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Information on EC 3.2.1.166 - heparanase
for references in articles please use BRENDA:EC3.2.1.166
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EC Tree 3 Hydrolases
3.2 Glycosylases
3.2.1 Glycosidases, i.e. enzymes that hydrolyse O- and S-glycosyl compounds
3.2.1.166 heparanase
IUBMB Comments
Heparanase cleaves the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying either a 3-O-sulfo or a 6-O-sulfo group . Heparanase-1 cuts macromolecular heparin into fragments of 5000–20000 Da . The enzyme 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 .
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
- 3.2.1.166
- metastasis
- proteoglycans
- angiogenesis
- endothelial
- heparin
-
endoglycosidase
-
basement
- glycosaminoglycans
- melanoma
- vessel
- oligosaccharide
- platelet
- syndecan-1
-
hspgs
- node
-
angiogenic
- myeloma
- nephropathy
-
anticoagulant
-
glycocalyx
-
clinicopathological
- metalloproteinases
- glomerular
-
procoagulant
-
heparin-binding
-
antimetastatic
- heparinase
- neovascularization
- fgf-2
-
extravasation
- bfgf
- perlecan
-
subendothelial
- matrigel
-
microvessel
- chondroitin
-
pro-tumorigenic
-
o-sulfation
-
matrix-degrading
- vegf-c
- pharmacology
-
glypicans
- diagnostics
-
proangiogenic
- medicine
-
non-anticoagulant
-
iduronic
- sdc1
-
prometastatic
- chondroitinase
-
intrachain
- drug development
-
tfpi-2
- analysis
Reaction Schemes
showendohydrolysis of (1->4)-beta-D-glycosidic bonds of heparan sulfate chains in heparan sulfate proteoglycan
Synonyms
heparanase, heparanase-1, endo-beta-d-glucuronidase, endo-beta-glucuronidase, heparanase 1, c1a heparanase, bphep, heparan sulfate glycosidase, more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
endo-beta-glucuronidase
heparanase-1
HPA
Hpa1
HPSE
T5
-
enzymatically inactive splice variant of human heparanase, in which 144 bp of intron 5 are joined with exon 4
HPSE
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
endohydrolysis of (1->4)-beta-D-glycosidic bonds of heparan sulfate chains in heparan sulfate proteoglycan
endohydrolysis of (1->4)-beta-D-glycosidic bonds of heparan sulfate chains in heparan sulfate proteoglycan
-
-
-
-
endohydrolysis of (1->4)-beta-D-glycosidic bonds of heparan sulfate chains in heparan sulfate proteoglycan
reaction mechanism with transition states and glycosyl-enzyme intermediate, overview
endohydrolysis of (1->4)-beta-D-glycosidic bonds of heparan sulfate chains in heparan sulfate proteoglycan
mode of action, overview
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PATHWAY SOURCE
PATHWAYS
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SYSTEMATIC NAME
IUBMB Comments
heparan sulfate N-sulfo-D-glucosamine endoglucanase
Heparanase cleaves the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying either a 3-O-sulfo or a 6-O-sulfo group [2]. Heparanase-1 cuts macromolecular heparin into fragments of 5000--20000 Da [5]. The enzyme 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 [1].
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
2'-N,6'-O-bis-sulfated heparin sulfate disaccharide + H2O
?
Substrates: the enzyme cleaves heparin sulfate chains at D-glucuronic acid residues
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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
Substrates: more than 95% cleavage
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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)-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
Substrates: 26% cleavage
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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)-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
Substrates: 85% cleavage
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?
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
Substrates: 40% cleavage
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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
Substrates: more than 95% cleavage
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?
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
Substrates: 21% cleavage
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?
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
Substrates: 44% cleavage
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?
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
Substrates: more than 95% cleavage
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?
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
Substrates: 59% cleavage
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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
Substrates: 60% cleavage
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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
Substrates: 30% cleavage
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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 + 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
Substrates: 56% cleavage
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?
completely de-sulfated, N-sulfated heparin + H2O
?
-
Substrates: -
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?
GlcA-GlcNS-GlcA-GlcNS-GlcA-GlcNAc-GlcA-Az + H2O
GlcA + GlcNS-GlcA + GlcNS-GlcA + GlcNAc-GlcA-Az
-
Substrates: -
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?
GlcA-GlcNS-GlcA-GlcNS-GlcA-GlcNS-IdoA2S-GlcNS-GlcA-Az + H2O
GlcA + GlcNS-GlcA + GlcNS-GlcA + GlcNS-IdoA2S-GlcNS-GlcA-Az
-
Substrates: -
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?
GlcNAc-GlcA-GlcNS-IdoA-GlcNS-GlcA-Az + H2O
GlcNAc-GlcA + GlcNS-IdoA-GlcNS-GlcA-Az
-
Substrates: -
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?
GlcNAc-GlcA-GlcNS-IdoA2S-GlcNS-GlcA-Az + H2O
GlcNAc-GlcA + GlcNS-IdoA2S-GlcNS-GlcA-Az
-
Substrates: -
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?
GlcNS-GlcA-GlcNAc-GlcA-GlcNAc-GlcA-GlcNAc-GlcA-Az + H2O
GlcNS-GlcA + GlcNAc-GlcA + GlcNAc-GlcA + GlcNAc-GlcA-Az
-
Substrates: -
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?
GlcNS6S-GlcA-GlcNAc6S-GlcA-GlcNAc6S-GlcA-GlcNAc6S-GlcA-Az + H2O
GlcNS6S-GlcA-GlcNAc6S-GlcA + GlcNAc6S-GlcA + GlcNAc6S-GlcA-Az
-
Substrates: -
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?
heparan sulfate + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
Substrates: catalytic mechanism that involves two conserved acidic residues, a putative proton donor at Glu225 and a nucleophile at Glu343
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
heparan sulfate proteolycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
Substrates: -
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?
heparan sulphate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
Substrates: -
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?
heparin octasaccharide + H2O
?
Substrates: cleavage of the single beta-D-glucuronidic linkage in a heparin-derived octasaccharide with high affinity for antithrombin
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?
heparin sulfate + H2O
?
Substrates: cleavage to 5000 Da oligosaccharides
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?
insulin-like growth factor 2 receptor + H2O
?
Substrates: -
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?
low density receptor-related protein-1 + H2O
?
Substrates: -
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?
low molecular weight heparin + H2O
?
-
Substrates: the enzyme selectively breaks the beta-1,4 linkages between D-glucuronic acid and N-acetyl-D-glucosamine
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?
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
Substrates: i.e. fondaparinux
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?
N-deacetylated, N-sulfoheparosan + H2O
GlcNS-GlcA + ?
-
Substrates: -
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?
[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
Substrates: 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
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[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
Substrates: 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
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[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
Substrates: heparanase does not cleave the linkage of GlcA2S-GlcNS but rather cleaves the linkage of GlcA-GlcNS nearby
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fondaparinux + H2O
2N-sulfo-6-O-sulfo-alpha-D-GlcN-(1->4)-beta-GlcA + a trisaccharide
-
Substrates: a pentasaccharide substrate, heparanase is a retaining glycosidase, NMR spectroscopic analysis, overview
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fondaparinux + H2O
2N-sulfo-6-O-sulfo-alpha-D-GlcN-(1->4)-beta-GlcA + a trisaccharide
Substrates: -
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?
heparan sulfate + H2O
?
-
Substrates: enzyme BpHep is specific for heparan sulfate
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heparan sulfate + H2O
?
Substrates: 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
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heparan sulfate + H2O
?
-
Substrates: 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
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heparan sulfate + H2O
?
-
Substrates: 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
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heparan sulfate proteoglycan + H2O
?
Substrates: only a limited number of sites are cut by the enzyme thus releasing 5-10 kDa fragments of heparin sulfate (10-20 sugar units)
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heparan sulfate proteoglycan + H2O
?
Substrates: -
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
Substrates: -
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
Substrates: HPSE may play a role in ovulation
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
Substrates: 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
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
Substrates: 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
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
Substrates: 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
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
Substrates: -
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
Substrates: 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
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
Substrates: 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
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
Substrates: 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
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
Substrates: -
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
Substrates: -
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
Substrates: 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
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
Substrates: -
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
Substrates: the average molecular mass of the degradation products is determined to be 2000030000 Da
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
Substrates: -
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
Substrates: cleavage to 5000 Da oligosaccharides
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
Substrates: -
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
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Substrates: 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
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
Substrates: 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
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
-
Substrates: -
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heparin + H2O
?
Substrates: heparanase cleaves macromolecular heparin at multiple sites. Heparanase primarily cleaves target structures distinct from the antithrombin-binding sequence
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syndecan-1 + H2O
?
