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Information on EC 2.4.1.225 - N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase
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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
-
hspgs
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thsd7a
-
ext-like
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extls
- tout-velu
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nell-1
- medicine
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Reaction Schemes
Synonyms
extl3, exostosin, rib-1, rib-2, ext-1, ext-2, tout velu, heparan sulfate co-polymerase, ext-3, glucuronic acid/n-acetylglucosamine co-polymerase-1, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
diphosphoglucuronate:oligosaccharide uridine glucuronosyltransferase
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exostosin-1
exostosin-2
exotose-2
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EXT-1
EXT1
EXT2
EXTL3
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the EXTL proteins exhibit overlapping glycosyltransferase activities in vitro, so it is not apparent what reactions they catalyze in vivo
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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sotv
ttv
UDP-glucuronate:oligosaccharide
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exostosin-1
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exostosin-2
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EXT1
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EXT1 and EXT2 form a Golgi-located hetero-oligomeric complex that catalyzes the chain elongation step in heparan sulfate biosynthesis
EXT2
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EXT1 and EXT2 form a Golgi-located hetero-oligomeric complex that catalyzes the chain elongation step in heparan sulfate biosynthesis
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
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
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PATHWAY SOURCE
PATHWAYS
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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.
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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
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
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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?
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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?
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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?
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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?
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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?
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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?
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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?
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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?
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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?
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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?
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
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?
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
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?
additional information
?
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formation of homo- and heterooligomeric complexes of EXT1 and EXT2, heterooligomeric complexes have substantially higher glycosyltransferase activity than EXT1 or EXT2 alone
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additional information
?
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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
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additional information
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formation of homo- and heterooligomeric complexes of EXT1 and EXT2, heterooligomeric complexes have substantially higher glycosyltransferase activity than EXT1 or EXT2 has alone
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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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additional information
?
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the Ext1/Ext2 complex possesses higher glycosyltransferase activity than Ext1 or Ext2 alone
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?
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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
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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?
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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?
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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?
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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?
additional information
?
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the Ext1/Ext2 complex possesses higher glycosyltransferase activity than Ext1 or Ext2 alone
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?
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Autoimmune Diseases
Immunopathological analysis of the expression of glomerular exostosin 1 and exostosin 2 in Japanese patients with lupus nephritis.
Breast Neoplasms
Exostosin 1 regulates cancer cell stemness in doxorubicin-resistant breast cancer cells.
Breast Neoplasms
Identification of a third EXT-like gene (EXTL3) belonging to the EXT gene family.
Breast Neoplasms
The exostosin family of glycosyltransferases: mRNA expression profiles and heparan sulphate structure in human breast carcinoma cell lines.
Carcinogenesis
REG3A/REG3B promotes acinar to ductal metaplasia through binding to EXTL3 and activating the RAS-RAF-MEK-ERK signaling pathway.
Cholangiocarcinoma
Increase of exostosin 1 in plasma as a potential biomarker for opisthorchiasis-associated cholangiocarcinoma.
Chondrosarcoma
Aberrant heparan sulfate proteoglycan localization, despite normal exostosin, in central chondrosarcoma.
Chondrosarcoma
Structural Features of Heparan Sulfate from Multiple Osteochondromas and Chondrosarcomas.
Colorectal Neoplasms
EXTL3 promoter methylation down-regulates EXTL3 and heparan sulphate expression in mucinous colorectal cancers.
Diabetes Mellitus, Type 2
Association between variants of EXT2 and type 2 diabetes: a replication and meta-analysis.
Diabetes Mellitus, Type 2
No correlation between the variants of exostosin 2 gene and type 2 diabetes in Burkina Faso population.
Endometriosis
EXTL3-interacting endometriosis-specific serum factors induce colony formation of endometrial stromal cells.
Exostoses
Structural analysis of glycosaminoglycans in animals bearing mutations in sugarless, sulfateless, and tout-velu. Drosophila homologues of vertebrate genes encoding glycosaminoglycan biosynthetic enzymes.
Exostoses
The molecular and cellular basis of exostosis formation in hereditary multiple exostoses.
Exostoses, Multiple Hereditary
A family with limb girdle muscular dystrophy type 1B and multiple exostoses.
Exostoses, Multiple Hereditary
Assessing the general population frequency of rare coding variants in the EXT1 and EXT2 genes previously implicated in hereditary multiple exostoses.
