Information on EC 2.4.1.225 - N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase

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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria

EC NUMBER
COMMENTARY
2.4.1.225
-
RECOMMENDED NAME
GeneOntology No.
N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-proteoglycan = UDP + beta-D-glucuronosyl-(1->4)-N-acetyl-alpha-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-proteoglycan
show the reaction diagram
-
-
-
-
PATHWAY
KEGG Link
MetaCyc Link
Glycosaminoglycan biosynthesis - heparan sulfate / heparin
-
heparan sulfate biosynthesis (late stages)
-
Metabolic pathways
-
SYSTEMATIC NAME
IUBMB Comments
UDP-alpha-D-glucuronate:N-acetyl-alpha-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-proteoglycan 4-beta-glucuronosyltransferase
Involved in the biosynthesis of heparin and heparan sulfate. Some forms of the human enzyme (particularly the enzyme complex encoded by the EXT1 and EXT2 genes) act as bifunctional glycosyltransferases, which also have the glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase (EC 2.4.1.224) activity required for the synthesis of the heparan sulfate disaccharide repeats.
SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
diphosphoglucuronate:oligosaccharide uridine glucuronosyltransferase
-
-
-
-
exostosin
-
-
exostosin-1
-
-
-
-
exostosin-1
Q9V730
isozyme
exostosin-1
-
-
exostosin-1
Q16394
-
exostosin-2
-
-
-
-
exostosin-2
Q9Y169
isozyme
exostosin-2
Q93063
-
Exostosin1
-
-
Exostosin2
-
-
exotose-2
-
-
-
-
EXT-1
-
-
EXT-1
Q16394
isozyme
EXT-2
Q93063
isozyme
EXT-3
-
isozyme
EXT1
-
-
EXT1
-
EXT1 and EXT2 form a Golgi-located hetero-oligomeric complex that catalyzes the chain elongation step in heparan sulfate biosynthesis
EXT1
Q16394
-
EXT1
-
gene name
EXT1
P97464
-
EXT2
-
gene name
EXT2
-
EXT1 and EXT2 form a Golgi-located hetero-oligomeric complex that catalyzes the chain elongation step in heparan sulfate biosynthesis
EXT2
Q93063
-
EXT2
-
-
EXT2
-
gene name
EXT2
Mus musculus BALB/c
-
gene name
-
EXTL3
-
the EXTL proteins exhibit overlapping glycosyltransferase activities in vitro, so it is not apparent what reactions they catalyze in vivo
gene EXTL1 glycosyltransferase
-
-
-
-
gene EXTL2 glycosyltransferase
-
-
-
-
glucuronic acid/N-acetylglucosamine co-polymerase-1
-
-
glucuronosyltransferase
-
-
-
-
heparan glucuronosyltransferase II
-
-
-
-
heparan sulfate co-polymerase
-
-
-
-
heparan sulfate glucuronosyltransferase
-
-
-
-
N-acetylglucosaminylproteoglycan beta-1,4-glucuronosyltransferase
-
-
-
-
RIB-1
-
isozyme
RIB-2
-
isozyme
sister of tout velu
-
-
sister of tout-velu
-
c.f. EC 2.4.1.224
sotv
-
c.f. EC 2.4.1.224
tout-velu
-
c.f. EC 2.4.1.224
ttv
-
c.f. EC 2.4.1.224
UDP-glucuronate:oligosaccharide
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY
145539-84-0
-
ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
enzyme EXT2, enzyme EXT1 from Homo sapiens
-
-
Manually annotated by BRENDA team
gene ext2
-
-
Manually annotated by BRENDA team
enzyme sotv, homologue of mammalian EXT2
-
-
Manually annotated by BRENDA team
enzymes ttv and sotv
-
-
Manually annotated by BRENDA team
Escherichia coli K5
K5
-
-
Manually annotated by BRENDA team
enzyme EXT1, EXT2 constructs from Bos taurus
-
-
Manually annotated by BRENDA team
enzymes EXT1 and EXT2
-
-
Manually annotated by BRENDA team
recombinant enzymes EXT1 and EXT2 lacking transmembrane domains
-
-
Manually annotated by BRENDA team
gene sext1 and ext2
-
-
Manually annotated by BRENDA team
Mus musculus BALB/c
gene sext1 and ext2
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
malfunction
-
slight change in the number of developing B cells in B-cell Ext1-deficient mice, but alteration does not cause a change in antibody production
malfunction
-
EXT1 influences fibroblast matrix interactions. Essential role of EXT1 in providing specific binding sites for growth factors and extracellular matrix proteins. Phosphorylation of ERK1/2 in response to FGF2 stimulation is markedly decreased in the Ext1 mutant fibroblasts, whereas neither PDGF-BB nor FGF10 signaling is significantly affected. Ext1 mutants display reduced ability to attach to collagen I and to contract collagen lattices. Reintroduction of Ext1 in Ext1 mutant fibroblasts rescues heparan sulfate chain length, FGF2 signaling, and the ability of the fibroblasts to contract collagen
