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Chondroitin D-glucuronate = dermatan L-iduronate
Chondroitin D-glucuronate = dermatan L-iduronate
two-base reaction mechanism, involving a monoprotic L-iso-specific base and a polyprotic D-gluco-specific base
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Chondroitin D-glucuronate = dermatan L-iduronate
after inversion, a hydrogen from the medium is reinserted into the uronosyl residue
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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
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Chondroitin D-glucuronate = dermatan L-iduronate
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Chondroitin D-glucuronate
Dermatan L-iduronate
Chondroitin D-glucuronosyl residues
Chondroitin L-iduronosyl residues
D-glucuronate
L-iduronate
D-glucuronic acid
L-iduronic acid
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?
D-glucuronosyl residues
L-iduronosyl residues
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-
-
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?
Dermatan D-glucuronosyl residues
Dermatan L-iduronosyl residues
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?
additional information
?
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Chondroitin D-glucuronate
Dermatan L-iduronate
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r
Chondroitin D-glucuronate
Dermatan L-iduronate
-
-
-
?
Chondroitin D-glucuronate
Dermatan L-iduronate
-
-
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?
Chondroitin D-glucuronate
Dermatan L-iduronate
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-
-
?
Chondroitin D-glucuronate
Dermatan L-iduronate
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-
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?
Chondroitin D-glucuronate
Dermatan L-iduronate
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-
-
-
?
Chondroitin D-glucuronate
Dermatan L-iduronate
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-
-
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r
Chondroitin D-glucuronate
Dermatan L-iduronate
-
-
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?
Chondroitin D-glucuronate
Dermatan L-iduronate
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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
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?
Chondroitin D-glucuronate
Dermatan L-iduronate
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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
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?
Chondroitin D-glucuronate
Dermatan L-iduronate
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-
-
r
Chondroitin D-glucuronosyl residues
Chondroitin L-iduronosyl residues
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-
-
?
Chondroitin D-glucuronosyl residues
Chondroitin L-iduronosyl residues
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-
-
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?
D-glucuronate
L-iduronate
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?
D-glucuronate
L-iduronate
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in dermatan sulfate, iduronic acid residues are either clustered together in blocks or alternating with glucuronic acid, forming hybrid structures
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D-glucuronate
L-iduronate
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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
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D-glucuronate
L-iduronate
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D-glucuronate
L-iduronate
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?
additional information
?
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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
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additional information
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dermatan sulfate and chondroitin sulfate are inactive as substrates, which indicates that epimerization takes place before sulfation
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additional information
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epimerization of D-glucuronosyl residues to L-iduronosyl during biosynthesis of dermatan sulfate
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additional information
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epimerization of D-glucuronosyl residues to L-iduronosyl during biosynthesis of dermatan sulfate
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additional information
?
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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
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additional information
?
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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
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Breast Neoplasms
Dermatan sulfate epimerase 1 expression and mislocalization may interfere with dermatan sulfate synthesis and breast cancer cell growth.
Carcinoma
Biosynthesis of dermatan sulfate: chondroitin-glucuronate C5-epimerase is identical to SART2.
Carcinoma
Expression of tumor rejection antigens in colorectal carcinomas.
Carcinoma, Hepatocellular
DSE regulates the malignant characters of hepatocellular carcinoma cells by modulating CCL5/CCR1 axis.
Carcinoma, Hepatocellular
Expression of chondroitin-glucuronate C5-epimerase and cellular immune responses in patients with hepatocellular carcinoma.
chondroitin-glucuronate 5-epimerase deficiency
Delineation of musculocontractural Ehlers-Danlos Syndrome caused by dermatan sulfate epimerase deficiency.
Colorectal Neoplasms
Expression of tumor rejection antigens in colorectal carcinomas.
Ehlers-Danlos Syndrome
Delineation of musculocontractural Ehlers-Danlos Syndrome caused by dermatan sulfate epimerase deficiency.
Ehlers-Danlos Syndrome
Loss of dermatan sulfate epimerase (DSE) function results in musculocontractural Ehlers-Danlos syndrome.
Endometrial Neoplasms
Expression of tumor-rejection antigens in gynecologic cancers.
Melanoma
Musculocontractural Ehlers-Danlos syndrome and neurocristopathies: dermatan sulfate is required for Xenopus neural crest cells to migrate and adhere to fibronectin.
Neoplasm Metastasis
Musculocontractural Ehlers-Danlos syndrome and neurocristopathies: dermatan sulfate is required for Xenopus neural crest cells to migrate and adhere to fibronectin.
Neoplasms
Biosynthesis of dermatan sulfate: chondroitin-glucuronate C5-epimerase is identical to SART2.
Neoplasms
Dermatan sulfate epimerase 1 expression and mislocalization may interfere with dermatan sulfate synthesis and breast cancer cell growth.
Neoplasms
Dermatan sulfate is involved in the tumorigenic properties of Esophagus Squamous Cell Carcinoma.
Neoplasms
DSE promotes aggressive glioma cell phenotypes by enhancing HB-EGF/ErbB signaling.
Neoplasms
DSE regulates the malignant characters of hepatocellular carcinoma cells by modulating CCL5/CCR1 axis.
Neoplasms
Expression of chondroitin-glucuronate C5-epimerase and cellular immune responses in patients with hepatocellular carcinoma.
Neoplasms
Expression of tumor rejection antigens in colorectal carcinomas.
Neoplasms
Expression of tumor-rejection antigens in gynecologic cancers.
