, M.A.
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Homo sapiens (Q9Y251)
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Loka, R.S.; Yu, F.; Sletten, E.T.; Nguyen, H.M.
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Homo sapiens (Q9Y251)
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Vlodavsky, I.; Singh, P.; Boyango, I.; Gutter-Kapon, L.; Elkin, M.; Sanderson, R.D.; Ilan, N.
Heparanase from basic research to therapeutic applications in cancer and inflammation
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Homo sapiens (Q9Y251), Homo sapiens
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Messore, A.; Madia, V.N.; Pescatori, L.; Saccoliti, F.; Tudino, V.; De Leo, A.; Bortolami, M.; De Vita, D.; Scipione, L.; Pepi, F.; Costi, R.; Rivara, S.; Scalvini, L.; Mor, M.; Ferrara, F.F.; Pavoni, E.; Roscilli, G.; Cassinelli, G.; Milazzo, F.M.; Battistuzzi, G.; Di Santo, R.; Giannini, G.
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Homo sapiens (Q9Y251)
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Burkholderia pseudomallei
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Homo sapiens (Q9Y251), Homo sapiens
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Bohdan, N.; Espin, S.; Aguila, S.; Teruel-Montoya, R.; Vicente, V.; Corral, J.; Martinez-Martinez, I.
Heparanase activates antithrombin through the binding to its heparin binding site
PLoS ONE
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Homo sapiens (Q9Y251)
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Gutter-Kapon, L.; Alishekevitz, D.; Shaked, Y.; Li, J.P.; Aronheim, A.; Ilan, N.; Vlodavsky, I.
Heparanase is required for activation and function of macrophages
Proc. Natl. Acad. Sci. USA
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Mus musculus (Q6YGZ1)
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Ushakov, V.; Tsidulko, A.; De La Bourdonnaye, G.; Kazanskaya, G.; Volkov, A.; Kiselev, R.; Kobozev, V.; Kostromskaya, D.; Gaytan, A.; Krivoshapkin, A.; Aidagulova, S.; Grigorieva, E.
Heparan sulfate biosynthetic system is inhibited in human glioma due to EXT1/2 and HS6ST1/2 down-regulation
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Homo sapiens (Q9Y251)
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