malfunction
-
Fgf targeted gene expression is reduced in ext2 mutants and the remaining expression is readily inhibited by SU5402, an FGF receptor inhibitor. In the ext2 mutants, Fgf signaling is affected during nervous system development, mechanism, overview, and reduction of Fgf ligands in the mutants affects tail development. Wnt signaling is also affected in the ext2 mutants, while Hh dependent signaling is apparently unaffected in the ext2 mutants, Hh targeted gene expression is not reduced, the Hh inhibitor cyclopamine is not more affective in the mutants and Hh-dependent cell differentiation in the retina and in the myotome are normal in ext2 mutants, ext2 mutant phenotypes, overview
malfunction
-
a reduction in either Ext1 or Ext2 can cause a reduction in heparan sulfate biosynthesis, overview. Suppression of Ext1 by siRNA in FBJ-S1 cells results in the decreased expression of heparan sulfate and enhanced motility
malfunction
Mus musculus BALB/c
-
a reduction in either Ext1 or Ext2 can cause a reduction in heparan sulfate biosynthesis, overview. Suppression of Ext1 by siRNA in FBJ-S1 cells results in the decreased expression of heparan sulfate and enhanced motility
-
physiological function
-
the level of expression of EXT1 and EXT2 affects the amount of glucosaminyl N-deacetylase/N-sulfotransferase 1 (NDST1) present in the cell, which, in turn, greatly influences heparan sulfate structure. Overexpression of EXT2 in HEK 293 cells enhances NDST1 expression, increases NDST1 N-glycosylation, and results in elevated heparan sulfate sulfation, overexpression of EXT1 has opposite effects. Heart tissue from transgenic mice overexpressing EXT2 shows increased NDST activity. NDST1 interacts with EXT2, NDST1 may compete with EXT1 for binding to EXT2
physiological function
-
Ext1 and Ext2 together form a copolymerase which is responsible for the polymerization process where repeating units of N-acetylglucosamine and glucuronic acid are incorporated in the growing linear polysaccharide chain, see also EC 2.4.1.224. Gene ext2 is involved in Fgf and Wnt signaling but not in Hh signaling, ext2 is a general enhancer of Fgf target gene expression, ext2 interacts genetically with Fgf signaling during tail development, specificity for gene ext2 in signaling pathways during embryonic development, overview
physiological function
-
Ext1 and Ext2 are tumor suppressors. In the biosynthesis of heparan sulfate, after the attachment of a GlcNAc residue to GlcA-Gal-Gal-Xyl, Ext1 and Ext2 catalyze the subsequent elongation of glycosaminoglycans by alternately adding GlcA and GlcNAc to the end of the growing chain. Involvement of Ext1 and heparanase in migration of FBJ osteosarcoma cells, overview
physiological function
Mus musculus BALB/c
-
Ext1 and Ext2 are tumor suppressors. In the biosynthesis of heparan sulfate, after the attachment of a GlcNAc residue to GlcA-Gal-Gal-Xyl, Ext1 and Ext2 catalyze the subsequent elongation of glycosaminoglycans by alternately adding GlcA and GlcNAc to the end of the growing chain. Involvement of Ext1 and heparanase in migration of FBJ osteosarcoma cells, overview
-
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
show the reaction diagram
-
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
show the reaction diagram
-
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
show the reaction diagram
-
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
show the reaction diagram
Q16394, Q93063
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
show the reaction diagram
-
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
show the reaction diagram
O77783
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
show the reaction diagram
-
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
show the reaction diagram
-
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
show the reaction diagram
-
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
show the reaction diagram
-
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
show the reaction diagram
Q9V730, Q9Y169
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
show the reaction diagram
P97464
-
-
-
?
