Information on EC 3.2.1.166 - heparanase

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The enzyme appears in viruses and cellular organisms

EC NUMBER
COMMENTARY hide
3.2.1.166
-
RECOMMENDED NAME
GeneOntology No.
heparanase
-
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
endohydrolysis of (1->4)-beta-D-glycosidic bonds of heparan sulfate chains in heparan sulfate proteoglycan
show the reaction diagram
PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
Glycosaminoglycan degradation
-
-
Metabolic 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].
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
malfunction
metabolism
-
key enzymes sulfatases and heparanase of the pathway actively influence cancer cell proliferation, signaling, invasion, and metastasis
physiological function
additional information
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
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
show the reaction diagram
-
more than 95% cleavage
-
-
?
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid 2-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-IdoUA-(beta-1,4)-GlcNAc-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-3-O-sulfate-6-O-sulfate + H2O
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid 2-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-IdoUA-(beta-1,4)-GlcNAc-6-O-sulfate-(alpha-1,4)-GlcUA + GlcN-2-N-sulfate-3-O-sulfate-6-O-sulfate
show the reaction diagram
-
26% cleavage
-
-
?
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid 2-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-IdoUA-(beta-1,4)-GlcNAc-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate + H2O
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid 2-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-IdoUA-(beta-1,4)-GlcNAc-6-O-sulfate-(alpha-1,4)-GlcUA + GlcN-2-N-sulfate-6-O-sulfate
show the reaction diagram
-
85% cleavage
-
-
?
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate + H2O
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-GlcUA + GlcN-2-N-sulfate-6-O-sulfate
show the reaction diagram
-
40% cleavage
-
-
?
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate + H2O
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-GlcUA + GlcN-2-N-sulfate-6-O-sulfate
show the reaction diagram
-
more than 95% cleavage
-
-
?
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-(beta-1,4)-GlcNAc-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-3-O-sulfate + H2O
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-(beta-1,4)-GlcNAc-6-O-sulfate-(alpha-1,4)-GlcUA + GlcN-2-N-sulfate-3-O-sulfate
show the reaction diagram
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21% cleavage
-
-
?
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-2-O-sulfate-(beta-1,4)-GlcN-2-N-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate + H2O
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-2-O-sulfate-(beta-1,4)-GlcN-2-N-sulfate-(alpha-1,4)-GlcUA + GlcN-2-N-sulfate-6-O-sulfate
show the reaction diagram
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44% cleavage
-
-
?
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-2-O-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate + H2O
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-2-O-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-GlcUA + GlcN-2-N-sulfate-6-O-sulfate
show the reaction diagram
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more than 95% cleavage
-
-
?
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-2-O-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-IdoUA-(beta-1,4)-GlcNAc-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate + H2O
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-2-O-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-IdoUA-(beta-1,4)-GlcNAc-6-O-sulfate-(alpha-1,4)-GlcUA + GlcN-2-N-sulfate
show the reaction diagram
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59% cleavage
-
-
?
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-2-O-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-IdoUA-(beta-1,4)-GlcNAc-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-3-O-sulfate + H2O
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-2-O-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-IdoUA-(beta-1,4)-GlcNAc-6-O-sulfate-(alpha-1,4)-GlcUA + GlcN-2-N-sulfate-3-O-sulfate
show the reaction diagram
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60% cleavage
-
-
?
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-2-O-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-IdoUA-2-O-sulfate-(beta-1,4)-GlcNAc-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate + H2O
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-2-O-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-IdoUA-2-O-sulfate-(beta-1,4)-GlcNAc-(alpha-1,4)-GlcUA + GlcN-2-N-sulfate-6-O-sulfate
show the reaction diagram
-
30% cleavage
-
-
?
