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Information on EC 5.1.3.19 - chondroitin-glucuronate 5-epimerase and Organism(s) Homo sapiens and UniProt Accession Q8IZU8
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5.1.3.19 chondroitin-glucuronate 5-epimeraseIUBMB Comments
Not identical with EC 5.1.3.17 heparosan-N-sulfate-glucuronate 5-epimerase.
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Word Map
- 5.1.3.19
-
iduronic
- glycosaminoglycans
- proteoglycans
-
epimerization
- decorin
-
d-glucuronic
- ehlers-danlos
-
musculocontractural
- chst14
-
4-o-sulfotransferase
-
mceds
-
idoa
-
4-o-sulfated
- analysis
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Synonyms
ds-epi1, ds-epi2, sart2, dermatan sulfate epimerase, chondroitin-glucuronate c5-epimerase, ds-epimerase 1, dermatan sulfate epimerase 1, chondroitin-glucuronate 5-epimerase, ds epimerase 1, chondroitin d-glucuronosyl 5-epimerase, 
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topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Chondroitin D-glucuronosyl 5-epimerase
-
-
-
-
dermatan sulfate epimerase
Dermatan-sulfate 5-epimerase
-
-
-
-
DS-epi1
DSE
Epimerase, chondroitin glucuronate 5-
-
-
-
-
Polyglucuronate 5-epimerase
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
Chondroitin D-glucuronate = dermatan L-iduronate
two-base reaction mechanism, involving a monoprotic L-iso-specific base and a polyprotic D-gluco-specific base
-
Chondroitin D-glucuronate = dermatan L-iduronate
after inversion, a hydrogen from the medium is reinserted into the uronosyl residue
-
Chondroitin D-glucuronate = dermatan L-iduronate
His-450 functions as a general base abstracting the C5 proton from glucuronic acid. Subsequent cleavage of the glycosidic linkage by Tyr-261 generates a 4,5-unsaturated hexuronic intermediate, which is protonated at the C5 carbon by His-205 from the side of the sugar plane opposite to the side of previous proton abstraction. Concomitant recreation of the glycosidic linkage ends the reaction, generating iduronic acid, proposed molecular mechanism of epimerization, overview
Chondroitin D-glucuronate = dermatan L-iduronate
processive reducing to non-reducing end mode of action of DS-epi1, in silico modeling of site-specific information
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
epimerization
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-
-
-
PATHWAY SOURCE
PATHWAYS
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-
SYSTEMATIC NAME
IUBMB Comments
chondroitin-D-glucuronate 5-epimerase
Not identical with EC 5.1.3.17 heparosan-N-sulfate-glucuronate 5-epimerase.
CAS REGISTRY NUMBER
COMMENTARY
70766-66-4
-
86417-91-6
identical to EC 6.2.1.26
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
Chondroitin D-glucuronate
Dermatan L-iduronate
-
capsular polysaccharide from Escherichia coli K4 consists of a chondroitin backbone to which beta-fructofuranose units are linked to C-3 of the D-glucuronic acid residues. Removal of the fructose units by mild acid hydrolysis provides a substrate for the chondroitin-glucuronate 5-epimerase
-
?
Chondroitin D-glucuronate
Dermatan L-iduronate
-
C5-inversion of D-glucuronic acid to L-iduronic acid occurs on the polymer level. This transformation is greatly promoted by 4-sulfation of neighboring N-acetylgalactosamine moieties
-
?
Chondroitin D-glucuronosyl residues
Chondroitin L-iduronosyl residues
-
-
-
?
D-glucuronate
L-iduronate
-
in dermatan sulfate, iduronic acid residues are either clustered together in blocks or alternating with glucuronic acid, forming hybrid structures
-
-
?
D-glucuronate
L-iduronate
-
DS-epi2 has epimerase activity, which involves conversion of D-glucuronic acid to L-iduronic acid, EC 5.1.3.19, but no O-sulfotransferase activity, ovcerview
-
-
?
additional information
?
-
-
most of the L-iduronic acid residues generated by the enzyme occur singly, although some formation of two or three consecutive L-iduronic acid residue containing disaccharide units is observed
-
-
?
additional information
?
-
-
dermatan sulfate and chondroitin sulfate are inactive as substrates, which indicates that epimerization takes place before sulfation
-
-
?
additional information
?
-
-
epimerization of D-glucuronosyl residues to L-iduronosyl during biosynthesis of dermatan sulfate
-
-
?
additional information
?
-
-
epimerization of D-glucuronosyl residues to L-iduronosyl during biosynthesis of dermatan sulfate
-
-
?
additional information
?
