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Information on EC 2.4.1.225 - N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase and Organism(s) Mus musculus and UniProt Accession P97464
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2.4.1.225 N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferaseIUBMB Comments
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.
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Word Map
- 2.4.1.225
- exostoses
- proteoglycans
- osteochondroma
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hspgs
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thsd7a
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ext-like
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extls
- tout-velu
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nell-1
- medicine
The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Reaction Schemes
Synonyms
extl3, exostosin, rib-1, ext-1, rib-2, ext-2, tout velu, heparan sulfate co-polymerase, ext-3, glucuronic acid/n-acetylglucosamine co-polymerase-1, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
diphosphoglucuronate:oligosaccharide uridine glucuronosyltransferase
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exostosin-1
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exostosin-2
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exotose-2
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gene EXTL1 glycosyltransferase
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gene EXTL2 glycosyltransferase
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glucuronosyltransferase
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heparan glucuronosyltransferase II
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heparan sulfate co-polymerase
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heparan sulfate glucuronosyltransferase
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N-acetylglucosaminylproteoglycan beta-1,4-glucuronosyltransferase
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UDP-glucuronate:oligosaccharide
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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.
CAS REGISTRY NUMBER
COMMENTARY
145539-84-0
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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
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
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-
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?
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
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?
additional information
?
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the Ext1/Ext2 complex possesses higher glycosyltransferase activity than Ext1 or Ext2 alone
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?
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
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
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?
additional information
?
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the Ext1/Ext2 complex possesses higher glycosyltransferase activity than Ext1 or Ext2 alone
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-
?
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
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FBJ, highly metastatic mouse osteosarcoma FBJ-LL cells and the poorly metastatic FBJ-S1 cells are produced from a FBJ virus-induced osteosarcoma
additional information
additional information
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kidney extract is devoid of EXT2 in EXT2-overexpressing mice
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
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Ext1 and Ext2 are type II transmembrane glycoproteins
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
Exostosin glycosyltransferases exclusively catalyze heparan sulfate polymerization. Heparan sulfate/heparin, chondroitin sulfate, dermatan sulfate, and keratan sulfate form glycosaminoglycans, long linear polysaccharide chains consisting of repeat disaccharide units. Glycosaminoglycans are the major components of the extracellular matrix and play critical roles in regulating transport and signaling of numerous growth factors during embryonic development
physiological function
malfunction
physiological function
malfunction
deletion of Ext1 in the mesoderm induces a cardiac phenotype similar to that of a mutant with conditional deletion of UDP-glucose dehydrogenase, a key enzyme responsible for synthesis of all glycosaminoglycans. The outflow tract defect in conditional Ext1 knockout (Ext1f/f:Mesp1Cre) mice is attributable to the reduced contribution of second heart field and neural crest cells. Ext1 deletion leads to downregulation of FGF signaling in the pharyngeal mesoderm. Exogenous FGF8 ameliorates the defects in the outflow tract and pharyngeal explants. Phenotype, detailed overview
malfunction
ectopic cartilage forms in Ext1-deficient mouse embryo long bones, phenotype overview. perichondrium phenotype and border function regulation is deregulated in hereditary multiple exostoses. Ext1 deficiency stimulates cartilage formation
malfunction
effect of heterozygous mutations in heparan sulfate elongation genes EXT1 and EXT2 on endothelial function in vitro as well as in vivo, phenotype, overview
physiological function
Ext1 is a glycosyltransferase responsible for heparan sulfate synthesis. Function of Ext1 in heart development, overview. Ext1 expression in second heart field and neural crest cells is required for outflow tract remodeling. Ext1 is crucial for outflow tract formation in distinct progenitor cells, and heparan sulfate modulates FGF signaling during early heart development. Proper expression of Ext1 is required for cardiogenesis, heparan sulfate is required for heart development
physiological function
heparan sulfate elongation genes EXT1 and EXT2 are involved in heparan sulfate elongation and in maintaining endothelial homeostasis, presumably via increased nitric oxide bioavailability
physiological function
perichondrium phenotype and border function are deranged by Ext1 and heparan sulfate in developing long bones, and in ectopic cartilage formation
malfunction
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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
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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
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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
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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
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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
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). EXT1_MOUSE
746
1
86308
Swiss-Prot
Secretory Pathway (Reliability: 4)
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
generation of Ext1+/- mice, endothelial glycocalyx and maximal arteriolar dilatation are significantly altered in Ext1+/- mice compared to wild-type littermates
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene EXT1, creation of loxP-modified Ext1 allele and establishment of the Ext1 floxed mouse line (Ext1flox/flox), expression of the enzyme in Gdf-5-Cre transgenic mice, semiquantitative real-time PCR enzyme expression analysis
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
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full-length Ext1 cDNA cloned into the pBudCE4.1 vector and transfected into Ext1Gt/Gt fibroblasts
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Lidholt, K.; Fjelstad, M.; Jann, K.; Lindahl, U.