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-2-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-GlcUA-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate + H2O
4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid-2-sulfate-(beta-1,4)-GlcN-2-N-sulfate-6-O-sulfate-(alpha-1,4)-GlcUA + GlcN-2-N-sulfate-6-O-sulfate
show the reaction diagram
-
56% cleavage
-
-
?
extracellular matrix + H2O
?
show the reaction diagram
-
-
-
-
?
fondaparinux + H2O
2N-sulfo-6-O-sulfo-alpha-D-GlcN-(1->4)-beta-GlcA + a trisaccharide
show the reaction diagram
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a pentasaccharide substrate, heparanase is a retaining glycosidase, NMR spectroscopic analysis, overview
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-
?
fondaparinux + H2O
?
show the reaction diagram
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-
-
-
?
heparan sulfate + H2O
?
show the reaction diagram
heparan sulfate + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
show the reaction diagram
-
catalytic mechanism that involves two conserved acidic residues, a putative proton donor at Glu225 and a nucleophile at Glu343
-
-
?
heparan sulfate proteoglycan + H2O
?
show the reaction diagram
heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
show the reaction diagram
heparan sulfate proteolycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
show the reaction diagram
-
-
-
-
?
heparan sulphate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
show the reaction diagram
-
-
-
?
heparansulfate proteoglycan + H2O
?
show the reaction diagram
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-
-
-
?
heparin + H2O
?
show the reaction diagram
heparin octasaccharide + H2O
?
show the reaction diagram
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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
?
show the reaction diagram
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cleavage to 5000 Da oligosaccharides
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-
?
insulin-like growth factor 2 receptor + H2O
?
show the reaction diagram
-
-
-
-
?
low density receptor-related protein-1 + H2O
?
show the reaction diagram
-
-
-
-
?
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
show the reaction diagram
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i.e. fondaparinux
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-
?
sulfated PG545 + H2O
?
show the reaction diagram
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-
-
-
?
sulfated trisaccharide from PG545 + H2O
?
show the reaction diagram
-
-
-
-
?
syndecan-1 + H2O
?
show the reaction diagram
[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
show the reaction diagram
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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
show the reaction diagram
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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
show the reaction diagram
-
heparanase does not cleave the linkage of GlcA2S-GlcNS but rather cleaves the linkage of GlcA-GlcNS nearby
-
-
?
additional information
?
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
heparan sulfate + H2O
?
show the reaction diagram
-
heparanase is a strict endo-beta-glucuronidase with no exolytic glucuronidase activity. The enzyme only cleaves the glycosidic bond in the middle of the substrate. Heparan sulfate is a polysaccharide that has the disaccharide repeating unit of glucuronic acid or iduronic acid and glucosamine. Certain parts of heparan sulfate are occupied by the repeating disaccharide of -GlcA-GlcNAc-, known as the lowly sulfated domain. Other parts of HS are dominated by the highly sulfated disaccharide repeating unit of GlcA-GlcNS3S6S-IdoA2SGlcNS6S-, known as highly sulfated domain, overview
-
-
?
heparan sulfate proteoglycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
show the reaction diagram
heparan sulfate proteolycan + H2O
heparan sulfate fragment + truncated heparan sulfate proteoglycan
show the reaction diagram
-
-
-
-
?
syndecan-1 + H2O
?
show the reaction diagram
-
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
?