-
Substrates: 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
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additional information
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Substrates: activity assays using fluorescein isothiocyanate (FITC)-labeled glycosaminoglycans. NMR spectroscopic study of enzyme cleavage site specificity, overview
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additional information
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Substrates: the endolytic enzyme acts only on a glucuronic acid residue beta-(->4) linked to an N-acetylglucosamine, N-sulfoglucosamine or N-acetyl-6-O-sulfoglucosamine residue. A substrate is required to have a length of pentasaccharide or longer
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additional information
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Substrates: the enzyme also can act on hyaluronan and chondroitin sulfate, acting also as hyaluronidase/chondroitinase cleaving GlcA beta(1->3) GlcNAc/N-acetyl-D-galactosamine
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additional information
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Substrates: no activity with N-deacetylated, N-sulfated, 6-O-sulfated heparosan, N-deacetylated, N-sulfated, C5-epimerase treated 2-O-sulfated heparosan, partially 6-O-sulfated heparosan, N-deacetylated, N-sulfated, 6-O-sulfated, C5-epimerase treated 2-O-sulfated heparosan (also known as non-anticoagulant heparin). The enzyme does not cleave the oligosaccharides GlcNAc6S-GlcA-GlcNS6S-IdoA-GlcNS6S-GlcA-Az, GlcNS6S-GlcA-GlcNS6S-GlcA2S-GlcNS-GlcA-Az, and GlcA-GlcNS6S-GlcA-GlcNS6S3S-IdoA2S-GlcNS6S-GlcA-Az
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additional information
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Substrates: 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
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additional information
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Substrates: 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
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additional information
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Substrates: 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
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additional information
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Substrates: 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
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additional information
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Substrates: 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
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additional information
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Substrates: 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
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additional information
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Substrates: 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
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additional information
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Substrates: 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
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additional information
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Substrates: 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
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additional information
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Substrates: 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
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additional information
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Substrates: heparanase is an endo-beta-glucuronidase that cleaves heparan sulfate side chains of proteoglycans in basement membranes and the extracellular matrix
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additional information
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Substrates: 6-O-sulfo heparosan and N-sulfo heparosan are resistant to cleavage by heparanase
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additional information
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Substrates: 6-O-sulfo heparosan and N-sulfo heparosan are resistant to cleavage by heparanase
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additional information
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Substrates: 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
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additional information
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Substrates: 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
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additional information
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Substrates: 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
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additional information
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Substrates: 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
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additional information
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Substrates: 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
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additional information
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Substrates: fondaparinux assay method
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additional information
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Substrates: 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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additional information
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Substrates: 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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additional information
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Substrates: N-SO3- at +1 subsite and 6-O-SO3- at -2 subsite of trisaccharides are critical for enzyme recognition. Addition of 2-O-SO3- at the -1 subsite and of 3-O-SO3- to GlcN unit is not advantageous. The anomeric configuration (alpha or beta) at the reducing end is crucial in controlling enzyme activity
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
heparan sulfate proteolycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
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Substrates: -
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syndecan-1 + H2O
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Substrates: 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
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heparan sulfate + H2O
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Substrates: 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
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heparan sulfate proteoglycan + H2O
?
Substrates: only a limited number of sites are cut by the enzyme thus releasing 5-10 kDa fragments of heparin sulfate (10-20 sugar units)
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heparan sulfate proteoglycan + H2O
?
Substrates: -
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
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Substrates: -
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
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Substrates: 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
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
Substrates: 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
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
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Substrates: 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
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heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
Substrates: 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
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additional information
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Substrates: 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
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additional information
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Substrates: 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
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additional information
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Substrates: 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
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additional information
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Substrates: 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
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additional information
?
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Substrates: heparanase is an endo-beta-glucuronidase that cleaves heparan sulfate side chains of proteoglycans in basement membranes and the extracellular matrix
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additional information
?
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Substrates: 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
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additional information
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Substrates: 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
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additional information
?
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Substrates: 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
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(((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
-
-
(3S,4S,5R,6R)-4,5-dihydroxy-6-[(trifluoroacetyl)amino]piperidine-3-carboxylic acid
-
-
(IdoA2S-GlcNS)n
polysaccharide containing IdoA2S-GlcNS repeating unit, inhibits the activity of heparanase
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-N-sulfo-ethyl(2-acetamido-2-deoxy-6-O-sulfo-alpha-D-glucopyranosyl)-(1->4)-(beta-D-glucopyranosyl-uronate)-(1->4)-2-N-sulfo-2-deoxy-6-O-sulfo-alpha-D-glucopyranoside
-
-
2-N-sulfo-ethyl(2-N-sulfo-2-deoxy-3,6-di-O-sulfo-alpha-D-glucopyranosyl)-(1->4)-(beta-D-glucopyranosyl-uronate)-(1->4)-2-N-sulfo-2-deoxy-3,6-di-O-sulfo-alpha-D-glucopyranoside
-
-
2-N-sulfo-ethyl(2-N-sulfo-2-deoxy-3,6-di-O-sulfo-alpha-D-glucopyranosyl)-(1->4)-(beta-D-glucopyranosyl-uronate)-(1->4)-2-N-sulfo-2-deoxy-6-O-sulfo-alpha-D-glucopyranoside
-
-
2-N-sulfo-ethyl(2-N-sulfo-2-deoxy-6-O-sulfo-alpha-D-glucopyranosyl)-(1->4)-(2-O-sulfo-beta-D-gluco-pyranosyluronate)-(1->4)-2-N-sulfo-2-deoxy-6-O-sulfo-alpha-D-glucopyranoside
-
-
2-N-sulfo-ethyl(2-N-sulfo-2-deoxy-6-O-sulfo-alpha-D-glucopyranosyl)-(1->4)-(beta-D glucopyranosyl-uronate)-(1->4)-2-N-sulfo-2-deoxy-6-O-sulfo-alpha-D-glucopyranoside
-
-
2-N-sulfo-ethyl(2-N-sulfo-2-deoxy-6-O-sulfo-alpha-D-glucopyranosyl)-(1->4)-(beta-D-glucopyranosyl-uronate)-(1->4)-2-acetamido-2-deoxy-6-O-sulfo-alpha-D-glucopyranoside
-
-
2-N-sulfo-ethyl(2-N-sulfo-2-deoxy-6-O-sulfo-alpha-D-glucopyranosyl)-(1->4)-(beta-D-glucopyranosyl-uronate)-(1->4)-2-N-sulfo-2-deoxy-3,6-di-O-sulfo-alpha-D-glucopyranoside
-
-
2-N-sulfo-ethyl(2-N-sulfo-2-deoxy-6-O-sulfo-alpha-D-glucopyranosyl)-(1->4)-(beta-D-glucopyranosyl-uronate)-(1->4)-2-N-sulfo-2-deoxy-6-O-sulfo-beta-D-glucopyranoside
