2.4.1.224: glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase
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For detailed information about glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase, go to the full flat file.
Word Map on EC 2.4.1.224
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2.4.1.224
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proteoglycans
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exostoses
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osteochondroma
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glycosaminoglycans
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glycosyltransferase
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hedgehog
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hspgs
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chondrosarcoma
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cartilaginous
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syndecan-1
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glypicans
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cartilage-capped
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wingless
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perlecan
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metaphyses
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decapentaplegic
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co-polymerase
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medicine
- 2.4.1.224
- proteoglycans
- exostoses
- osteochondroma
- glycosaminoglycans
- glycosyltransferase
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hedgehog
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hspgs
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chondrosarcoma
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cartilaginous
- syndecan-1
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glypicans
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cartilage-capped
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wingless
- perlecan
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metaphyses
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decapentaplegic
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co-polymerase
- medicine
Reaction
Synonyms
alpha-N-acetylglucosaminyltransferase II, exostosin-1, exostosin-2, Exostosin1, Exostosin2, EXT1, EXT2, extosin, glucuronyl-N-acetylglucosaminoproteoglycan 4-alpha-N-acetylglucosaminyltransferase, heparan sulfate polymerase, heparan sulfate synthesis enzyme, KfiA, More, N-acetyl-D-glucosaminyl-(N-acetyl-D-glucosamine) transferase, sister of tout velu, sister of tout-velu, sotv, tout-velu, ttv, UDP-GlcNAc:oligosaccharide beta-N-acetylglucosaminyltransferase
ECTree
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General Information
General Information on EC 2.4.1.224 - glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase
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malfunction
metabolism
physiological function
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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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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
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conditional Ext1 mutant mice display severe limb skeletal defects, including shortened and malformed limb bones, oligodactyly, and fusion of joints. the segregation of the pSmad1/5/8-expressing chondrocytes and fibronectin-expressing perichondrium-like cells surrounding chondrocyte nodules is disrupted in mutant micromass cultures, Ext2-mutant phenotypes, detailed overview
malfunction
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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
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
malfunction
effect of heterozygous mutations in heparan sulfate elongation genes EXT1 and EXT2 on endothelial function in vitro as well as in vivo. Silencing of microvascular endothelial cell EXT1 and EXT2 under flow led to significant upregulation of endothelial nitric oxide synthesis and phospho-endothelial nitric oxide synthesis protein expression. Brachial artery flow-mediated dilation is significantly increased in hereditary multiple exostoses (HME) patients. In humans, heterozygous loss of function mutation in EXT1 and EXT2 are known to be involved in the development of HME syndrome, a disorder associated with bony tumor formation. In these humans, the loss-of-function mutations lead to alterations in the structure of tissue and plasma heparan sulfate composition, phenotype, overview
malfunction
mutations in the tumor suppressor genes EXT1 and EXT2 disturb heparan sulfate proteoglycan biosynthesis and cause multiple osteochondroma. A reduction in Rti shifts the steady-state distribution of EXTs to the trans-Golgi. These accumulated EXTs tend to be degraded and their re-entrance towards the route for polymerizing GAG chains is disengaged. Conversely, EXTs are mislocalized towards the transitional endoplasmic reticulum/cis-Golgi when Rti is overexpressed. Both loss of function and overexpression of rti result in incomplete heparan sulfate proteoglycans and perturb Hedgehog signaling
malfunction
phenotype of four patients showing clinical seizures-scoliosis-macrocephaly syndrome with seizures and macrocephaly due to decreased EXT2 expression and mutations M87R and R95C. SSM syndrome is characterised by seizures, intellectual disability, hypotonia, scoliosis, macrocephaly, hypertelorism and renal dysfunction. Phenotype, overview
malfunction
Ext1 knock-down reduces heparan sulfate, and increases chondrogenic markers and proteoglycan accumulation. Ext1 knock-down reduces active Wnt/beta-catenin signaling
malfunction
screening and identifying the gene mutation of EXT1 associated with multiple exostosis and the expression in tumor tissues
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
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malfunction
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conditional Ext1 mutant mice display severe limb skeletal defects, including shortened and malformed limb bones, oligodactyly, and fusion of joints. the segregation of the pSmad1/5/8-expressing chondrocytes and fibronectin-expressing perichondrium-like cells surrounding chondrocyte nodules is disrupted in mutant micromass cultures, Ext2-mutant phenotypes, detailed overview
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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
metabolism
the enzymes is involved in heparan sulfate biosynthesis. EXT1, NDST1, and NDST2 differentially regulate heparan sulfate biosynthesis in human tooth germ
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in patients with hereditary multiple exostoses, functional loss of EXT1 results in exostoses (osteochondromas), but inactivation of both copies of the gene (germline mutation plus loss of the remaining wild-type allele) is not required for development of the bone lesions. No reported association between EXT1 abnormalities and renal disease. Deficiency of heparan sulfate and perlecan, together with accumulation of collagens, in the matrix of EXT1-associated osteochondromas
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
physiological function
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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 2.4.1.225. 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
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Ext1 encodes an essential glycosyltransferase for heparan sulfate synthesis, heparan sulfate is essential for patterning of limb skeletal elements
physiological function
exostosin (EXT) genes encode glycosyltransferases required for glycosaminoglycan chain polymerization in the biosynthesis of heparan sulfate proteoglycans. Synthesis of heparan sulfate proteoglycans requires sequential enzymatic modifications of glycoproteins in the Golgi. Drosophila Golgi phosphoprotein 3, GOLPH3 or rotini, Rti, regulates the biosynthesis of heparan sulfate proteoglycans by modulating the retrograde trafficking of exostosins. Rti regulates the stability of EXTs
physiological function
exostosin (EXT) genes encode glycosyltransferases required for glycosaminoglycan chain polymerization in the biosynthesis of heparan sulfate proteoglycans. Synthesis of heparan sulfate proteoglycans requires sequential enzymatic modifications of glycoproteins in the Golgi. Drosophila Golgi phosphoprotein 3, GOLPH3 or rotini, Rti, regulates the biosynthesis of heparan sulfate proteoglycans by modulating the retrograde trafficking of exostosins. Rti regulates the stability of EXTs. Proper function of EXTs depends not only on their enzymatic activities but also on their sub-compartmental distributions
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
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
physiological function
key enzyme contributing to the generation of heparan sulfate chains. EXT1, with tumour suppressor properties, is involved in the initiation and polymerisation of the growing heparan sulfate chain. The study may suggest that no association exists between EXT1 and multiple sclerosis
physiological function
key enzymes contributing to the generation of heparan sulfate chains. EXT1, with documented tumour suppressor properties, is involved in the initiation and polymerisation of the growing heparan sulfate chain
physiological function
the enzyme is involved in heparan sulfate biosynthesis
physiological function
the enzyme is required for heparan sulfate chain elongation in heparan sulfate-proteoglycan biosynthesis. EXT1 affects chondrogenic differentiation of precursor cells, in part via changes in the activity of Wnt/beta-catenin signaling. Wnt/beta-catenin signaling controls Ext1 expression, suggesting a regulatory loop between EXT1 and Wnt/beta-catenin signaling during chondrogenesis
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
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physiological function
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Ext1 encodes an essential glycosyltransferase for heparan sulfate synthesis, heparan sulfate is essential for patterning of limb skeletal elements
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