UDP-N-acetyl-D-glucosamine + alpha-D-glucuronosyl-(1-4)-N-acetylglucoside
UDP + alpha-N-acetyl-D-glucosaminyl-alpha-D-glucuronosyl-(1-4)-N-acetylglucoside
show the reaction diagram
-
-
-
-
?
K5 heptasaccharide + UDP-alpha-D-glucuronate
?
show the reaction diagram
Escherichia coli, Escherichia coli K5, Escherichia coli O18:K5
-
-
-
-
?
additional information
?
-
-
EXT1 has both GlcNAc transferase activity of EC 2.4.1.224 and GlcA transferase activity of EC 2.4.1.225, EXT2 only has low activity of EC 2.4.1.225, coexpression of EXT1 and EXT2 yields high activity of EC 2.4.1.225 and low activity of EC 2.4.1.224
-
-
-
additional information
?
-
-
formation of homo- and heterooligomeric complexes of EXT1 and EXT2, heterooligomeric complexes have substantially higher glycosyltransferase activity than EXT1 or EXT2 alone
-
-
-
additional information
?
-
-
formation of homo- and heterooligomeric complexes of EXT1 and EXT2, heterooligomeric complexes have substantially higher glycosyltransferase activity than EXT1 or EXT2 has alone
-
-
-
additional information
?
-
Mus musculus, Mus musculus BALB/c
-
the Ext1/Ext2 complex possesses higher glycosyltransferase activity than Ext1 or Ext2 alone
-
-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
show the reaction diagram
-
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
show the reaction diagram
O77783
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
show the reaction diagram
-
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
UDP + beta-glucuronosyl-(1-4)-N-acetyl-alpha-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-proteoglycan
show the reaction diagram
-
-
-
-
?
additional information
?
-
Mus musculus, Mus musculus BALB/c
-
the Ext1/Ext2 complex possesses higher glycosyltransferase activity than Ext1 or Ext2 alone
-
-
-
SPECIFIC ACTIVITY [µmol/min/mg]
SPECIFIC ACTIVITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
0.000012
-
-
-
additional information
-
-
12000000 dpm 3H/mg; 6700000 dpm 14C/mg
pI VALUE
pI VALUE MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
6
-
-
EXT2, calculated
7.5
-
-
heterodimer EXT1/EXT2, calculated
9
-
-
EXT1, calculated
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
-
loss of one copy of either the EXT1 or EXT2 gene product compromises the perichondrial chondrocytes’ ability to differentiate normally and to survive in a differentiated state in vitro
Manually annotated by BRENDA team
-
peripheral chondrosarcoma; peripheral chondrosarcoma
Manually annotated by BRENDA team
-
Sv40 embryonic cell line
Manually annotated by BRENDA team
-
high level of EXT2 in EXT2-overexpressing mice
Manually annotated by BRENDA team
-
enzyme EXT1
Manually annotated by BRENDA team
-
FBJ, highly metastatic mouse osteosarcoma FBJ-LL cells and the poorly metastatic FBJ-S1 cells are produced from a FBJ virus-induced osteosarcoma
Manually annotated by BRENDA team
Mus musculus BALB/c
-
FBJ, highly metastatic mouse osteosarcoma FBJ-LL cells and the poorly metastatic FBJ-S1 cells are produced from a FBJ virus-induced osteosarcoma
-
Manually annotated by BRENDA team
additional information
-
T cells and B cells
Manually annotated by BRENDA team
additional information
-
kidney extract is devoid of EXT2 in EXT2-overexpressing mice
Manually annotated by BRENDA team
additional information
-
zebrafish ext2 gene is ubiquitously expressed during zebrafish development
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
identical localization of sotv and ttv
Manually annotated by BRENDA team
-
Ext1 and Ext2 are type II transmembrane glycoproteins
Manually annotated by BRENDA team
Mus musculus BALB/c
-
Ext1 and Ext2 are type II transmembrane glycoproteins
-
Manually annotated by BRENDA team
-
identical localization of sotv and ttv
Manually annotated by BRENDA team
-
transmembrane glycoprotein
Manually annotated by BRENDA team
Escherichia coli K5, Escherichia coli O18:K5
-
-
-
Manually annotated by BRENDA team