-
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(2E)-N-(3,4-dichlorophenyl)-3-[3-fluoro-4-[5-(2-oxopropyl)-1,3-benzoxazol-2-yl]phenyl]prop-2-enamide
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(3R,5S)-8-nonyl-9-oxo-1,6-dioxaspiro[4.4]non-7-ene-2,2,3-tricarboxylic acid
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(3S,4S,5R,6R)-4,5-dihydroxy-6-[(trifluoroacetyl)amino]piperidine-3-carboxylic acid
-
-
(3S,4S,5R,6R)-6-(acetylamino)-4,5-dihydroxypiperidine-3-carboxylic acid
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(5R)-3-heptadecanoyl-5-(hydroxymethyl)-4-methoxyfuran-2(5H)-one
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(5R)-4-(benzyloxy)-3-heptadecanoyl-5-(hydroxymethyl)furan-2(5H)-one
-
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(5S)-8-nonyl-9-oxo-1,6-dioxaspiro[4.4]non-7-ene-2,2,3-tricarboxylic acid
-
-
(IdoA2S-GlcNS)n
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polysaccharide containing IdoA2S-GlcNS repeating unit, inhibits the activity of heparanase
1,3-bis[4-(1H-benzimidazol-2-yl)phenyl]urea
-
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1,3-bis[4-(5,6-dimethyl-1H-benzimidazol-2-yl)phenyl]urea
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1-[2-([3-[(7-chloroquinolin-4-yl)amino]-5-(hydroxymethyl)benzyl]amino)prop-2-en-1-yl]piperidin-4-ol
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1-[3-[(7-chloroquinolin-4-yl)amino]-5-([[3-(piperidin-1-yl)prop-1-en-2-yl]amino]methyl)benzyl]piperidin-4-ol
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2-[(3-[4-[3-(4-chloro-2-cyclohexylphenoxy)-5-nitrophenoxy]phenyl]propanoyl)amino]ethanesulfonic acid
-
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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
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2-[3-[5-(4-chlorophenyl)-1,3-benzoxazol-2-yl]-4-(propylamino)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid
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2-[3-[5-(4-fluorophenyl)-1,3-benzoxazol-2-yl]-4-(propylamino)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid
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2-[4-[4-(6-amino-1H-benzimidazol-2-yl)phenoxy]phenyl]-1H-benzimidazol-5-amine
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3-heptadecanoyl-4-hydroxy-5-(hydroxymethyl)furan-2(5H)-one
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3-[(7-chloroquinolin-4-yl)amino]-N-[2-(dimethylamino)ethyl]-5-([[3-(piperidin-1-yl)prop-1-en-2-yl]amino]methyl)benzamide
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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
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4-[(4-carboxy-3-hydroxy-5-methylphenoxy)carbonyl]-3-hydroxy-5-pentadecylphenyl beta-D-glucopyranosiduronic acid
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4-[(4-carboxy-3-hydroxy-5-methylphenoxy)carbonyl]-3-hydroxy-5-pentadecylphenyl methyl beta-D-glucopyranosiduronate
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4-[(7-chloroquinolin-4-yl)amino]-2-(pyrrolidin-1-ylmethyl)phenol
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4-[(7-chloroquinolin-4-yl)amino]phenol
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4-[[5-(3,6-dibromo-9H-fluoren-9-yl)-4-hydroxy-2-(2-phenylethyl)pentanethioyl]amino]benzenesulfonic acid
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5-bromo-2-hydroxy-N-[(E)-(3-[2-[(4-methylphenyl)amino]-2-oxoethyl]-2-oxo-2,3-dihydro-1H-inden-1-ylidene)methyl]benzamide
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5-[3-(2-methylidenenonadecyl)-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]-2-phenoxybenzenesulfonic acid
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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
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7-chloro-N-[3-[(diethylamino)methyl]-4-(morpholin-4-yl)phenyl]quinolin-4-amine
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7-chloro-N-[4-(furan-2-yl)-3-(pyrrolidin-1-ylmethyl)phenyl]quinolin-4-amine
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7-chloro-N-[4-ethoxy-3-(pyrrolidin-1-ylmethyl)phenyl]quinolin-4-amine
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amodiaquine
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an antimalarial drug
astemizole
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basic fibroblast growth factor
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cisapride
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heparanase inhibitor PI-88
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a mixture of highly sulfated, monophosphorylated mannose oligosaccharides, derived from the extracellular phosphomannan of the yeast Pichia holstii, with potential antiangiogenic activity
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heparin
hesperidin
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labetalol
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laminarin sulfate
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0.01 mM, complete inhibition
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low molecular weight heparin
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-
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Lys-Lys-Asp-Cys
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0.025 mM or above
M402
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a glycol-split heparin compound similar to SST0001 yet smaller in molecular mass
maltohexaose sulfate
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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