-
-
2-N-sulfo-ethyl(2-N-sulfo-2-deoxy-6-O-sulfo-alpha-D-glucopyranosyl)-(1->4)-(beta-D-glucopyranosyl-uronate)-(1->4)-2-N-sulfo-2-deoxy-alpha-D-glucopyranoside
-
-
2-N-sulfo-ethyl(2-N-sulfo-2-deoxy-6-O-sulfo-alpha-D-glucopyranosyl)-(1->4)-(beta-D-glucopyranosyl-uronate)-(1->4)-2-N-sulfo-2-deoxy-beta-D-glucopyranoside
-
-
2-N-sulfo-ethyl(2-N-sulfo-2-deoxy-alpha-D-glucopyranosyl)-(1->4)-(beta-D-glucopyranosyl-uronate)-(1->4)-2-N-sulfo-2-deoxy-6-O-sulfo-alpha-D-glucopyranoside
-
-
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-[(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-[[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
-
-
defibrotide
a polydisperse oligonucleotide isolated from porcine mucosa that has multiple biological effects including inhibition of heparanase gene expression and enzymatic activity
-
fucosylated glycosaminoglycan
fucosylated glycosaminoglycan from Holothuria floridana is composed of repeating trisaccharide units -[(L-FucS-alpha1,3-)-D-GlcA-beta1,3-D-GalNAc4S6S-beta1,4-]-, in which sulfated fucose (FucS) includes Fuc2S4S, Fuc3S4S and Fuc4S residues linked to O-3 of GlcA in a ratio of 45:35:20
-
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
-
HPSE-2
the catalytically inactive isoform HPSE-2 plays an inhibitory role against the enzyme
-
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
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
-
-
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
-
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
sodium octyl 4-O-[2-deoxy-2-(sulfoamino)-alpha-D-glucopyranosyl]-beta-D-glucopyranosiduronate
-
specific inhibition
[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-(4-[[(2E)-3-(4-bromophenyl)prop-2-enoyl]amino]-2-chlorophenyl)furan-2-yl]-1,3-thiazol-2-yl]acetic acid
-
-
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
M402
-
a glycol-split heparin compound similar to SST0001 yet smaller in molecular mass
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
-
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
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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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
histidine-rich glycoprotein
GeneBank accession number: BAA21613. Directly interacts with platelet-derived heparanase and enhances its enzymatic activity
-
palmitic acid
-
palmitic acid-induced nuclear entry of heparanase facilitates heparan sulfate cleavage
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.01031
2'-N,6'-O-bis-sulfated heparin sulfate disaccharide
pH and temperature not specified in the publication
-
0.046
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
pH 5.0, 37°C, i.e. fondaparinux
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000331
2'-N,6'-O-bis-sulfated heparin sulfate disaccharide
pH and temperature not specified in the publication
-
3.5
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
pH 5.0, 37°C, i.e. fondaparinux
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
PG517: 162 nM, PG518: 59 nM, PG536: 6 nM, PG537: 6 nM, PG545: 6 nM, PG546: 4 nM, PG547: 16 nM, PG554: 9 nM, PG561: 11 nM, PG562: 9 nM, PI-88: 8 nM
-
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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
0.01121
2-N-sulfo-ethyl(2-acetamido-2-deoxy-6-O-sulfo-alpha-D-glucopyranosyl)-(1->4)-(beta-D-glucopyranosyl-uronate)-(1->4)-2-N-sulfo-2-deoxy-6-O-sulfo-alpha-D-glucopyranoside
Homo sapiens
at pH 7.5 and 37°C
-
0.009961
2-N-sulfo-ethyl(2-N-sulfo-2-deoxy-3,6-di-O-sulfo-alpha-D-glucopyranosyl)-(1->4)-(beta-D-glucopyranosyl-uronate)-(1->4)-2-N-sulfo-2-deoxy-3,6-di-O-sulfo-alpha-D-glucopyranoside
Homo sapiens
at pH 7.5 and 37°C
-
0.01239
2-N-sulfo-ethyl(2-N-sulfo-2-deoxy-3,6-di-O-sulfo-alpha-D-glucopyranosyl)-(1->4)-(beta-D-glucopyranosyl-uronate)-(1->4)-2-N-sulfo-2-deoxy-6-O-sulfo-alpha-D-glucopyranoside
Homo sapiens
at pH 7.5 and 37°C
-
0.011961
2-N-sulfo-ethyl(2-N-sulfo-2-deoxy-6-O-sulfo-alpha-D-glucopyranosyl)-(1->4)-(2-O-sulfo-beta-D-gluco-pyranosyluronate)-(1->4)-2-N-sulfo-2-deoxy-6-O-sulfo-alpha-D-glucopyranoside
Homo sapiens
at pH 7.5 and 37°C
-
0.000393
2-N-sulfo-ethyl(2-N-sulfo-2-deoxy-6-O-sulfo-alpha-D-glucopyranosyl)-(1->4)-(beta-D glucopyranosyl-uronate)-(1->4)-2-N-sulfo-2-deoxy-6-O-sulfo-alpha-D-glucopyranoside
Homo sapiens
at pH 7.5 and 37°C
-
0.01079
2-N-sulfo-ethyl(2-N-sulfo-2-deoxy-6-O-sulfo-alpha-D-glucopyranosyl)-(1->4)-(beta-D-glucopyranosyl-uronate)-(1->4)-2-acetamido-2-deoxy-6-O-sulfo-alpha-D-glucopyranoside
Homo sapiens
at pH 7.5 and 37°C
-
0.008118
2-N-sulfo-ethyl(2-N-sulfo-2-deoxy-6-O-sulfo-alpha-D-glucopyranosyl)-(1->4)-(beta-D-glucopyranosyl-uronate)-(1->4)-2-N-sulfo-2-deoxy-3,6-di-O-sulfo-alpha-D-glucopyranoside
Homo sapiens
at pH 7.5 and 37°C
-
0.04206
2-N-sulfo-ethyl(2-N-sulfo-2-deoxy-6-O-sulfo-alpha-D-glucopyranosyl)-(1->4)-(beta-D-glucopyranosyl-uronate)-(1->4)-2-N-sulfo-2-deoxy-6-O-sulfo-beta-D-glucopyranoside
Homo sapiens
at pH 7.5 and 37°C
-
0.008225
2-N-sulfo-ethyl(2-N-sulfo-2-deoxy-6-O-sulfo-alpha-D-glucopyranosyl)-(1->4)-(beta-D-glucopyranosyl-uronate)-(1->4)-2-N-sulfo-2-deoxy-alpha-D-glucopyranoside
Homo sapiens
at pH 7.5 and 37°C
-
0.003012
2-N-sulfo-ethyl(2-N-sulfo-2-deoxy-6-O-sulfo-alpha-D-glucopyranosyl)-(1->4)-(beta-D-glucopyranosyl-uronate)-(1->4)-2-N-sulfo-2-deoxy-beta-D-glucopyranoside
Homo sapiens
at pH 7.5 and 37°C
-
0.009537
2-N-sulfo-ethyl(2-N-sulfo-2-deoxy-alpha-D-glucopyranosyl)-(1->4)-(beta-D-glucopyranosyl-uronate)-(1->4)-2-N-sulfo-2-deoxy-6-O-sulfo-alpha-D-glucopyranoside
Homo sapiens
at pH 7.5 and 37°C
-
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
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
0.00042
[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
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
additional information
additional information
Homo sapiens
-
dissociation constants, overview
-
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
4.2
5.5 - 5.8
7.4
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
4 - 5.5
pH 4.0: about 80% of maximal activity, pH 5.5: about 60% of maximal activity. pH 7.0: about 20% of maximal activity
4.2 - 6
pH 4.2: maximal activity, pH 6.0: about 50% of maximal activity. No significant activity is observed below pH 3.5 and above pH 7.0
5 - 7.5
-
pH 5.0: maximal activity, pH 7.5: almost 10-fold more enzyme is necessary to achieve activity comparable to pH 5. Little or no enzymatic activity is detected at pH 4.0 or pH 8.0
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
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pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
UniProt
brenda
-
714936, 714960, 715155, 715536, 715656, 715737, 716701, 731254, 731350, 731355, 731425, 731468, 731586, 731626, 731648, 731820
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-
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
heparanase protein is detected primarily within the cytoplasm of the cells, indicating that the enzyme is produced and stored within the cytoplasm of myeloid cells, with limited expression on the cell surface
brenda
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overexpression of heparanase in pancreatic adenocarcinomas
brenda
elevated levels of heparanasen activity are detected in sera and urine samples of patients suffering from diabetic nephropathy or aggressive metastatic disease
brenda
elevated level of heparanase-activity in bone marrow plasma of myeloma patients
brenda
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metastatic breast carcinoma cell lines show a substantial increase in hpa gene expression
brenda
elevated expression of human heparanase-1 protein occurs in endothelial cells of sprouting capillaries and small vessels in the vicinity of a tumour, but not of mature, quiescent blood vessels
brenda
the enzyme penetrates the endothelial layer that lines blood vessels
brenda
-
heparanase expression in lung cancer samples to understand lung tumor progression and malignancy, overview. Heparanase expression tends to correlate with tumor node metastasis staging in non-small cell lung carcinoma
brenda
isolated from trabecular bone specimens of patients with osteoporosis and from healthy subjects
brenda
heparanase expression is up-regulated in the synovial fluid and tissue of patients suffering from rheumatoid arthritis, but not in unaffected individuals
brenda
elevated level of heparanase-activity is detected in sera and urine samples of patients suffering from diabetic nephropathy or aggressive metastatic disease
brenda
additional information
-
heparanase protein is mainly detected in neurons. Heparanase transcript and protein reach their greatest levels at early postnatal stages, in particular within the neocortex. At adulthood the increased heparanase transcript level correlates in the hippocampus with enhanced angiogenesis following repeated hypoxia exposures. Potential importance of heparanase in brain homeostasis
brenda
-
activity and expression of the enzyme is modified in cancer tissue compared to control tissue, high expression levels in primary tumors and lymph nodes, detailed overview
brenda
-
14 adenocarcinomas, 13 squamous cell carcinomas, 5 large cell carcinomas, and 5 small cell carcinomas. All of the tumor types express heparanase, which is predominantly localized within the cytoplasm and nucleus. Squamous cell carcinomas, large cell carcinomas, and small cell carcinomas have a similar subcellular distribution of heparanase to adenocarcinomas but the distribution is less widespread
brenda
-
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
brenda
heparanase expression is up-regulated in the colon of patients suffering from Crohn's disease and ulcerative colitis
brenda
-
both the chicken heparanase mRNA and protein are expressed 12 h post fertilization, in cells migrating from the epiblast and forming the hypoblast layer. Later on 72 h, the enzyme is preferentially expressed in cells of the developing vascular and nervous systems
brenda
heparanase-1 mRNA and protein are expressed in the liver and colon of 18-week and 22-week human foetuses, but not in the corresponding mature tissues
brenda
under normal conditions, heparanase-1 expression is restricted primarily to placental trophoblasts, blood-borne cells and keratinocytes
brenda
heparanase induction is found in biopsies of human inflammatory lung disease
brenda
heparanase gene expression increases dramatically in myeloma patients following chemotherapy
brenda
-
increased heparanase expression during NGF-induced neuronal differentiation in PC12 cells
brenda
under normal conditions, heparanase-1 expression is restricted primarily to placental trophoblasts, blood-borne cells and keratinocytes
brenda
-
variant HPSE v1 and v2 mRNA are localised to the cuboidal trophoblast cells of the folded bilayer located nearest to the maternal endometrium. The enzyme likely plays a role in the development and modification of the pig placenta
brenda
-
heparanase is preferentially expressed by epidermal keratinocytes in human psoriatic lesions
brenda
-
heparanase occupies regulatory regions of active genes in T cells
brenda
additional information
highly metastatic cells and tumours often show elevated expression of heparanase-1 in comparison with their non-invasive counterparts and normal tissues