-
identification of the catalytic site, and of three putative catalytic residues in DS-epimerase 1, His205, Tyr261, and His450, by tertiary structure modeling and amino acid conservation to heparinase II
-
-
?
additional information
?
-
-
tandem mass spectrometry analysis, based on fragment analysis of reducing-end labeled GAG oligosaccharides, of heterogeneous epimerase products, DS-epi1-catalyzed incorporation of deuterium into the oligosaccharide substrates causes a discernible shift of the isotopic pattern in the mass spectra, and generation of site-specific modification information by acid-catalyzed glycan sequencing (PRAGS). Optimal substrate binding requires an octasaccharide or longer
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
D-glucuronate
L-iduronate
-
in dermatan sulfate, iduronic acid residues are either clustered together in blocks or alternating with glucuronic acid, forming hybrid structures
-
-
?
additional information
?
-
-
most of the L-iduronic acid residues generated by the enzyme occur singly, although some formation of two or three consecutive L-iduronic acid residue containing disaccharide units is observed
-
-
?
additional information
?
-
-
dermatan sulfate and chondroitin sulfate are inactive as substrates, which indicates that epimerization takes place before sulfation
-
-
?
additional information
?
-
-
epimerization of D-glucuronosyl residues to L-iduronosyl during biosynthesis of dermatan sulfate
-
-
?
additional information
?
-
-
epimerization of D-glucuronosyl residues to L-iduronosyl during biosynthesis of dermatan sulfate
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mn2+
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Small proteoglycan core proteins
-
may have a role as a modulator of the activity of these enzyme
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
5.5
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
30-50% decreased activity in fibroblasts treated with high xyloside concentrations
-
fetal. Enzyme activity is reduced 25% in TGF-beta1 treated cells and 50% in fibroblasts treated with a combination of TGF-beta, epidermal growth factor and platelet-derived growth factor
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
the enzyme catalyzes a step in dermatan sulfate and chondroitin sulfate biosynthesis, pathway overview
malfunction
metabolism
the enzyme catalyzes a step in dermatan sulfate and chondroitin sulfte biosynthesis, pathway overview
physiological function
additional information
-
polysaccharide processivity opens up the possibility for an efficient formation of long stretches of IdoA, which have been shown to be of major importance for CS/DS regulatory effect on collagen fibrillization
malfunction
-
DS-epi2 is genetically linked to bipolar disorder, which suggests that the dermatan sulfate domains generated by a defective enzyme may be involved in the etiology of the disease
malfunction
a naturally occuring homozygous DSE mutation c.803C>T, pS268L, causes musculocontractural type of Ehlers-Danlos syndrome, MCEDS. The mutant enzymes shows a loss of activity towards partially desulfated dermatan sulfate, patient-derived fibroblasts also show a significant reduction in epimerase activity. Dermatan sulfate disaccharides are reduced, while chondroitin sulfate disaccharides are increased in cultured fibroblasts. Stable transfection of patient fibroblasts with a DSE expression vector increases the amount of secreted dermatan sulfate disaccharides
physiological function
-
DS-epi2 and DS-epi1 are both involved in the biosynthesis of the iduronic acid blocks in fibroblasts and that DS-epi2 can also synthesize the hybrid structures
physiological function
the enzyme is important in human development and extracellular matrix maintenance
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
glycoprotein
proper N-glycosylation of DS-epimerase 1 is required for enzyme activity
glycoprotein
-
predicted N-glycans in DS-epi1 that are necessary for optimal enzymatic activity
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
H205A
site-directed mutagenesis of the catalytic site residue, the mutant shows complete loss of epimerase activity
H450A
site-directed mutagenesis of the catalytic site residue, the mutant shows complete loss of epimerase activity
N183S
site-directed mutagenesis of an N-glycosylation site in DS-epi1 altering reaction kinetics
N336S
site-directed mutagenesis of an N-glycosylation site in DS-epi1 altering reaction kinetics and reducing the activity 13fold
N642S
site-directed mutagenesis of an N-glycosylation site in DS-epi1 altering reaction kinetics
N648S
site-directed mutagenesis of an N-glycosylation site in DS-epi1 altering reaction kinetics and reducing the activity 43fold
S268L
a naturally occuring homozygous DSE mutation c.803C>T in a patient with musculocontractural type of Ehlers-Danlos syndrome, MCEDS. The mutant enzymes shows a loss of activity towards partially desulfated dermatan sulfate, patient-derived fibroblasts also show a significant reduction in epimerase activity
Y261A
site-directed mutagenesis of the catalytic site residue, the mutant shows complete loss of epimerase activity
additional information
-
siRNA gene silencing of DS-epi2 and DS-epi1 in lung HFL-1 fibroblasts
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant myc/His-tagged DS-epi1 and FLAG-tagged DS-epi2 partially in HEK-293 cell microsomes
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
cloning and genomic structures of DS-epi1 and DS-epi2, transient functional overexpression of myc/His-tagged DS-epi1 and FLAG-tagged DS-epi2 in HEK-293 cell microsomes
-
functional recombinant enzyme expression in HEK-293 cells, all predicted N-glycans in DS-epi1 are present when the protein is expressed in the cells
-
gene DSE, transient expression of wild-type and mutant enzymes in COS-7 cells
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
analysis
-
assay procedure for chondroitin-glucuronate 5-epimerase which is based on the use of a two-phase system for liquid scintillation. 3H2O formed during the reaction, is extracted into an organic phase containing fluorine and isoamyl alcohol, while unreacted pol
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Campbell, P.; Feingold, D.S.; Jensen, J.W.; Malmström, A.; Roden, L.
