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Information on EC 5.1.3.17 - heparosan-N-sulfate-glucuronate 5-epimerase and Organism(s) Homo sapiens and UniProt Accession O94923

for references in articles please use BRENDA:EC5.1.3.17
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EC Tree
IUBMB Comments
The enzyme acts on D-glucosyluronate residues in N-sulfated heparosan polymers, converting them to L-iduronate, thus modifying the polymer to heparan-N-sulfate. The enzyme requires that at least the N-acetylglucosamine residue linked to C-4 of the substrate has been deacetylated and N-sulfated, and activity is highest with fully N-sulfated substrate. It does not act on glucuronate residues that are O-sulfated or are adjacent to N-acetylglucosamine residues that are O-sulfated at the 6 position. Thus the epimerization from D-glucuronate to L-iduronate occurs after N-sulfation of glucosamine residues but before O-sulfation. Not identical with EC 5.1.3.19 chondroitin-glucuronate 5-epimerase or with EC 5.1.3.36, heparosan-glucuronate 5-epimerase.
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Homo sapiens
UNIPROT: O94923
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Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Synonyms
c5-epimerase, hsepi, d-glucuronyl c5-epimerase, glucuronyl c5-epimerase, c5-epi, hg-5epi, hs c5-epimerase, heparosan n-sulfate d-glucuronosyl 5-epimerase, d-glucuronyl c-5 epimerase, hs glucuronyl c5-epimerase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
D-glucuronyl C5-epimerase
-
heparan sulfate C-5 epimerase
-
HS C5-epimerase
-
C5 uronosyl epimerase
-
-
-
-
C5-epi
-
-
C5-epimerase
-
-
D-Glucuronyl C-5 epimerase
-
-
-
-
D-glucuronyl C5-epimerase
-
-
Epimerase, polyglucuronate
-
-
-
-
Glce
-
-
Heparan sulfate C5-epimerase
-
-
Heparosan N-sulfate D-glucuronosyl 5-epimerase
-
-
-
-
Heparosan-N-sulfate-D-glucuronosyl-5-epimerase
-
-
-
-
HS C5-epimerase
-
-
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
Epimerization of D-glucuronate in heparosan-N-sulfate to L-iduronate
show the reaction diagram
proposed catalytic mechanisms of C5-epi, overview
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
epimerization
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
poly[(1->4)-beta-D-glucuronosyl-(1->4)-N-sulfo-alpha-D-glucosaminyl] glucurono-5-epimerase
The enzyme acts on D-glucosyluronate residues in N-sulfated heparosan polymers, converting them to L-iduronate, thus modifying the polymer to heparan-N-sulfate. The enzyme requires that at least the N-acetylglucosamine residue linked to C-4 of the substrate has been deacetylated and N-sulfated, and activity is highest with fully N-sulfated substrate. It does not act on glucuronate residues that are O-sulfated or are adjacent to N-acetylglucosamine residues that are O-sulfated at the 6 position. Thus the epimerization from D-glucuronate to L-iduronate occurs after N-sulfation of glucosamine residues but before O-sulfation. Not identical with EC 5.1.3.19 chondroitin-glucuronate 5-epimerase or with EC 5.1.3.36, heparosan-glucuronate 5-epimerase.
CAS REGISTRY NUMBER
COMMENTARY hide
112567-86-9
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
Heparosan-N-sulfate D-glucuronate
Heparosan-N-sulfate L-iduronate
show the reaction diagram
-
-
-
?