brenda
additional information
highly expressed in tumors and metastatic cell lines derived from a variety of tissues
brenda
additional information
-
in human cancer cells, when expression of heparanase is enhanced or when tumor cells are exposed to exogenous heparanase, exosome secretion is dramatically increased
brenda
additional information
-
heparanase is up-regulated in essentially all human tumors examined
brenda
additional information
-
the enzyme is secreted in invasive cells such as inflammatory cells and highly migratory tumor cells
brenda
additional information
heparanase expression is enhanced in almost all cancers examined including various carcinomas, sarcomas and hematological malignancies
brenda
additional information
-
heparanase expression is enhanced in almost all cancers examined including various carcinomas, sarcomas and hematological malignancies
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
heparanase is the only known mammalian endoglycosidase capable of degrading heparan sulfate glycosaminoglycan, both in extracellular space and within the cells
brenda
in blood-borne cells, active heparanase-1 is stored in specific granules, but in response to chemoattractants or inflammatory stimuli it is redistributed to the cell surface and released by degranulation
brenda
additional information
-
the signal peptide sequence accounts for the chicken heparanase being readily secreted and localized in close proximity to the cell surface
brenda
HPSE can be trafficked to the cell surface or released into the extracellular matrix in order to effect breakdown of extracellular pools of heparan sulfate
brenda
heparanase-1 is mostly an intracellular, lysosomal enzyme. Only in cases where the receptor-system is absent or defective, the enzyme accumulates extracellularly. The presence of extracellular (active) heparanase-1 seems to be tightly regulated and restricted by at least two independent mechanisms, on one hand by regulated secretion and on the other hand by lipoprotein receptor-related proteins mediated (re-)uptake
-
brenda
-
the enzyme is secreted in invasive cells such as inflammatory cells and highly migratory tumor cells
-
brenda
HPSE can be trafficked to the cell surface or released into the extracellular matrix in order to effect breakdown of extracellular pools of heparan sulfate
-
brenda
-
heparanase is the only known mammalian endoglycosidase capable of degrading heparan sulfate glycosaminoglycan, both in extracellular space and within the cells
-
brenda
heparanase-1 is mostly an intracellular, lysosomal enzyme. Only in cases where the receptor-system is absent or defective, the enzyme accumulates extracellularly. The enzyme is stored within the acidic compartments in a stable form. Active enzyme can be secreted from intracellular compartments in response to a proper and effective stimulus
brenda
heparanase is translocated into the cell nucleus where it may degrade the nuclear heparan sulfate and thereby affect nuclear functions. 7% of the cytosolic enzyme. Nuclear heparanase colocalizes with nuclear heparan sulfate and is enzymaticaly active
brenda
the latent (65000 Da) and active (50000 Da) forms of human heparanase-1 accumulate in the nucleus of non-transfected human breast carcinoma cells and in the nucleus of glioma cells that are transfected or uploaded with exogenous human heparanase-1. The amount of nuclear heparanase-1 is up to 7% of the total levels found in the cytosol
brenda
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palmitic acid triggers lysosome permeabilization, nuclear shuttling of released heparanase by Hsp90
brenda
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nuclear heparanase preferentially associates with euchromatin in active and resting Jurkat T cells. Heparanase is recruited to both the promoter and transcribed regions of a distinct cohort of transcriptionally active genes. 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
brenda
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heparanase is translocated into the cell nucleus where it may degrade the nuclear heparan sulfate and thereby affect nuclear functions. 7% of the cytosolic enzyme. Nuclear heparanase colocalizes with nuclear heparan sulfate and is enzymaticaly active
brenda
additional information
-
heparanase occupies regulatory regions of active genes in T cells
-
brenda
additional information
the enzyme contains an N-terminal signal peptide, Met1-Ala35
-
brenda
additional information
-
the enzyme contains an N-terminal signal peptide, Met1-Ala35
-
brenda
Highest Expressing Human Cell Lines
Cell Line LinksPlease wait a moment until the data is sorted. This message will disappear when the data is sorted.
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
physiological function
additional information
evolution
-
the enzyme belongs to the clan A glycoside hydrolase family 79, GH79
evolution
-
the enzyme belongs to the glycoxadside hydrolase family 79, GH79, from GH clan A
evolution
the enzyme belongs to the glycoxadside hydrolase family 79, GH79
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
-
enzymatically inactive heparanase: mutated heparanase designated M343 fails to stimulate exosome secretion, whereas mutant M225 has a mild stimulatory effect
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
-
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
-
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
-
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
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
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
metabolism
-
key enzymes sulfatases and heparanase of the pathway actively influence cancer cell proliferation, signaling, invasion, and metastasis
metabolism
the enzyme is responsible for the cutting of heparan sulfate chains at the level of the proteoglycans of the endothelial glycocalyx
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
-
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 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 promotes the nerve growth factor-induced neuritogenesis via MAPK p38 pathway
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
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
-
heparanase variant T5 activates Src and facilitates cell proliferation and enhances myeloma xenograft development
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
-
biologically active interleukin-2 is released from the surface of endothelial cells and smooth muscle cells lining blood vessels by heparanase
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 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
-
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
-
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
-
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
-
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
-
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
-
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
-
the enzyme is involved in the process of tumor metastasis
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
-
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
-
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 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
-
the enzyme is implicated in several diverse pathological processes associated with extracellular matrix degradation such as metastasis, inflammation and angiogenesis
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 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 a key enzyme involved in the dissemination of metastatic cancer cells
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
-
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 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 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 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 upregulation of heparanase expression increases tumor size, angiogenesis, and metastasis, represents a validated target in the anti-cancer field
physiological function
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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
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 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
the enzyme is involved in heparan sulfate biosynthesis
physiological function
the consequences of heparin sulfate cleavage by the enzyme lead to an activated and inflamed endothelium that results in tissue edema and hypoperfusion that sustain end-organ injury
physiological function
the enzyme activity is one of the driving forces in severe coronavirus disease-2019 manifestations
physiological function
the enzyme is involved in prostate cancer progression. The enzyme regulates epithelial-mesenchymal transition and cancer stem cell properties in prostate tumors
physiological function
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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
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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
additional information
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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
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
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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
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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
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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
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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
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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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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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
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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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Show AA Sequence and Transmembrane Helices (975 entries)
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
45000
50000
65000
8000
45000
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1 * 45000, glycosylated subunit formed by residues Lys158-Ile543, + 1 * 8000, formed by residues Gln36-Glu109, SDS-PAGE
45000
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1 * 45000, glycosylated subunit, + 1 * 8000, non-covalently binding, SDS-PAGE
50000
-
1 * 50000 + 1 * 8000, non-covalently bound heterodimer of the 50000 Da protein (Lys150Ile535) and the 8000 Da peptide (Asp28Lys100), SDS-PAGE
8000
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1 * 50000 + 1 * 8000, non-covalently bound heterodimer of the 50000 Da protein (Lys150Ile535) and the 8000 Da peptide (Asp28Lys100), SDS-PAGE
8000
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1 * 45000, glycosylated subunit formed by residues Lys158-Ile543, + 1 * 8000, formed by residues Gln36-Glu109, SDS-PAGE
8000
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1 * 45000, glycosylated subunit, + 1 * 8000, non-covalently binding, SDS-PAGE
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
heterodimer
monomer
additional information
?