New assay for uronosyl 5-epimerase
Anal. Biochem.
131
146-152
1983
Homo sapiens
Malmström, A.
Biosynthesis of dermatan sulfate. II. Substrate specificity of the C-5 uronosyl epimerase
J. Biol. Chem.
259
161-165
1984
Homo sapiens
Malmström, A.; Aberg, L.
Biosynthesis of dermatan sulphate. Assay and properties of the uronosyl C-5 epimerase
Biochem. J.
201
489-493
1982
Homo sapiens
Malmström, A.; Frasson, L.A.; Höök, M.; Lindahl, U.
Biosynthesis of dermatan sulfate. I. Formation of L-iduronic acid residues
J. Biol. Chem.
250
3419-3425
1975
Homo sapiens
Cöster, L.; Hernnäs, J.; Malmström, A.
Biosynthesis of dermatan sulphate proteoglycans. The effect of beta-D-xyloside addition on the polymer-modification process in fibroblast cultures
Biochem. J.
276
533-539
1991
Homo sapiens
Hannesson, H.H.; Hagner-McWhirter, A.; Tiedemann, K.; Lindahl, U.; Malmström, A.
Biosynthesis of dermatan sulphate. Defructosylated Escherichia coli K4 capsular polysaccharide as a substrate for the D-glucuronyl C-5 epimerase, and an indication of a two-base reaction mechanism
Biochem. J.
313
589-596
1996
Homo sapiens
Tiedemann, K.; Olander, B.; Eklund, E.; Todorova, L.; Bengtsson, M.; Maccarana, M.; Westergren-Thorsson, G.; Malmstroem, A.
Regulation of the chondroitin/dermatan fine structure by transforming growth factor-b1 through effects on polymer-modifying enzymes
Glycobiology
15
1277-1285
2005
Homo sapiens
Pacheco, B.; Maccarana, M.; Goodlett, D.R.; Malmstroem, A.; Malmstroem, L.
Identification of the active site of DS-epimerase 1 and requirement of N-glycosylation for enzyme function
J. Biol. Chem.
284
1741-1747
2009
Homo sapiens (Q9UL01)
Pacheco, B.; Malmstroem, A.; Maccarana, M.
Two dermatan sulfate epimerases form iduronic acid domains in dermatan sulfate
J. Biol. Chem.
284
9788-9795
2009
Homo sapiens
Mueller, T.; Mizumoto, S.; Suresh, I.; Komatsu, Y.; Vodopiutz, J.; Dundar, M.; Straub, V.; Lingenhel, A.; Melmer, A.; Lechner, S.; Zschocke, J.; Sugahara, K.; Janecke, A.R.
Loss of dermatan sulfate epimerase (DSE) function results in musculocontractural Ehlers-Danlos syndrome
Hum. Mol. Genet.
22
3761-3772
2013
Homo sapiens (Q8IZU8), Homo sapiens (Q9UL01), Homo sapiens
Tykesson, E.; Mao, Y.; Maccarana, M.; Pu, Y.; Gao, J.; Lin, C.; Zaia, J.; Westergren-Thorsson, G.; Ellervik, U.; Malmstroem, L.; Malmstroem, A.
Deciphering the mode of action of the processive polysaccharide modifying enzyme dermatan sulfate epimerase 1 by hydrogen-deuterium exchange mass spectrometry
Chem. Sci.
7
1447-1456
2016
Homo sapiens
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