metergoline
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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
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N-[4-([[4-(1H-benzimidazol-2-yl)phenyl]amino]methyl)phenyl]-3-bromo-4-methoxybenzamide
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N-[4-([[5-(1H-benzimidazol-2-yl)pyridin-2-yl]amino]methyl)phenyl]-3-bromo-4-methoxybenzamide
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N-[4-bromo-3-[(diethylamino)methyl]phenyl]-7-chloroquinolin-4-amine
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naringin
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oligomannurarate sulfate
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the heparanase inhibitor simultaneously targets basic fibroblast growth factor, combats tumor angiogenesis and metastasis. The inhibitor is a promising candidate agent for cancer therapy
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oligomannurarate sulphate
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oligomanurarate sulfate
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JG3, a marine-derived oligosaccharide and a heparanase inhibitor
PG545
PG545 cholestanol aglycon
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the cholestanol aglycon of PG545 significantly increased affinity for heparanase and also modified the inhibition mode, parabolic competition
PG545 trisaccharide derivative
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PI-88
roneparstat
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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
sodium octyl 2-deoxy-2-(sulfonatoamino)-alpha-D-glucopyranoside
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sodium octyl 4-O-[2-deoxy-2-(sulfoamino)-alpha-D-glucopyranosyl]-beta-D-glucopyranosiduronate
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specific inhibition
sodium octyl beta-D-glucopyranosiduronate
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SST0001
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sulfated PG545
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competitive inhibition
sulfated trisaccharide from PG545
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partial competitive inhibition
sulodexide
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-
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suramin
[2-(2-carboxybenzoyl)-6-(phenylsulfanyl)phenyl](hydroxy)oxoammonium
-
-
[3-[(7-chloroquinolin-4-yl)amino]-5-([[3-(morpholin-4-yl)prop-1-en-2-yl]amino]methyl)phenyl]methanol
-
-
[3-[(7-chloroquinolin-4-yl)amino]-5-([[3-(piperidin-1-yl)prop-1-en-2-yl]amino]methyl)phenyl](morpholin-4-yl)methanone
-
-
[4-(5-[2-chloro-4-[(4-chlorobenzoyl)amino]phenyl]furan-2-yl)-1,3-thiazol-2-yl]acetic acid
-
-
[4-[5-(2,4-dichlorophenyl)furan-2-yl]-1,3-oxazol-2-yl]acetic acid
-
-
[4-[5-(4-[[(2E)-3-(4-bromophenyl)prop-2-enoyl]amino]-2-chlorophenyl)furan-2-yl]-1,3-thiazol-2-yl]acetic acid
-
-
additional information
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
angiotensin II
-
-
Astragalus membranaceus extract
-
-
-
histidine-rich glycoprotein
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GeneBank accession number: BAA21613. Directly interacts with platelet-derived heparanase and enhances its enzymatic activity
-
oxidized LDL
-
-
-
palmitic acid
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palmitic acid-induced nuclear entry of heparanase facilitates heparan sulfate cleavage
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0036
fondaparinux
-
pH 5.0, 37°C
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
0.0124
sulfated PG545
-
pH 5.0, 37°C
0.197
sulfated trisaccharide from PG545
-
pH 5.0, 37°C
additional information
additional information
-
Michaelis-Menten kinetics
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
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
Homo sapiens
-
pH 5.0, 37°C, i.e. fondaparinux
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0000079
heparanase inhibitor PI-88
-
pH 5.0, 37°C
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0.00444
PG545
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pH 5.0, 37°C
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
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.000025
heparanase inhibitor PI-88
Homo sapiens
-
pH 5.0, 37°C
-
0.00002 - 0.001
heparin
0.00005
laminarin sulfate
Mus musculus
-
-
-
0.012
PG545
Homo sapiens
-
pH 5.0, 37°C
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
0.416
sulfated PG545
Homo sapiens
-
pH 5.0, 37°C
4.82
sulfated trisaccharide from PG545
Homo sapiens
-
pH 5.0, 37°C
0.05
suramin
Mus musculus
-
-
additional information
additional information
Homo sapiens
-
dissociation constants, overview
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
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
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5.5 - 5.8
5.5 - 6
-
-
6
-
assay at
7.4
-
assay at
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
3.5 - 7
-
no significant activity below pH 3.5 and above pH 7.0
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
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pI VALUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
9.2
-
calculated from amino acid sequence
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
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
Manually annotated by BRENDA team
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overexpression of heparanase in pancreatic adenocarcinomas
Manually annotated by BRENDA team