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x * 48000, untagged enzyme, calculated from amino acid sequence
heterodimer
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1 * 45000, glycosylated subunit formed by residues Lys158-Ile543, + 1 * 8000, formed by residues Gln36-Glu109, SDS-PAGE
heterodimer
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1 * 45000, glycosylated subunit, + 1 * 8000, non-covalently binding, SDS-PAGE
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
heterodimer
1 * 50000 + 1 * 8000, calculated from amino acid sequence
heterodimer
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1 * 50000 + 1 * 8000, non-covalently bound heterodimer of the 50000 Da protein (Lys150Ile535) and the 8000 Da peptide (Asp28Lys100), SDS-PAGE
additional information
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wild-type enzyme BpHep comprises two funcxadtional domains: a catalytic domain consisting of an (alpha/beta)8 barrel and a beta-sandwich C-terminal domain. In the catalytic domain of BpHepwt, amino acid residues Glu144 and Glu255, with commenxadsurate residues highly conserved in hHep, are the catalytic residues, with Glu144 acting as a proton donor and Glu255 as a nucleoxadphile. A canyon-like cleft made up of several polar and nonpolar residue forms a putative binding site. Three-dimensional structure analysis, overview
additional information
human heparanase cDNA encodes the prepro-enzyme, which consists of 543 amino acid residues (65 kDa). Peptide cleavage of the prepro-enzyme at Ala35 generates the latent (pro-heparanase) 65 kDa heparanase. Proteolytic processing of the pro-enzyme removes a 6 kDa linker peptide (Ser110-Gln157), yielding an 8 kDa domain at the N-terminus (Gln36-Glu109) and a noncovalently linked 50 kDa catalytic domain with a lysine residue at the N-terminus (Lys158-Ile543). These two polypeptides form a heterodimer, which is the mature and active form of heparanase
additional information
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human heparanase cDNA encodes the prepro-enzyme, which consists of 543 amino acid residues (65 kDa). Peptide cleavage of the prepro-enzyme at Ala35 generates the latent (pro-heparanase) 65 kDa heparanase. Proteolytic processing of the pro-enzyme removes a 6 kDa linker peptide (Ser110-Gln157), yielding an 8 kDa domain at the N-terminus (Gln36-Glu109) and a noncovalently linked 50 kDa catalytic domain with a lysine residue at the N-terminus (Lys158-Ile543). These two polypeptides form a heterodimer, which is the mature and active form of heparanase
additional information
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chemical shift assignments, secondary structure and chemical shift deviations from random coil of the domain of human heparanase comprising residues Lys158-Lys417, overview
additional information
tertiary structure of enzyme HPSE, overview. The domain architecture of HPSE comprises a (beta/alpha)8 domain flanked by a smaller beta-sandwich domain. Both 8 kDa and 50 kDa subunits are structurally involved in both domains: the 8 kDa subunit contributes one beta-sheet to the beta-sandwich, and the 1st beta-alpha-beta fold of the (beta/alpha)8 domain, with the remaining folds contributed by the 50 kDa subunit
additional information
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tertiary structure of enzyme HPSE, overview. The domain architecture of HPSE comprises a (beta/alpha)8 domain flanked by a smaller beta-sandwich domain. Both 8 kDa and 50 kDa subunits are structurally involved in both domains: the 8 kDa subunit contributes one beta-sheet to the beta-sandwich, and the 1st beta-alpha-beta fold of the (beta/alpha)8 domain, with the remaining folds contributed by the 50 kDa subunit
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
proteolytic modification
glycoprotein
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synthesized as an inactive 65000 Da glycoprotein that is cleaved at the N-terminus to generate the active enzyme
glycoprotein
synthesized as an inactive 65000 Da glycoprotein that is cleaved at the N-terminus to generate the active enzyme
glycoprotein
enzyme HPSE contains 6 putative N-glycosylation sites, all residing on the 50 kDa subunit. N-linked GlcNAcs (corresponding to N-glycan trees trimmed by endoglycosidase (Endo)H during protein preparation) are found in the apo-HPSE structure at Asn162, Asn200, Asn217, Asn238 and Asn459. Additionally a core alpha1->6 linked fucose is located on the GlcNAc linked to Asn459. No noticeable density corresponding to GlcNAc is observed at the N-glycosylation site Asn178, suggesting this position may not be well N-glycosylated during baculoviral expression, or that N-GlcNAc here is not compatible with crystal packing
glycoprotein
glycosylation of the enzyme is fundamental for its transport through the endoplasmic reticulum and the Golgi apparatus and its secretion
glycoprotein
the enzyme has six putative N-glycosylation sites in its 50-kDa subunit. Glycosylation regulates enzyme secretion and endoplasmic reticulum-to-Golgi transport, but it is not required for enzymatic activity
proteolytic modification
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synthesized as an inactive 65000 Da glycoprotein that is cleaved at the N-terminus to generate the active enzyme
proteolytic modification
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the full-length chicken heparanase cDNA encodes a 60000 Da proenzyme that is processed at the N-terminus into a 45000 Da highly active enzyme. The signal peptide sequence accounts for the chicken heparanase being readily secreted and localized in close proximity to the cell surface
proteolytic modification
Hpa1 protein is initially synthesized as an inactive 65000 Da proenzyme and subsequently activated by proteolytic cleavage to generate an active heterodimer of 8000 Da and 50000 Da polypeptides
proteolytic modification
heparanase-1 is synthesized as an inactive precursor of about 65000 Da that subsequently undergoes proteolytic cleavage, yielding 8000 Da and 50000 Da protein subunits that heterodimerize to form the active enzyme. The protein contains a putative N-terminal signal peptide (Met1-Ala35) and a C-terminal hydrophobic region (Pro515-Ile534)
proteolytic modification
synthesized as an inactive 65000 Da glycoprotein that is cleaved at the N-terminus to generate the active enzyme
proteolytic modification
the 8000 Da and 50000 Da chains which make up the active enzyme reside, respectively, at the NH2-terminal and COOH-terminal regions of the inactive precursor, proheparanase. The heparanase heterodimer is produced by excision and loss of an internal linking segment
proteolytic modification
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the 65 kDa precursor polypeptide that is enzymatically inactive. Proteolytic excision by cathepsin L of a 48 amino acid peptide yields an active heterodimer comprising 8 and 50 kDa subunits
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
proteolytic modification
an endo-acting binding cleft is exposed by proteolytic activation of latent proenzyme, proHPSE. Enzyme HPSE is initially translated as a pre-proenzyme, containing a signal sequence spanning Met1-Ala35. Cleavage of this signal sequence by signal peptidase leaves an inactive 65 kDa proHPSE, which must undergo further processing for activity. Proteolytic removal by cathepsin L of a linker spanning Ser110-Gln157 liberates an N-terminal 8 kDa subunit and a C-terminal 50 kDa subunit, which remain associated as a non-covalent heterodimer in mature active HPSE29
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
wild-type enzyme BpHep, X-ray diffraction structure determination and analysis at 1.60 A resolution, PDB ID 5BWI
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purified recombinant heterodimeric wild-type apo-enzyme, X-ray diffraction structure determiantion and analysis at 1.75 A resolution
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
E144A
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site-directed mutagenesis, conserved active site residue mutant
E255A
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site-directed mutagenesis, conserved active site residue mutant
additional information
additional information
deletion mutants lacking heparin binding domains (Lys158-Asn162 or Gln270-Lys280) exhibit no enzymatic activity
additional information
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deletion mutants lacking heparin binding domains (Lys158-Asn162 or Gln270-Lys280) exhibit no enzymatic activity
additional information
the mutant P6 with 26 substitutions is thermostable and structurally isomorphous to compared to the wild type enzyme
additional information
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generation of Hpa-tg mice in which transgenic heparanase is driven by a constitutive beta-actin promoter in a BALB/c genetic background. The skin of Hpa-tg mice has normal appearance and is characterized by an enhanced hair re-growth, no differences in proliferation of interfollicular keratinocytes between healthy Hpa-tg and wild-type mice. Heparanase overexpression preserves psoriasislike phenotype in mouse skin following multiple 12-O-tetradecanoyl phorbol 12-myristate 13-acetate application
additional information
generation of heparanase-knockout (Hpa-KO) mice, reduced cytokine expression and motility of heparanase-deficient macrophages, phenotype, overview
additional information
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generation of Hpa-tg mice in which transgenic heparanase is driven by a constitutive beta-actin promoter in a BALB/c genetic background. The skin of Hpa-tg mice has normal appearance and is characterized by an enhanced hair re-growth, no differences in proliferation of interfollicular keratinocytes between healthy Hpa-tg and wild-type mice. Heparanase overexpression preserves psoriasislike phenotype in mouse skin following multiple 12-O-tetradecanoyl phorbol 12-myristate 13-acetate application
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additional information
a splice variant of the Spalax enzyme lacking 16 aa encoded by exon 7. This deletion results in a major defect in trafficking and processing of the heparanase protein, leading to a loss of its enzymatic activity
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
4°C, loss of 50% activity after storage for 1 year, recombinantly expressed enzyme
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
Ni-NTA column chromatography, heparin column chromatography, and Superdex 200 gel filtration
purifiecation of the His-tagged smaller subunit fragment of the human heparanase to homogeneity by immobilized metal affinity chromatography and dialysis from Escherichia coli strain BL21 (DE3)plysS
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recombinant GST-tagged enzyme from Escherichia coli strain BL21 by glutathione affinity chromatography
recombinant His-tagged enzyme from Escherichia coli BL21-DE3 codon plus by metal affinity chromatography
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recombinant myc-DDK-tagged proheparanase partially by tangential ultrafiltration