Neoplasms
Musculocontractural Ehlers-Danlos syndrome and neurocristopathies: dermatan sulfate is required for Xenopus neural crest cells to migrate and adhere to fibronectin.
Neoplasms
Progression-specific genes identified by expression profiling of matched ductal carcinomas in situ and invasive breast tumors, combining laser capture microdissection and oligonucleotide microarray analysis.
Neuroblastoma
Musculocontractural Ehlers-Danlos syndrome and neurocristopathies: dermatan sulfate is required for Xenopus neural crest cells to migrate and adhere to fibronectin.
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evolution
conversion of GlcA residues into the stereoisomer IdoA is mediated by two dermatan sulfate epimerases, DSE (DS-epi1) and DSEL (DS-epi2)
malfunction
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DS-epi1 deficiency alters skin morphology, collagen fibril ultrastructure, and skin tensile strength, phenotype, overview
malfunction
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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
metabolism
the enzyme catalyzes a step in dermatan sulfate and chondroitin sulfate biosynthesis, pathway overview
metabolism
the enzyme catalyzes a step in dermatan sulfate and chondroitin sulfte biosynthesis, pathway overview
metabolism
the enzyme is involved in the chondroitin/dermatan sulfate biosynthesis, overview
physiological function
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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
isoform DS-epi2 plays key roles in the epimerization of chondroitin sulfate and dermatan sulfate during its biosynthesis. The L-iduronate-containing structures in the developing brain are mainly produced by the actions of isoform DS-epi2 and play crucial roles in postnatal development
physiological function
the enzyme is important in human development and extracellular matrix maintenance
physiological function
conversion of GlcA residues into the stereoisomer IdoA is mediated by two dermatan sulfate epimerases, DSE (DS-epi1) and DSEL (DS-epi2), modification reactions in chondroitin/dermatan sulfate biosynthesis, overview
physiological function
the enzyme converts chondroitin sulfate (CS) to a CS/dermatan sulfate (DS) hybrid chain, which is structurally and conformationally richer than CS, favouring interaction with matrix proteins and growth factors
physiological function
the enzyme converts chondroitin sulfate (CS) to a CS/dermatan sulfate (DS) hybrid chain, which is structurally and conformationally richer than CS, favouring interaction with matrix proteins and growth factors. Xenopus Dse is essential for the migration of neural crest cells by allowing cell surface CS/DS proteoglycans to adhere to fibronectin
additional information
enzyme Dsel harbors a C-terminal sulfotransferase-like domain
additional information
enzyme Dsel harbors a C-terminal sulfotransferase-like domain
additional information
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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
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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
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expression of wild-type and mutant enzymes in HEK-293 cells
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
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gene dse, DNA and amino acid sequence determination and analysis, sequence comparisons and phylogenetic analysis
gene dse, located on chromosome 5S, genetic structure, quantitative enzyme real-time PCR expression analysis
gene DSE, transient expression of wild-type and mutant enzymes in COS-7 cells
gene dsel, located on chromosome 5L, genetic structure, quantitative enzyme real-time PCR expression analysis
gene dsela, DNA and amino acid sequence determination and analysis, sequence comparisons and phylogenetic analysis
gene dselb, DNA and amino acid sequence determination and analysis, sequence comparisons and phylogenetic analysis
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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
brenda
Malmström, A.
Biosynthesis of dermatan sulfate. II. Substrate specificity of the C-5 uronosyl epimerase
J. Biol. Chem.
259
161-165
1984
Homo sapiens
brenda
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
brenda
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
brenda
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
brenda
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
brenda
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
brenda
Maccarana, M.; Olander, B.; Malmstroem, J.; Tiedemann, K.; Aebersold, R.; Lindahl, U.; Li, J.P.; Malmstroem, A.
Biosynthesis of dermatan sulfate: chondroitin-glucuronate C5-epimerase is identical to SART2
J. Biol. Chem.
281
11560-11568
2006
Bos taurus
brenda
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)
brenda
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
brenda
Maccarana, M.; Kalamajski, S.; Kongsgaard, M.; Magnusson, S.P.; Oldberg, A.; Malmstroem, A.
Dermatan sulfate epimerase 1-deficient mice have reduced content and changed distribution of iduronic acids in dermatan sulfate and an altered collagen structure in skin
Mol. Cell. Biol.
29
5517-5528
2009
Mus musculus
brenda
Akatsu, C.; Mizumoto, S.; Kaneiwa, T.; Maccarana, M.; Malmstroem, A.; Yamada, S.; Sugahara, K.
Dermatan sulfate epimerase 2 is the predominant isozyme in the formation of the chondroitin sulfate/dermatan sulfate hybrid structure in postnatal developing mouse brain
Glycobiology
21
565-574
2011
Mus musculus (Q0VBN2), Mus musculus (Q8BLI4), Mus musculus
brenda
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
brenda
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
brenda
Habicher, J.; Haitina, T.; Eriksson, I.; Holmborn, K.; Dierker, T.; Ahlberg, P.E.; Ledin, J.
Chondroitin / dermatan sulfate modification enzymes in zebrafish development
PLoS ONE
10
e0121957
2015
Danio rerio, Danio rerio (B8A5U5), Danio rerio (Q5RGL8)
brenda
Gouignard, N.; Schoen, T.; Holmgren, C.; Strate, I.; Tasoez, E.; Wetzel, F.; Maccarana, M.; Pera, E.
Gene expression of the two developmentally regulated dermatan sulfate epimerases in the Xenopus embryo
PLoS ONE
13
e0191751
2018
Xenopus laevis (A0A166W7U1), Xenopus laevis (B1H189)
brenda