Exostoses, Multiple Hereditary
Case Report of the positive exostosin-1 without B-cell lymphoma-2 gene expression of giant cell tumor lesion in hereditary multiple exostosis.
Exostoses, Multiple Hereditary
Evaluation of the anatomic burden of patients with hereditary multiple exostoses.
Exostoses, Multiple Hereditary
Ext1 heterozygosity causes a modest effect on postprandial lipid clearance in humans.
Exostoses, Multiple Hereditary
Familial Solitary Chondrosarcoma Resulting from Germline EXT2 Mutation.
Exostoses, Multiple Hereditary
Functional conservation of the human EXT1 tumor suppressor gene and its Drosophila homolog tout velu.
Exostoses, Multiple Hereditary
Functional Requirements for Heparan Sulfate Biosynthesis in Morphogenesis and Nervous System Development in C. elegans.
Exostoses, Multiple Hereditary
Glycosaminoglycans in blood of hereditary multiple exostoses patients: Half reduction of heparan sulfate to chondroitin sulfate ratio and the possible diagnostic application.
Exostoses, Multiple Hereditary
Hereditary multiple osteochondromas in Jordanian patients: Mutational and immunohistochemical analysis of EXT1 and EXT2 genes.
Exostoses, Multiple Hereditary
Identification of Two Novel Frameshift Mutations in Exostosin 1 in Two Families with Multiple Osteochondromas.
Exostoses, Multiple Hereditary
Location of the glucuronosyltransferase domain in the heparan sulfate copolymerase EXT1 by analysis of Chinese hamster ovary cell mutants.
Exostoses, Multiple Hereditary
Mutation spectrum of EXT1 and EXT2 in the Saudi patients with hereditary multiple exostoses.
Exostoses, Multiple Hereditary
Mutational Analysis of Exostosin 1 and 2 Genes in Multiple Osteochondroma.
Exostoses, Multiple Hereditary
Mutational spectrum and clinical signatures in 114 families with hereditary multiple osteochondromas: insights into molecular properties of selected exostosin variants.
Exostoses, Multiple Hereditary
Novel mutation in the EXT-1 gene in an Iranian family affected with hereditary multiple exostoses.
Exostoses, Multiple Hereditary
Regulation of zebrafish skeletogenesis by ext2/dackel and papst1/pinscher.
Exostoses, Multiple Hereditary
Whole?exome sequencing identifies a novel mutation of SLC20A2 (c.C1849T) as a possible cause of hereditary multiple exostoses in a Chinese family.
Genetic Diseases, Inborn
Mutation spectrum of EXT1 and EXT2 in the Saudi patients with hereditary multiple exostoses.
Giant Cell Tumors
Case Report of the positive exostosin-1 without B-cell lymphoma-2 gene expression of giant cell tumor lesion in hereditary multiple exostosis.
Glomerulonephritis, Membranous
A Target Antigen-Based Approach to the Classification of Membranous Nephropathy.
Glomerulonephritis, Membranous
Immunopathological analysis of the expression of glomerular exostosin 1 and exostosin 2 in Japanese patients with lupus nephritis.
Glomerulonephritis, Membranous
In Patients with Membranous Lupus Nephritis, Exostosin-Positivity and Exostosin-Negativity Represent Two Different Phenotypes.
Glomerulonephritis, Membranous
Primary Membranous Nephropathy With Enhanced Staining of Exostosin 1/Exostosin 2 in the Glomeruli: A Report of 2 Cases.
Glomerulonephritis, Membranous
The Exostosin Immunohistochemical Status Differentiates Lupus Membranous Nephropathy Subsets With Different Outcomes.
Hypercholesterolemia
Ext1 heterozygosity causes a modest effect on postprandial lipid clearance in humans.
Lupus Nephritis
Immunopathological analysis of the expression of glomerular exostosin 1 and exostosin 2 in Japanese patients with lupus nephritis.
Lupus Nephritis
Treatment of exostosin 1-associated membranous lupus nephritis with multiple low doses of rituximab: A case report.
Mucopolysaccharidoses
Gene silencing of EXTL2 and EXTL3 as a substrate deprivation therapy for heparan sulphate storing mucopolysaccharidoses.
Muscular Diseases
A family with limb girdle muscular dystrophy type 1B and multiple exostoses.