recombinant N-terminally His-tagged truncated enzyme form from Escherichia coli strain BL21-CodonPlus (DE3)-RIL by nickel affinity chromatography and dialysis
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression of an N-terminally His-tagged truncated enzyme form, residues 36-543, containing a TEV protease cleavage site, in Escherichia coli strain BL21-CodonPlus (DE3)-RIL
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expression of the cloned cDNA in insect and mammalian cells yields 65000 Da and 50000 Da recombinant heparanase proteins. The 50000 Da enzyme represents an N-terminally processed enzyme, at least 100fold more active than the 65000 Da form
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expression of the enzyme in Spodoptera frugiperda Sf9 cells and secretion to the cell culture medium
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insect cell expression system is used for the generation of large amounts of recombinant protein of high specific activity. Individual subunits are cloned into baculoviral secretory vectors and coexpressed in insect cells
NIH3T3 and COS-7 cells stably transfected with pBK-CMV expression vectors
recombinant expression of GST-tagged enzyme from vector pGEX-2TK-heparanase in Escherichia coli strain BL21
recombinant expression of His-tagged smaller 8 kDa subunit in Escherichia coli strain BL21 (DE3)plysS
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recombinant expression of the His-tagged enzyme from pET-15b expression vector containing a TEV cleavage site in Escherichia coli BL21-DE3 codon plus
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single gene, recombinant expression in Spodoptera frugiperda cells via baculovrius transfection method. The two subunits cotranslationally fold into mature heterodimeric HPSE, bypassing the 65 kDa proenzyme form and ensuring expression of only active enzyme
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
bovine serum albumin and advanced glycation end-product, but not high glucose levels, increase heparanase expression in adult tubular cells via the AKT/PI3K signaling pathway 1.68 and 2.81times, respectively
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expression is up-regulated as tumors become more aggressive and is associated with enhanced tumor growth, angiogenesis, and metastasis
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expression of the enzyme heparanase is clearly linked to colon carcinoma progression
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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
heparanase is up-regulated in essentially all human tumors examined. Oxidized lipid- or angiotensin-induced expression of heparanase in macrophages may be a primary mechanism increasing heparanase in atherosclerotic plaques
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heparanase variant T5 expression is up-regulated in 75% of human renal cell carcinoma biopsies
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in patients with severe acute respiratory distress syndrome, an increase in the enzyme activity on day 1 and day 3 is observed when compared to patients with moderate and mild acute respiratory distress syndrome. Unlike with heparanase activity, there is no increase in heparanase levels with an increase in acute respiratory distress syndrome severity
phorbol 12-myristate 13-acetate/calcium ionomycin stimulation results in a substantial increase in nuclear heparanase in the 53 kDa active form
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plasma heparanase activity is significantly elevated in coronavirus disease-2019 patients
sepsis-associated inflammatory lung disease causes rapid induction of heparanase activity through a TNFlpha-dependent mechanism in pulmonary microvascular endothelial cells. Heparanase induction is also found in biopsies of human inflammatory lung disease
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the overall transcriptional activity of the main heparan sulfate biosynthesis-involved genes (EXT1, EXT2, NDST1, NDST2, GLCE, HS2ST1, HS3ST1, HS3ST2, HS6ST1, HS6ST2, SULF1, SULF2, HPSE) is decreased by 1.5-2fold in Grade II-III glioma (p < 0.01) and by 3-fold in Grade IV glioma (glioblastoma multiforme, GBM) (p < 0.05), as compared with the para-tumourous tissue
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
analysis
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
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
drug development
medicine
pharmacology
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targeting enzymes that degrade heparan sulfate proteoglycans highlights one approach to maintain normal tissue architecture, inhibit tumor progression, and block metastasis
drug development
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heparanase is an important target for anti-cancer and anti-inflammatory drug discovery
drug development
the natural heparan sulfate-heparanase interactions are used as a template for the design of heparan sulfate-mimicking glycopolymers
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
drug development
the upregulation of heparanase expression increases tumor size, angiogenesis, and metastasis, represents a validated target in the anti-cancer field. 2-(4-(4-(bromo-methoxybenzamido)benzylamino)phenyl) benzazole derivatives act as anti-heparanase agents, proposing this scaffold for development of broadly effective heparanase inhibitors. Symmetrical 2-aminophenyl benzazolyl-5-acetate derivatives, proving that symmetrical compounds, are more effective than asymmetrical analogues
drug development
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overexpression of hepaxadranase in cancers is well known and is associated with angiogenesis, inflammation and increased metastatic potential, making this enzyme a promising drug target
drug development
the emerging role of heparanase in tumor initiation, growth, metastasis, and chemoresistance is well recognized and is encouraging the development of heparanase inhibitors as anticancer drugs for humans
medicine
heparanase-1 is an approach towards developing new therapeutics suitable for the treatment of cancer or inflammatory diseases. The identification of only a single predominant functional heparanase suggests that if its activity can be inhibited, other heparanases may not be available to cover for it. Heparanase-inhibiting compounds might interfere with physiological processes such as wound healing and tissue-repair
medicine
upregulation of heparanase may be a novel therapeutic approach in the prevention and treatment of osteoporosis
medicine
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increased heparanase levels are most often associated with reduced patient survival post operation, increased tumor metastasis and higher microvessel density
medicine
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specific inhibitors for heparanase are important for suppression of tumor progression and metastasis
medicine
enzyme inhibition is a therapeutic option to prevent glycocalyx degradation
medicine
the enzyme activity is strongly associated with major human pathological complications, including but not limited to tumor progress, angiogenesis and inflammation, which make the enzyme a valuable therapeutic target
medicine
the enzyme is a pharmacological target in prostate cancer treatment
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Bame, K.J.; Hassall, A.; Sanderson, C.; Venkatesan, I.; Sun, C.
Partial purification of heparanase activities in Chinese hamster ovary cells: evidence for multiple intracellular heparanases
Biochem. J.
336
191-200
1998
Cricetulus griseus
brenda
McKenzie, E.; Young, K.; Hircock, M.; Bennett, J.; Bhaman, M.; Felix, R.; Turner, P.; Stamps, A.; McMillan, D.; Saville, G.; Ng, S.; Mason, S.; Snell, D.; Schofield, D.; Gong, H.; Townsend, R.; Gallagher, J.; Page, M.; Parekh, R.; Stubberfield, C.
Biochemical characterization of the active heterodimer form of human heparanase (Hpa1) protein expressed in insect cells
Biochem. J.
373
423-435
2003
Homo sapiens (Q9Y251), Homo sapiens
brenda
Hulett, M.D.; Hornby, J.R.; Ohms, S.J.; Zuegg, J.; Freeman, C.; Gready, J.E.; Parish, C.R.
Identification of active-site residues of the pro-metastatic endoglycosidase heparanase
Biochemistry
39
15659-15667
2000
Homo sapiens (Q9Y251), Homo sapiens
brenda
Zhao, H.; Liu, H.; Chen, Y.; Xin, X.; Li, J.; Hou, Y.; Zhang, Z.; Zhang, X.; Xie, C.; Geng, M.; Ding, J.
Oligomannurarate sulfate, a novel heparanase inhibitor simultaneously targeting basic fibroblast growth factor, combats tumor angiogenesis and metastasis
Cancer Res.
66
8779-8787
2006
Homo sapiens (Q9Y251)
brenda
Klipper, E.; Tatz, E.; Kisliouk, T.; Vlodavsky, I.; Moallem, U.; Schams, D.; Lavon, Y.; Wolfenson, D.; Meidan, R.
Induction of heparanase in bovine granulosa cells by luteinizing hormone: possible role during the ovulatory process
Endocrinology
150
413-421
2009
Bos taurus
brenda
Bame, K.J.
Heparanases: endoglycosidases that degrade heparan sulfate proteoglycans
Glycobiology
11
91R-98R
2001
Homo sapiens (Q9Y251), Cricetulus griseus
brenda
Dredge, K.; Hammond, E.; Davis, K.; Li, C.P.; Liu, L.; Johnstone, K.; Handley, P.; Wimmer, N.; Gonda, T.J.; Gautam, A.; Ferro, V.; Bytheway, I.
The PG500 series: novel heparan sulfate mimetics as potent angiogenesis and heparanase inhibitors for cancer therapy
Invest. New Drugs
28
276-283
2010
Homo sapiens (Q9Y251)
brenda
Pikas, D.S.; Li, J.P.; Vlodavsky, I.; Lindahl, U.
Substrate specificity of heparanases from human hepatoma and platelets
J. Biol. Chem.
273
18770-18777
1998
Homo sapiens (Q9Y251), Homo sapiens
brenda
Toyoshima, M.; Nakajima, M.
Human heparanase. Purification, characterization, cloning, and expression
J. Biol. Chem.
274
24153-24160
1999
Homo sapiens (Q9Y251), Homo sapiens
brenda
Fairbanks, M.B.; Mildner, A.M.; Leone, J.W.; Cavey, G.S.; Mathews, W.R.; Drong, R.F.; Slightom, J.L.; Bienkowski, M.J.; Smith, C.W.; Bannow, C.A.; Heinrikson, R.L.
Processing of the human heparanase precursor and evidence that the active enzyme is a heterodimer
J. Biol. Chem.
274
29587-29590
1999
Homo sapiens (Q9Y251), Homo sapiens
brenda
Goldshmidt, O.; Zcharia, E.; Aingorn, H.; Guatta-Rangini, Z.; Atzmon, R.; Michal, I.; Pecker, I.; Mitrani, E.; Vlodavsky, I.
Expression pattern and secretion of human and chicken heparanase are determined by their signal peptide sequence
J. Biol. Chem.
276
29178-29187
2001
Gallus gallus
brenda
Okada, Y.; Yamada, S.; Toyoshima, M.; Dong, J.; Nakajima, M.; Sugahara, K.
Structural recognition by recombinant human heparanase that plays critical roles in tumor metastasis. Hierarchical sulfate groups with different effects and the essential target disulfated trisaccharide sequence
J. Biol. Chem.
277
42488-42495
2002
Homo sapiens (Q9Y251), Homo sapiens
brenda
Gong, F.; Jemth, P.; Escobar Galvis, M.L.; Vlodavsky, I.; Horner, A.; Lindahl, U.; Li, J.P.
Processing of macromolecular heparin by heparanase
J. Biol. Chem.
278
35152-35158
2003
Homo sapiens (Q9Y251), Homo sapiens
brenda
Levy-Adam, F.; Abboud-Jarrous, G.; Guerrini, M.; Beccati, D.; Vlodavsky, I.; Ilan, N.