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elevated levels of heparanasen activity are detected in sera and urine samples of patients suffering from diabetic nephropathy or aggressive metastatic disease
Manually annotated by BRENDA team
-
elevated level of heparanase-activity in bone marrow plasma of myeloma patients
Manually annotated by BRENDA team
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metastatic breast carcinoma cell lines show a substantial increase in hpa gene expression
Manually annotated by BRENDA team
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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
Manually annotated by BRENDA team
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-
Manually annotated by BRENDA team
-
heparanase expression in coronary artery disease
Manually annotated by BRENDA team
-
induction of heparanase by luteinizing hormone
Manually annotated by BRENDA team
-
under normal conditions, heparanase-1 expression is restricted primarily to placental trophoblasts, blood-borne cells and keratinocytes
Manually annotated by BRENDA team
-
-
Manually annotated by BRENDA team
-
-
Manually annotated by BRENDA team
-
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
Manually annotated by BRENDA team
-
isolated from trabecular bone specimens of patients with osteoporosis and from healthy subjects
Manually annotated by BRENDA team
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plantar stratum corneum
Manually annotated by BRENDA team
-
-
Manually annotated by BRENDA team
-
elevated level of heparanase-activity is detected in sera and urine samples of patients suffering from diabetic nephropathy or aggressive metastatic disease
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
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
Manually annotated by BRENDA team
-
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
Manually annotated by BRENDA team
additional information
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
15000
-
x * 15000, heparanase splice variant T5, SDS-PAGE
51000
-
x * 51000, active enzyme form, SDS-PAGE
53000
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1 * 53000 + 1 * 8000, active heterodimeric form, SDS-PAGE
57700
-
x * 57700, calculated from amino acid sequence
80000
-
1 * 50000 + 1 * 80000, SDS-PAGE
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer
-
1 * 50000 + 1 * 80000, SDS-PAGE
heterodimer
monomer
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
glycoprotein
proteolytic modification
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
crystal structure analyses and homology modelling, overview
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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
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 His-tagged enzyme from Escherichia coli BL21-DE3 codon plus by metal affinity chromatography
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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
expressed in Mus musculus
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expression in CHO cells
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expression in COS-7 cells
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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
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NIH3T3 and COS-7 cells stably transfected with pBK-CMV expression vectors
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recombinant expression in insect cells
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recombinant expression of His-tagged smaller 8 kDa subunit in Escherichia coli strain BL21 (DE3)plysS
-
recombinant expression of the His-tagged enzyme from pET-15b expression vector containing a TEV cleavage site in Escherichia coli BL21-DE3 codon plus
-
stably expressed in NS0 myeloma cells
-
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
-
expression is up-regulated as tumors become more aggressive and is associated with enhanced tumor growth, angiogenesis, and metastasis
-
expression of the enzyme heparanase is clearly linked to colon carcinoma progression
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heparanase expression is induced by nerve growth factor
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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 is upregulated in essentially all human carcinomas
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heparanase is upregulated in primary human tumors
-
heparanase variant T5 expression is up-regulated in 75% of human renal cell carcinoma biopsies
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no effect by TGF-beta on the enzyme expression in enzyme-silenced cells
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phorbol 12-myristate 13-acetate/calcium iono­mycin stimulation results in a substantial increase in nuclear heparanase in the 53 kDa active form
-
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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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
D367A
-
mutant enzyme is not expressed
Q225A
-
mutation results in the complete loss of heparanase activity
Q343A
-
mutation results in the complete loss of heparanase activity
Q378A
-
mutation does not reduce activity
Q396A
-
mutation does not reduce activity
Y156A
-
enzymatically inactive proenzyme
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
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
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