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
80000
-
-
EXT2, gel filtration
81900
-
O77783
calculation from amino acid sequence
160000
-
-
EXT1, and coexpressed EXT1/EXT2, gel filtration
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
dimer
-
2 * 80000, EXT1, calculated, 1 * 80000 + 1 * 80000, EXT1/EXT2 heterodimer, calculated
monomer
O77783
1 * 70000, SDS-PAGE
monomer
-
80000, EXT2, calculated
additional information
-
formation of heterooligomers of ttv and sotv, co-immunoprecipitation experiments
additional information
-
formation of homo- and heterooligomeric complexes of EXT1 and EXT2, heterooligomeric complexes have substantially higher glycosyltransferase activity than EXT1 or EXT2 alone
additional information
-
formation of homo- and heterooligomeric complexes of EXT1 and EXT2, heterooligomeric complexes have substantially higher glycosyltransferase activity than EXT1 or EXT2 has alone
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
glycoprotein
-
-
glycoprotein
-
Ext1 and Ext2 are type II transmembrane glycoproteins
glycoprotein
Mus musculus BALB/c
-
Ext1 and Ext2 are type II transmembrane glycoproteins
-
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
expression in COS-7 cells as His/FLAG fusion protein
O77783
expressed in HEK-293 cells
-
expressed in Drosophila melanogaster
-
expressed in HEK-293 cells
-
EXT1 and EXT2 cDNA, alone or in combination, cloned into the pBudCE4.1 vector, which contains two multiple cloning sites for simultaneous expression of two proteins. EXT1 cloned into the multiple cloning sites with the cytomegalovirus (CMV) immediate-early promotor and EXT2 into the multiple cloning sites with the human elongation factor 1alpha promotor. Constructs transfected into HEK-293 cells stably expressing NDST1 from the pCDNA3 vector. Mutated EXT2 cDNA cloned into the pBudCE4.1 vector and transfected into HEK-93 cells overexpressing NDST1. EXT2 cDNA inserted into the pCAGGS expression vector under the control of the CMV immediate-early enhancer and the chicken beta-actin promoter (CAG) for constitutively high tissue expression from fertilized eggs and early embryonic stage through adulthood. The cDNA construct cloned into the unique EcoR1 site between the CAG promoter and the rabbit beta-globin sequence. Vector linearized with BamH1 and SalI and injected into mice B6CBAF1 oocytes
-
full-length Ext1 cDNA cloned into the pBudCE4.1 vector and transfected into Ext1Gt/Gt fibroblasts
-
expression in CHO cells
-
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
medicine
-
the mutation status of patients with multiple osteochondromas correlates with decreased EXT1 or EXT2 expression, loss of EXT expression disrupts the function of the EXT1/2 complex in heparan sulfate proteoglycan biosynthesis, resulting in the intracellular accumulation of heparan sulfate proteoglycan core proteins in tumo tissues; the mutation status of patients with multiple osteochondromas correlates with decreased EXT1 or EXT2 expression, loss of EXT expression disrupts the function of the EXT1/2 complex in heparan sulfate proteoglycan biosynthesis, resulting in the intracellular accumulation of heparan sulfate proteoglycan core proteins in tumo tissues
Y419X
-
the EXT2 mutation results in a truncated protein
additional information
-
enzyme null mutants, defects in Hedgehog and Decapentaplegic signalling, abnormal distribution of Wingless morphogen
additional information
-
enzyme null mutant, dramatically reduced levels of heparan sulfate, impaired Hedgehog, Wingless and Decapentaplegic signalling, alterations in chondroitin sulfate composition and levels
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
medicine
-
analysis of enzyme mutations in patients with hereditary multiple exostoses, mutation spectrum
medicine
-
there is deficiency of heparan sulfate and perlecan, together with accumulation of collagens in the matrix of EXT1-associated osteosarcomas