Biosynthesis of heparin. XXV. Substrate specificities of glucosyltransferases involved in formation of heparin precursor and E. coli K5 capsular polysaccharides
Carbohydr. Res.
255
87-101
1994
Escherichia coli, Escherichia coli K5, Mus musculus
Nadanaka, S.; Ishida, M.; Ikegami, M.; Kitagawa, H.
Chondroitin 4-O-sulfotransferase-1 modulates Wnt-3a signaling through control of E disaccharide expression of chondroitin sulfate
J. Biol. Chem.
283
27333-27343
2008
Mus musculus (P97464)
Garner, O.B.; Yamaguchi, Y.; Esko, J.D.; Videm, V.
Small changes in lymphocyte development and activation in mice through tissue-specific alteration of heparan sulphate
Immunology
125
420-429
2008
Mus musculus
Osterholm, C.; Barczyk, M.M.; Busse, M.; Gronning, M.; Reed, R.K.; Kusche-Gullberg, M.
Mutation in the heparan sulfate biosynthesis enzyme EXT1 influences growth factor signaling and fibroblast interactions with the extracellular matrix
J. Biol. Chem.
284
34935-34943
2009
Mus musculus
Presto, J.; Thuveson, M.; Carlsson, P.; Busse, M.; Wilen, M.; Eriksson, I.; Kusche-Gullberg, M.; Kjellen, L.
Heparan sulfate biosynthesis enzymes EXT1 and EXT2 affect NDST1 expression and heparan sulfate sulfation
Proc. Natl. Acad. Sci. USA
105
4751-4756
2008
Mus musculus
Wang, Y.; Yang, X.; Yamagata, S.; Yamagata, T.; Sato, T.
Involvement of Ext1 and heparanase in migration of mouse FBJ osteosarcoma cells
Mol. Cell. Biochem.
373
63-72
2013
Mus musculus, Mus musculus BALB/c
Huegel, J.; Mundy, C.; Sgariglia, F.; Nygren, P.; Billings, P.C.; Yamaguchi, Y.; Koyama, E.; Pacifici, M.
Perichondrium phenotype and border function are regulated by Ext1 and heparan sulfate in developing long bones: a mechanism likely deranged in hereditary multiple exostoses
Dev. Biol.
377
100-112
2013
Mus musculus (P97464)
Mooij, H.L.; Cabrales, P.; Bernelot Moens, S.J.; Xu, D.; Udayappan, S.D.; Tsai, A.G.; van der Sande, M.A.; de Groot, E.; Intaglietta, M.; Kastelein, J.J.; Dallinga-Thie, G.M.; Esko, J.D.; Stroes, E.S.; Nieuwdorp, M.
Loss of function in heparan sulfate elongation genes EXT1 and EXT 2 results in improved nitric oxide bioavailability and endothelial function
J. Am. Heart Assoc.
3
e001274
2014
Homo sapiens (P70428), Homo sapiens (Q16394), Homo sapiens (Q93063), Mus musculus (P97464)
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