Identification and characterization of heparin/heparan sulfate binding domains of the endoglycosidase heparanase
J. Biol. Chem.
280
20457-20466
2005
Homo sapiens (Q9Y251), Homo sapiens
brenda
Vreys, V.; David G.
Mammalian heparanase: what is the message?
J. Cell. Mol. Med.
11
427-452
2007
Homo sapiens (Q9Y251)
brenda
Bernard, D.; Mehul, B.; Delattre, C.; Simonetti, L.; Thomas-Collignon, A.; Schmidt, R.
Purification and characterization of the endoglycosidase heparanase 1 from human plantar stratum corneum: a key enzyme in epidermal physiology?
J. Invest. Dermatol.
117
1266-1273
2001
Homo sapiens
brenda
Navarro, F.P.; Fares, R.P.; Sanchez, P.E.; Nadam, J.; Georges, B.; Moulin, C.; Morales, A.; Pequignot, J.M.; Bezin, L.
Brain heparanase expression is up-regulated during postnatal development and hypoxia-induced neovascularization in adult rats
J. Neurochem.
105
34-45
2008
Rattus norvegicus
brenda
Schubert, S.Y.; Ilan, N.; Shushy, M.; Ben-Izhak, O.; Vlodavsky, I.; Goldshmidt, O.
Human heparanase nuclear localization and enzymatic activity
Lab. Invest.
84
535-544
2004
Homo sapiens (Q9Y251), Homo sapiens, Rattus norvegicus
brenda
Vlodavsky, I.; Friedmann, Y.; Elkin, M.; Aingorn, H.; Atzmon, R.; Ishai-Michaeli, R.; Bitan, M.; Pappo, O.; Peretz, T.; Michal, I.; Spector, L.; Pecker, I.
Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis
Nat. Med.
5
793-802
1999
Homo sapiens
brenda
Nasser, N.J.; Nevo, E.; Shafat, I.; Ilan, N.; Vlodavsky, I.; Avivi, A.
Adaptive evolution of heparanase in hypoxia-tolerant Spalax: gene cloning and identification of a unique splice variant
Proc. Natl. Acad. Sci. USA
102
15161-15166
2005
Nannospalax judaei (Q333X5), Nannospalax galili
brenda
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
Protein Expr. Purif.
26
425-431
2002
Mus musculus
brenda
Miles, J.R.; Vallet, J.L.; Freking, B.A.; Nonneman, D.J.
Molecular cloning and characterisation of heparanase mRNA in the porcine placenta throughout gestation
Reprod. Fertil. Dev.
21
757-772
2009
Sus scrofa
brenda
Hammond, E.; Li, C.P.; Ferro, V.
Development of a colorimetric assay for heparanase activity suitable for kinetic analysis and inhibitor screening
Anal. Biochem.
396
112-116
2009
Homo sapiens (Q9Y251)
brenda
Poon, I.K.; Yee, D.Y.; Jones, A.L.; Wood, R.J.; Davis, D.S.; Freeman, C.; Parish, C.R.; Hulett, M.D.
Histidine-rich glycoprotein binds heparanase and regulates its enzymatic activity and cell surface interactions
Int. J. Biochem. Cell Biol.
42
1507-1516
2010
Homo sapiens (Q9Y251)
brenda
Peterson, S.B.; Liu, J.
Unraveling the specificity of heparanase utilizing synthetic substrates
J. Biol. Chem.
285
14504-14513
2010
Homo sapiens (Q9Y251)
brenda
Smith, P.N.; Freeman, C.; Yu, D.; Chen, M.; Gatenby, P.A.; Parish, C.R.; Li, R.W.
Heparanase in primary human osteoblast
J. Orthop. Res.
28
1315-1322
2010
Homo sapiens (Q9Y251), Homo sapiens
brenda
Zheng, L.D.; Jiang, G.S.; Pu, J.R.; Mei, H.; Dong, J.H.; Hou, X.H.; Tong, Q.S.
Stable knockdown of heparanase expression in gastric cancer cells in vitro
World J. Gastroenterol.
15
5442-5448
2009
Homo sapiens (Q9Y251), Homo sapiens
brenda
Cui, H.; Shao, C.; Liu, Q.; Yu, W.; Fang, J.; Yu, W.; Ali, A.; Ding, K.
Heparanase enhances nerve growth factor induced PC12 cell neuritogenesis via the p38 MAPK pathway
Biochem. J.
440
273-282
2011
Rattus norvegicus
brenda
Masola, V.; Gambaro, G.; Tibaldi, E.; Onisto, M.; Abaterusso, C.; Lupo, A.
Regulation of heparanase by albumin and advanced glycation end products in proximal tubular cells
Biochim. Biophys. Acta
1813
1475-1482
2011
Homo sapiens
brenda
Zhang, Y.; Ryan, D.; Bower, K.; Ilan, N.; Vlodavsky, I.; Laurie, G.
Focus on molecules: Heparanase
Exp. Eye Res.
91
476-477
2010
Homo sapiens (Q9Y251)
brenda
Barash, U.; Cohen-Kaplan, V.; Arvatz, G.; Gingis-Velitski, S.; Levy-Adam, F.; Nativ, O.; Shemesh, R.; Ayalon-Sofer, M.; Ilan, N.; Vlodavsky, I.
A novel human heparanase splice variant, T5, endowed with protumorigenic characteristics
FASEB J.
24
1239-1248
2010
Homo sapiens
brenda
Barash, U.; Cohen-Kaplan, V.; Dowek, I.; Sanderson, R.D.; Ilan, N.; Vlodavsky, I.
Proteoglycans in health and disease: new concepts for heparanase function in tumor progression and metastasis
FEBS J.
277
3890-3903
2010
Homo sapiens
brenda
Miller, J.D.; Clabaugh, S.E.; Smith, D.R.; Stevens, R.B.; Wrenshall, L.E.
Interleukin-2 is present in human blood vessels and released in biologically active form by heparanase
Immunol. Cell Biol.
90
159-167
2012
Homo sapiens
brenda
Levy-Adam, F.; Feld, S.; Cohen-Kaplan, V.; Shteingauz, A.; Gross, M.; Arvatz, G.; Naroditsky, I.; Ilan, N.; Doweck, I.; Vlodavsky, I.
Heparanase 2 interacts with heparan sulfate with high affinity and inhibits heparanase activity
J. Biol. Chem.
285
28010-28019
2010
Homo sapiens
brenda
Ramani, V.C.; Yang, Y.; Ren, Y.; Nan, L.; Sanderson, R.D.
Heparanase plays a dual role in driving hepatocyte growth factor (HGF) signaling by enhancing HGF expression and activity
J. Biol. Chem.
286
6490-6499
2011
Homo sapiens
brenda
Lerner, I.; Hermano, E.; Zcharia, E.; Rodkin, D.; Bulvik, R.; Doviner, V.; Rubinstein, A.M.; Ishai-Michaeli, R.; Atzmon, R.; Sherman, Y.; Meirovitz, A.; Peretz, T.; Vlodavsky, I.; Elkin, M.
Heparanase powers a chronic inflammatory circuit that promotes colitis-associated tumorigenesis in mice
J. Clin. Invest.
121
1709-1721
2011
Homo sapiens
brenda
Bitan, M.; Weiss, L.; Reibstein, I.; Zeira, M.; Fellig, Y.; Slavin, S.; Zcharia, E.; Nagler, A.; Vlodavsky, I.
Heparanase upregulates Th2 cytokines, ameliorating experimental autoimmune encephalitis
Mol. Immunol.
47
1890-1898
2010
Mus musculus
brenda
Planer, D.; Metzger, S.; Zcharia, E.; Wexler, I.D.; Vlodavsky, I.; Chajek-Shaul, T.
Role of heparanase on hepatic uptake of intestinal derived lipoprotein and fatty streak formation in mice
PLoS ONE
6
e18370
2011
Homo sapiens
brenda
Wilson, J.C.; Laloo, A.E.; Singh, S.; Ferro, V.
1H NMR spectroscopic studies establish that heparanase is a retaining glycosidase
Biochem. Biophys. Res. Commun.
443
185-188
2014
Homo sapiens
brenda
Fernandes dos Santos, T.C.; Gomes, A.M.; Paschoal, M.E.; Stelling, M.P.; Rumjanek, V.M.; Junior, A.d.o.R.; Valiante, P.M.; Madi, K.; Pereira de Souza, H.S.; Pavao, M.S.; Castelo-Branco, M.T.
Heparanase expression and localization in different types of human lung cancer
Biochim. Biophys. Acta
1840
2599-2608
2014
Homo sapiens
brenda
Masola, V.; Zaza, G.; Secchi, M.F.; Gambaro, G.; Lupo, A.; Onisto, M.
Heparanase is a key player in renal fibrosis by regulating TGF-beta expression and activity
Biochim. Biophys. Acta
1843
2122-2128
2014
Homo sapiens
brenda
Mosulen, S.; Pineda-Lucena, A.; Carbajo, R.J.