GlcA-beta-(1->4)-GlcNAc-beta-(1->4)-GlcA-beta-(1->4)-GlcNS-beta-(1->4)-GlcA-beta-(1->4)-GlcNAc-beta-(1->4)-GlcA-beta-(1->4)-2,5-andydro-D-mannitol
GlcA-beta-(1->4)-GlcNAc-beta-(1->4)-GlcA-beta-(1->4)-GlcNS-beta-(1->4)-IdoA-beta-(1->4)-GlcNAc-beta-(1->4)-GlcA-beta-(1->4)-2,5-andydro-D-mannitol
show the reaction diagram
-
i.e. Octa-4
i.e. epi-Octa-4
-
ir
GlcA-beta-(1->4)-GlcNAc-beta-(1->4)-GlcA-beta-(1->4)-GlcNS-beta-(1->4)-GlcA-beta-(1->4)-GlcNS-beta-(1->4)-GlcA-beta-(1->4)-2,5-andydro-D-mannitol
GlcA-beta-(1->4)-GlcNAc-beta-(1->4)-GlcA-beta-(1->4)-GlcNS-beta-(1->4)-GlcA-beta-(1->4)-GlcNS-beta-(1->4)-GlcA-beta-(1->4)-2,5-andydro-D-mannitol
show the reaction diagram
-
i.e. Octa-3, two GlcA units in Octa-1 are susceptible to C5-epi modification, and both epimerization sites are reversible
i.e. epi-Octa-3
-
ir
GlcA-beta-(1->4)-GlcNAc-beta-(1->4)-GlcA-beta-(1->4)-GlcNS-beta-(1->4)-GlcA-beta-(1->4)-GlcNS-beta-(1->4)-GlcA-beta-(1->4)-GlcNS-beta-(1->4)-GlcA-beta-(1->4)-2,5-andydro-D-mannitol
GlcA-beta-(1->4)-GlcNAc-beta-(1->4)-GlcA-beta-(1->4)-GlcNS-beta-(1->4)-IdoA-beta-(1->4)-GlcNS-beta-(1->4)-IdoA-beta-(1->4)-GlcNS-beta-(1->4)-GlcA-beta-(1->4)-2,5-andydro-D-mannitol
show the reaction diagram
-
i.e. Deca-8 with GlcA-beta-(1->4)-GlcNAc-beta-(1->4)-GlcA-beta-(1->4)-GlcNS-beta-(1->4)-GlcA(irreversible site)-beta-(1->4)-GlcNS-beta-(1->4)-GlcA (reversible site)-beta-(1->4)-GlcNS-beta-(1->4)-GlcA-beta-(1->4)-2,5-andydro-D-mannitol
i.e. epi-Deca-8
-
?
GlcA-beta-(1->4)-GlcNH2-beta-(1->4)-GlcA-beta-(1->4)-GlcNS-beta-(1->4)-GlcA-beta-(1->4)-GlcNS-beta-(1->4)-GlcA-beta-(1->4)-2,5-andydro-D-mannitol
GlcA-beta-(1->4)-GlcNH2-beta-(1->4)-GlcA-beta-(1->4)-GlcNS-beta-(1->4)-IdoA-beta-(1->4)-GlcNS-beta-(1->4)-GlcA-beta-(1->4)-2,5-andydro-D-mannitol
show the reaction diagram
-
i.e. Octa-6
i.e. epi-Octa-6
-
r
GlcA-beta-(1->4)-GlcNS-beta-(1->4)-GlcA-beta-(1->4)-GlcNS-beta-(1->4)-GlcA-beta-(1->4)-2,5-andydro-D-mannitol
GlcA-beta-(1->4)-GlcNS-beta-(1->4)-IdoA-beta-(1->4)-GlcNS-beta-(1->4)-GlcA-beta-(1->4)-2,5-andydro-D-mannitol
show the reaction diagram
-
i.e. Hexa-7
i.e. epi-Hexa-7
-
r
GlcA-beta-(1->4)-GlcNS-beta-(1->4)-GlcA-beta-(1->4)-GlcNS-beta-(1->4)-GlcA-beta-(1->4)-GlcNAc-beta-(1->4)-GlcA-beta-(1->4)-2,5-andydro-D-mannitol
GlcA-beta-(1->4)-beta-(1->4)-GlcNS-beta-(1->4)-L-IdoA-alpha-(1->4)-GlcNS-beta-(1->4)-L-IdoA-alpha-(1->4)-GlcNAc-beta-(1->4)-GlcA-beta-(1->4)-2,5-andydro-D-mannitol
show the reaction diagram
-
i.e. Octa-1, two GlcA units in Octa-1 are susceptible to C5-epi modification, and both epimerization sites are reversible
i.e. epi-Octa-1
-
r
GlcA-beta-(1->4)-GlcNS-beta-(1->4)-GlcA-beta-(1->4)-GlcNS-beta-(1->4)-GlcA-beta-(1->4)-GlcNS-beta-(1->4)-GlcA-beta-(1->4)-2,5-andydro-D-mannitol
GlcA-beta-(1->4)-GlcNS-beta-(1->4)-IdoA-beta-(1->4)-GlcNS-beta-(1->4)-IdoA-beta-(1->4)-GlcNS-beta-(1->4)-GlcA-beta-(1->4)-2,5-andydro-D-mannitol
show the reaction diagram
-
i.e. Octa-2
i.e. epi-Octa-2
-
r
Heparosan-N-sulfate D-glucuronate
Heparosan-N-sulfate L-iduronate
show the reaction diagram
additional information
?