Neoplasms
A tumorigenic cell line derived from a hamster cholangiocarcinoma associated with Opisthorchis felineus liver fluke infection.
Neoplasms
Case Report of the positive exostosin-1 without B-cell lymphoma-2 gene expression of giant cell tumor lesion in hereditary multiple exostosis.
Neoplasms
Chondroitin sulfate synthase 1 expression is associated with malignant potential of soft tissue sarcomas with myxoid substance.
Neoplasms
Exostosin 1 regulates cancer cell stemness in doxorubicin-resistant breast cancer cells.
Neoplasms
Expression of rib-1, a Caenorhabditis elegans homolog of the human tumor suppressor EXT genes, is indispensable for heparan sulfate synthesis and embryonic morphogenesis.
Neoplasms
Functional conservation of the human EXT1 tumor suppressor gene and its Drosophila homolog tout velu.
Neoplasms
Hedgehog movement is regulated through tout velu-dependent synthesis of a heparan sulfate proteoglycan.
Neoplasms
Human tumor suppressor EXT gene family members EXTL1 and EXTL3 encode alpha 1,4- N-acetylglucosaminyltransferases that likely are involved in heparan sulfate/ heparin biosynthesis.
Neoplasms
Location of the glucuronosyltransferase domain in the heparan sulfate copolymerase EXT1 by analysis of Chinese hamster ovary cell mutants.
Neoplasms
Mutation spectrum of EXT1 and EXT2 in the Saudi patients with hereditary multiple exostoses.
Neoplasms
rib-2, a Caenorhabditis elegans homolog of the human tumor suppressor EXT genes encodes a novel alpha1,4-N-acetylglucosaminyltransferase involved in the biosynthetic initiation and elongation of heparan sulfate.
Neoplasms
Structural analysis of glycosaminoglycans in Drosophila and Caenorhabditis elegans and demonstration that tout-velu, a Drosophila gene related to EXT tumor suppressors, affects heparan sulfate in vivo.
Neoplasms
Systematic interactome mapping of acute lymphoblastic leukemia cancer gene products reveals EXT-1 tumor suppressor as a Notch1 and FBWX7 common interactor.
Neoplasms
Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion.
Osteochondroma
Cell biology of osteochondromas: bone morphogenic protein signalling and heparan sulphates.
Osteochondroma
Detection of exostosin glycosyltransferase gene mutations in patients with non-hereditary osteochondromas of the mandibular condyle.
Osteochondroma
Differentiation-induced loss of heparan sulfate in human exostosis derived chondrocytes.
Osteochondroma
Structural Features of Heparan Sulfate from Multiple Osteochondromas and Chondrosarcomas.
Osteochondroma
The use of Bcl-2 and PTHLH immunohistochemistry in the diagnosis of peripheral chondrosarcoma in a clinicopathological setting.
Osteochondromatosis
A de novo mutation in the EXT2 gene associated with osteochondromatosis in a litter of American Staffordshire Terriers.
Osteosarcoma
Functional Requirements for Heparan Sulfate Biosynthesis in Morphogenesis and Nervous System Development in C. elegans.
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Systematic interactome mapping of acute lymphoblastic leukemia cancer gene products reveals EXT-1 tumor suppressor as a Notch1 and FBWX7 common interactor.
Sarcoma
Chondroitin sulfate synthase 1 expression is associated with malignant potential of soft tissue sarcomas with myxoid substance.
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
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pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
EXT1, NDST1, and NDST2 differentially regulate heparan sulfate biosynthesis in human tooth germ
brenda
additional information
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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
brenda
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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
brenda
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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
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brenda
additional information
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zebrafish ext2 gene is ubiquitously expressed during zebrafish development
brenda
additional information
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kidney extract is devoid of EXT2 in EXT2-overexpressing mice
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
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identical localization of sotv and ttv
brenda
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Ext1 and Ext2 are type II transmembrane glycoproteins
brenda
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Ext1 and Ext2 are type II transmembrane glycoproteins
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brenda
EXT isozymes are localized mainly in the cis- and middle-Golgi stacks. Rotini, Rti, mediates the retrograde transport of EXT enzymes within the Golgi complex. Rotini regulates the sub-compartmental distribution of EXTs in the Golgi
brenda
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
physiological function
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
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, 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
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 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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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