Chemical shift assignments and secondary structure of the surrogate domain for drug discovery studies of human heparanase
Biomol. NMR Assign.
9
15-19
2014
Homo sapiens
brenda
Gozalbes, R.; Mosulen, S.; Orti, L.; Rodriguez-Diaz, J.; Carbajo, R.J.; Melnyk, P.; Pineda-Lucena, A.
Hit identification of novel heparanase inhibitors by structure- and ligand-based approaches
Bioorg. Med. Chem.
21
1944-1951
2013
Homo sapiens
brenda
Winkler, S.; Schweiger, D.; Wei, Z.; Rajkovic, E.; Kungl, A.J.
Bacterial expression and functional reconstitution of human heparanase
Carbohydr. Res.
389
72-77
2014
Homo sapiens
brenda
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
Cell. Mol. Life Sci.
71
2347-2357
2014
Homo sapiens, Mus musculus, Mus musculus BALB/c
brenda
Ohmae, M.; Fujita, Y.; Takada, J.; Kimura, S.
Development of novel inhibitors specific for human heparanase-1
Chem. Lett.
42
797-798
2013
Homo sapiens
-
brenda
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
3
346-351
2013
Homo sapiens
brenda
Hammond, E.; Khurana, A.; Shridhar, V.; Dredge, K.
The role of heparanase and sulfatases in the modification of heparan sulfate proteoglycans within the tumour microenvironment and opportunities for novel cancer therapeutics
Front. Oncol.
4
195
2014
Homo sapiens
brenda
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)
Glycobiology
22
35-55
2012
Homo sapiens (Q9Y251), Homo sapiens
brenda
Thompson, C.A.; Purushothaman, A.; Ramani, V.C.; Vlodavsky, I.; Sanderson, R.D.
Heparanase regulates secretion, composition, and function of tumor cell-derived exosomes
J. Biol. Chem.
288
10093-10099
2013
Homo sapiens
brenda
Peterson, S.B.; Liu, J.
Multi-faceted substrate specificity of heparanase
Matrix Biol.
32
223-227
2013
Mammalia
brenda
Goldberg, R.; Meirovitz, A.; Hirshoren, N.; Bulvik, R.; Binder, A.; Rubinstein, A.M.; Elkin, M.
Versatile role of heparanase in inflammation
Matrix Biol.
32
234-240
2013
Mammalia
brenda
Vlodavsky, I.; Blich, M.; Li, J.P.; Sanderson, R.D.; Ilan, N.
Involvement of heparanase in atherosclerosis and other vessel wall pathologies
Matrix Biol.
32
241-251
2013
Homo sapiens
brenda
Qin, Q.; Niu, J.; Wang, Z.; Xu, W.; Qiao, Z.; Gu, Y.
Astragalus embranaceus extract activates immune response in macrophages via heparanase
Molecules
17
7232-7240
2012
Mus musculus
brenda
He, Y.Q.; Sutcliffe, E.L.; Bunting, K.L.; Li, J.; Goodall, K.J.; Poon, I.K.; Hulett, M.D.; Freeman, C.; Zafar, A.; McInnes, R.L.; Taya, T.; Parish, C.R.; Rao, S.
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
3
130-145
2012
Homo sapiens
brenda
Melo, C.M.; Tersariol, I.L.; Nader, H.B.; Pinhal, M.A.; Lima, M.A.
Development of new methods for determining the heparanase enzymatic activity
Carbohydr. Res.
412
66-70
2015
Homo sapiens (Q9Y251)
brenda
Loka, R.S.; Yu, F.; Sletten, E.T.; Nguyen, H.M.
Design, synthesis, and evaluation of heparan sulfate mimicking glycopolymers for inhibiting heparanase activity
Chem. Commun. (Camb.)
53
9163-9166
2017
Homo sapiens (Q9Y251)
brenda
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
Drug Resist. Updat.
29
54-75
2016
Homo sapiens (Q9Y251), Homo sapiens
brenda
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.
Novel symmetrical benzazolyl derivatives endowed with potent anti-heparanase activity
J. Med. Chem.
61
10834-10859
2018
Homo sapiens (Q9Y251)
brenda
Bohlmann, L.; Tredwell, G.D.; Yu, X.; Chang, C.W.; Haselhorst, T.; Winger, M.; Dyason, J.C.; Thomson, R.J.; Tiralongo, J.; Beacham, I.R.; Blanchard, H.; von Itzstein, M.
Functional and structural characterization of a heparanase
Nat. Chem. Biol.
11
955-957
2015
Burkholderia pseudomallei
brenda
Wu, L.; Viola, C.M.; Brzozowski, A.M.; Davies, G.J.
Structural characterization of human heparanase reveals insights into substrate recognition
Nat. Struct. Mol. Biol.
22
1016-1022
2015
Homo sapiens (Q9Y251), Homo sapiens
brenda
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
11
e0157834
2016
Homo sapiens (Q9Y251)
brenda
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
113
E7808-E7817
2016
Mus musculus (Q6YGZ1)
brenda
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
Int. J. Mol. Sci.
18
2301
2017
Homo sapiens (Q9Y251)
brenda
Wu, L.; Wimmer, N.; Davies, G.J.; Ferro, V.
Structural insights into heparanase activity using a fluorogenic heparan sulfate disaccharide
Chem. Commun. (Camb.)
56
13780-13783
2020
Homo sapiens (Q9Y251)
brenda
Yuan, F.; Yang, Y.; Zhou, H.; Quan, J.; Liu, C.; Wang, Y.; Zhang, Y.; Yu, X.
Heparanase in cancer progression Structure, substrate recognition and therapeutic potential
Front. Chem.
10
926353
2022
Homo sapiens (Q9Y251), Burkholderia pseudomallei
brenda
Buijsers, B.; Yanginlar, C.; de Nooijer, A.; Grondman, I.; Maciej-Hulme, M.L.; Jonkman, I.; Janssen, N.A.F.; Rother, N.; de Graaf, M.; Pickkers, P.; Kox, M.; Joosten, L.A.B.; Nijenhuis, T.; Netea, M.G.; Hilbrands, L.; van de Veerdonk, F.L.; Duivenvoorden, R.; de Mast, Q.; van der Vlag, J.
Increased plasma heparanase activity in COVID-19 patients
Front. Immunol.
11
575047
2020
Homo sapiens (Q9Y251)
brenda
Masola, V.; Franchi, M.; Zaza, G.; Atsina, F.M.; Gambaro, G.; Onisto, M.
Heparanase regulates EMT and cancer stem cell properties in prostate tumors
Front. Oncol.
12
918419
2022
Homo sapiens (Q9Y251)
brenda
Yu, Y.; Williams, A.; Zhang, X.; Fu, L.; Xia, K.; Xu, Y.; Zhang, F.; Liu, J.; Koffas, M.; Linhardt, R.J.
Specificity and action pattern of heparanase Bp, a beta-glucuronidase from Burkholderia pseudomallei
Glycobiology
29
572-581
2019
Burkholderia pseudomallei
brenda
Zechendorf, E.; Schroeder, K.; Stiehler, L.; Frank, N.; Beckers, C.; Kraemer, S.; Dreher, M.; Kersten, A.; Thiemermann, C.; Marx, G.; Simon, T.P.; Martin, L.
The potential impact of heparanase activity and endothelial damage in COVID-19 disease
J. Clin. Med.
11
5261
2022
Homo sapiens (Q9Y251)
brenda
Zhu, S.; Li, J.; Loka, R.S.; Song, Z.; Vlodavsky, I.; Zhang, K.; Nguyen, H.M.
Modulating heparanase activity Tuning sulfation pattern and glycosidic linkage of oligosaccharides
J. Med. Chem.
63
4227-4255
2020
Homo sapiens (Q9Y251)
brenda
Shi, X.; Guan, R.; Zhou, L.; Zuo, Z.; Tao, X.; Wang, P.; Zhou, Y.; Yin, R.; Zhao, L.; Gao, N.; Zhao, J.
Structural characterization and heparanase inhibitory activity of fucosylated glycosaminoglycan from Holothuria floridana
Mar. Drugs
19
162
2021
Homo sapiens (Q9Y251)
brenda
Masola, V.; Greco, N.; Gambaro, G.; Franchi, M.; Onisto, M.
Heparanase as active player in endothelial glycocalyx remodeling
Matrix Biol. Plus
13
100097
2022
Homo sapiens (Q9Y251)
brenda
Hammond, E.; Ferro, V.
An enzymatic activity assay for heparanase that is useful for evaluating clinically relevant inhibitors and studying kinetics
Methods Mol. Biol.
2619
227-238
2023
Homo sapiens (Q9Y251)
brenda
Whitefield, C.; Hong, N.; Mitchell, J.A.; Jackson, C.J.
Computational design and experimental characterisation of a stable human heparanase variant
RSC Chem. Biol.
3
341-349
2022
Homo sapiens (Q9Y251)
brenda
Gu, Y.; Peng, L.; Ding, W.; Wang, Y.; Zeng, X.
An ultrasensitive FRET-based fluorescent low molecular weight heparin nanoprobe for quantifying heparanase activity
Talanta
254
124207
2023
Homo sapiens
brenda
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