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
Heparosan-N-sulfate D-glucuronate
Heparosan-N-sulfate L-iduronate
show the reaction diagram
-
-
-
?
Heparosan-N-sulfate D-glucuronate
Heparosan-N-sulfate L-iduronate
show the reaction diagram
additional information
?
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Ca2+
-
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7
-
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37
assay at
30
-
assay at
37
-
assay at
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
decreased GLCE expression is observed in 10% of benign prostate hyperplasia tissues and 53% of prostate tumors, and increased GLCE mRNA levels are detected in 49% of benign prostate hyperplasia tissues and 21% of tumors, intratumoral heterogeneity of GLCE protein levels both in benign prostate hyperplasia and prostate cancer cells, resulting in a mixed population of GLCE-expressing and nonexpressing epithelial cells in vivo
Manually annotated by BRENDA team
-
decreased GLCE expression is observed in 10% of benign prostate hyperplasia tissues and 53% of prostate tumors, and increased GLCE mRNA levels are detected in 49% of benign prostate hyperplasia tissues and 21% of tumors, intratumoral heterogeneity of GLCE protein levels both in benign prostate hyperplasia and prostate cancer cells, resulting in a mixed population of GLCE-expressing and nonexpressing epithelial cells in vivo
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
-
transmembrane enzyme
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
D-glucuronyl C5-epimerase activity and presence of L-iduronic acid seem to be intrinsic properties of cells from prokaryotes to humans
metabolism
D-glucuronyl C5-epimerase is a key enzyme involved in the biosynthesis of heparan sulfate proteoglycans, which has an important role in cell-cell and cell-matrix interactions and signaling
physiological function
malfunction
-
complex deregulation of GLCE expression in prostatic diseases compared with healthy prostate tissue
physiological function
-
heparansulfate proteoglycans play an important role in cell-cell and cell-matrix interactions and signaling, and one of the key enzymes in heparansulfate biosynthesis is D-glucuronyl C5-epimerase. The enzyme has a tumor suppressor function in breast and lung carcinogenesis
additional information
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
GLCE_HUMAN
617
1
70101
Swiss-Prot
Secretory Pathway (Reliability: 1)
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
-
the human epimerase is a 617-amino acid protein that consists of three domains, cytoplasmic comprising residues Met1-Lys11, transmembrane with Thr12-Trp28, and catalytic domain formed by Asn29-Asn617
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Y146A
-
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type enzyme
Y162A
-
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type enzyme
Y168A
-
site-directed mutagenesis, inactive mutant
Y210A
-
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type enzyme
Y222A
-
site-directed mutagenesis, inactive mutant
additional information
high cell density fed-batch cultivation of recombinant Escherichia coli strains expressing 2-O-sulfotransferase and C5-epimerase at high level for the production of bioengineered heparin, method, overview. The first enzymatic step in this process uses heparan sulfate biosynthetic enzymes, 2-O-sulfotransferase (2-OST) and C5-epimerase (C5-epi), expressed as MBP-tagged proteins in Escherichia coli, to convert N-sulfo heparosan into an intermediate polysaccharide rich in -GlcNS(1->4)IdoA2S- sequences (where S is sulfo and IdoA is alpha-L-iduronic acid). This critical step in bioengineered heparin preparation relies on the use of recombinant arylsulfotransferase IV (AST-IV) to regenerate 3'-phospho adenosine-5'-phosphosulfate (PAPS) using p-nitrophenylsulfate as a sacrificial sulfur donor, one-pot reaction
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant enzyme from Escherichia coli
-
recombinant wild-type and mutant enzymes from Escherichia coli strain DE3
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
enzyme GLCE is ectopically re-expressed in morphologically different LNCaP and PC3 prostate cancer cells, quantitative real-time PCR enzyme expression analysis
expressed in U2020 cells
recombinant MBP-tagged enzyme in Escherichia coli strain Rosetta-gami B (DE3), coexpression with 2-O-sulfotransferase
expression of wild-type and mutant enzymes in Escherichia coli strain DE3
-
recombinant expression in Escherichia coli
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
D-glucuronyl C5-epimerase expression is decreased in lung cancer cells
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 3fold in Grade IV glioma (glioblastoma multiforme, GBM) (p < 0.05), as compared with the para-tumourous tissue
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
diagnostics
GLCE upregulation plus expression pattern of a panel of six genes, discriminating morphologically different prostate cancer cell subtypes, is a potential marker of aggressive prostate cancer
medicine
the anti-tumour effects associated with ectopic GLCE re-expression suggest that it may be a potential tumour-suppressor gene and a possible target for lung cancer diagnosis and treatment
synthesis
the enzyme, coexpressed with 2-O-sulfotransferase in bacteria, can be used for production of bioengineered heparin as a potential substitute for the animal-sourced anticoagulant drug
medicine
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Tiedemann, K.; Larsson, T.; Heinegard, D.; Malmstrom, A.
The glucuronyl C5-epimerase activity is the limiting factor in the dermatan sulfate biosynthesis
Arch. Biochem. Biophys.
391
65-71
2001
Homo sapiens
Manually annotated by BRENDA team
Ghiselli, G.; Agrawal, A.
The human D-glucuronyl C5-epimerase gene is transcriptionally activated through the beta-catenin-TCF4 pathway
Biochem. J.
390
493-499
2005
Homo sapiens (O94923), Homo sapiens
Manually annotated by BRENDA team
Hagner-McWhirter, A.; Li, J.P.; Oscarson, S.; Lindahl, U.
Irreversible glucuronyl C5-epimerization in the biosynthesis of heparan sulfate
J. Biol. Chem.
279
14631-14638
2004
Homo sapiens
Manually annotated by BRENDA team
Grigorieva, E.; Eshchenko, T.; Rykova, V.I.; Chernakov, A.; Zabarovsky, E.; Sidorov, S.V.
Decreased expression of human D-glucuronyl C5-epimerase in breast cancer
Int. J. Cancer
122
1172-1176
2008
Homo sapiens
Manually annotated by BRENDA team
Li, K.; Bethea, H.N.; Liu, J.
Using engineered 2-O-sulfotransferase to determine the activity of heparan sulfate C5-epimerase and its mutants
J. Biol. Chem.
285
11106-11113
2010
Homo sapiens
Manually annotated by BRENDA team
Grigorieva, E.; Prudnikova, T.; Domanitskaya, N.; Mostovich, L.; Pavlova, T.; Kashuba, V.; Zabarovsky, E.
D-Glucuronyl C5-epimerase suppresses small-cell lung cancer cell proliferation in vitro and tumour growth in vivo
Br. J. Cancer
105
74-82
2011
Homo sapiens (O94923), Homo sapiens
Manually annotated by BRENDA team
Prudnikova, T.Y.; Soulitzis, N.; Kutsenko, O.S.; Mostovich, L.A.; Haraldson, K.; Ernberg, I.; Kashuba, V.I.; Spandidos, D.A.; Zabarovsky, E.R.; Grigorieva, E.V.
Heterogeneity of D-glucuronyl C5-epimerase expression and epigenetic regulation in prostate cancer
Cancer Med.
2
654-661
2013
Homo sapiens
Manually annotated by BRENDA team
Sheng, J.; Xu, Y.; Dulaney, S.B.; Huang, X.; Liu, J.
Uncovering biphasic catalytic mode of C5-epimerase in heparan sulfate biosynthesis
J. Biol. Chem.
287
20996-21002
2012
Homo sapiens
Manually annotated by BRENDA team
Zhang, J.; Suflita, M.; Li, G.; Zhong, W.; Li, L.; Dordick, J.S.; Linhardt, R.J.; Zhang, F.
High cell density cultivation of recombinant Escherichia coli strains expressing 2-O-sulfotransferase and C5-epimerase for the production of bioengineered heparin
Appl. Biochem. Biotechnol.
175
2986-2995
2015
Homo sapiens (O94923)
Manually annotated by BRENDA team
Babu, P.; Victor, X.V.; Raman, K.; Kuberan, B.
A rapid, nonradioactive assay for measuring heparan sulfate C-5 epimerase activity using hydrogen/deuterium exchange-mass spectrometry
Methods Mol. Biol.
1229
209-219
2015
Homo sapiens (O94923), Homo sapiens
Manually annotated by BRENDA team
Rosenberg, E.; Prudnikova, T.; Zabarovsky, E.; Kashuba, V.; Grigorieva, E.
D-Glucuronyl C5-epimerase cell type specifically affects angiogenesis pathway in different prostate cancer cells
Tumor Biol.
35
3237-3245
2014
Homo sapiens (O94923)
Manually annotated by BRENDA team
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 (O94923)
Manually annotated by BRENDA team