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Information on EC 2.4.1.225 - N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase and Organism(s) Homo sapiens

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IUBMB 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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Homo sapiens
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Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
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
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
diphosphoglucuronate:oligosaccharide uridine glucuronosyltransferase
-
-
-
-
exostosin
-
-
exostosin-1
exostosin-2
exotose-2
-
-
-
-
EXT-1
EXT-2
isozyme
EXT-3
-
isozyme
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
-
-
-
-
gene EXTL2 glycosyltransferase
-
-
-
-
glucuronosyltransferase
-
-
-
-
heparan glucuronosyltransferase II
-
-
-
-
heparan sulfate co-polymerase
-
-
-
-
heparan sulfate glucuronosyltransferase
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-
-
-
heparan sulfate synthesis enzyme
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N-acetylglucosaminylproteoglycan beta-1,4-glucuronosyltransferase
-
-
-
-
UDP-glucuronate:oligosaccharide
-
-
-
-
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 hide
145539-84-0
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
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-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
-
-
-
-
?
additional information
?
-
pI VALUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6
-
EXT2, calculated
7.5
-
heterodimer EXT1/EXT2, calculated
9
-
EXT1, calculated
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
peripheral chondrosarcoma
Manually annotated by BRENDA team
skin-derived
Manually annotated by BRENDA team
-
enzyme EXT1
Manually annotated by BRENDA team
EXT1, NDST1, and NDST2 differentially regulate heparan sulfate biosynthesis in human tooth germ
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
-
transmembrane glycoprotein
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
metabolism
the enzymes is involved in heparan sulfate biosynthesis. EXT1, NDST1, and NDST2 differentially regulate heparan sulfate biosynthesis in human tooth germ
physiological function
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
EXT1_HUMAN
746
1
86255
Swiss-Prot
Secretory Pathway (Reliability: 4)
EXT2_HUMAN
718
1
82255
Swiss-Prot
Mitochondrion (Reliability: 5)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
160000
-
EXT1, and coexpressed EXT1/EXT2, gel filtration
80000
-
EXT2, gel filtration
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer
-
2 * 80000, EXT1, calculated, 1 * 80000 + 1 * 80000, EXT1/EXT2 heterodimer, calculated
monomer
-
80000, EXT2, calculated
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
COMMENTARY hide
LITERATURE
glycoprotein
-
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C333R
naturally occuring mutation in hereditary multiple exostoses syndrome
L462W
naturally occuring mutation in hereditary multiple exostoses syndrome
L46F
naturally occuring mutation in hereditary multiple exostoses syndrome
M87R
naturally occuring mutation from a patient with clinical seizures-scoliosis-macrocephaly syndrome
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
N288K
naturally occuring mutation in hereditary multiple exostoses syndrome
R227D
naturally occuring mutation in hereditary multiple exostoses syndrome
R340H
naturally occuring mutation in hereditary multiple exostoses syndrome
R95C
naturally occuring mutation from a patient with clinical seizures-scoliosis-macrocephaly syndrome
S344F
naturally occuring mutation in hereditary multiple exostoses syndrome
S478L
naturally occuring mutation in hereditary multiple exostoses syndrome
V68G
naturally occuring mutation in hereditary multiple exostoses syndrome
Y419X
-
the EXT2 mutation results in a truncated protein
additional information
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Drosophila melanogaster
-
expressed in HEK-293 cells
-
gene EXT2, genotyping, autozygosity mapping
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
EXT1 is significantly decreased in MCF7 cells compared with the non-tumorigenic MCF10A cells, while no significant difference is observed between the two triple-negative cell lines, MDA-MB-231 and HCC38, and the ER- and PR-positive MCF10A cells
EXT2 is down-regulated in MDA-MB-231 and HCC38 epithelial breast carcinoma cell lines
the expression of EXT2 is reduced in all cancer cell lines
the overall transcriptional activity of the main heparan sulfate biosynthesis-involved genes (EXT1, EXT2, NDST1,NDST2, GLCE, HS2ST1, HS3ST1, HS3ST2, HS6ST1, HS6ST2, SULF1, SULF2, HPSE) is decreased by 1.5-2fold in Grade II-III glioma (p < 0.01) and by 3-fold in Grade IV glioma (glioblastoma multiforme, GBM) (p < 0.05), as compared with the para-tumourous tissue
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Wuyts, W.; van Hul, W.
Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes
Hum. Mutat.
15
220-227
2000
Homo sapiens
Manually annotated by BRENDA team
Busse, M.; Kusche-Gullberg, M.
In vitro polymerization of heparan sulfate backbone by the EXT proteins
J. Biol. Chem.
278
41333-41337
2003
Homo sapiens
Manually annotated by BRENDA team
McCormick, C.; Duncan, G.; Goutsos, K.T.; Tufaro, F.
The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heapran sulfate
Proc. Natl. Acad. Sci. USA
97
668-673
2000
Bos taurus, Homo sapiens
Manually annotated by BRENDA team
Hecht, J.T.; Hayes, E.; Haynes, R.; Cole, W.G.; Long, R.J.; Farach-Carson, M.C.; Carson, D.D.
Differentiation-induced loss of heparan sulfate in human exostosis derived chondrocytes
Differentiation
73
212-221
2005
Homo sapiens
Manually annotated by BRENDA team
Dasgupta, U.; Dixit, B.L.; Rusch, M.; Selleck, S.; The, I.
Functional conservation of the human EXT1 tumor suppressor gene and its Drosophila homolog tout velu
Dev. Genes Evol.
217
555-561
2007
Drosophila melanogaster, Homo sapiens
Manually annotated by BRENDA team
Roberts, I.S.; Gleadle, J.M.
Familial nephropathy and multiple exostoses with exostosin-1 (EXT1) gene mutation
J. Am. Soc. Nephrol.
19
450-453
2008
Homo sapiens
Manually annotated by BRENDA team
Nadanaka, S.; Kitagawa, H.
Heparan sulphate biosynthesis and disease
J. Biochem.
144
7-14
2008
Caenorhabditis elegans, Homo sapiens, Homo sapiens (Q16394), Homo sapiens (Q93063), Drosophila melanogaster (Q9V730), Drosophila melanogaster (Q9Y169)
Manually annotated by BRENDA team
Busse, M.; Feta, A.; Presto, J.; Wilen, M.; Gronning, M.; Kjellen, L.; Kusche-Gullberg, M.
Contribution of EXT1, EXT2, and EXTL3 to heparan sulfate chain elongation
J. Biol. Chem.
282
32802-32810
2007
Homo sapiens
Manually annotated by BRENDA team
Hameetman, L.; David, G.; Yavas, A.; White, S.J.; Taminiau, A.H.; Cleton-Jansen, A.; Hogendoom, P.C.; Bovee, J.V.
Decreased EXT expression and intracellular accumulation of heparan sulphate proteoglycan in osteochondromas and peripheral chondrosarcomas
J. Pathol.
211
399-409
2007
Homo sapiens (Q16394), Homo sapiens (Q93063)
Manually annotated by BRENDA team
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)
Manually annotated by BRENDA team
Farhan, S.M.; Wang, J.; Robinson, J.F.; Prasad, A.N.; Rupar, C.A.; Siu, V.M.; Siu, V.M.; Hegele, R.A.
Old gene, new phenotype: mutations in heparan sulfate synthesis enzyme, EXT2 leads to seizure and developmental disorder, no exostoses
J. Med. Genet.
52
666-675
2015
Homo sapiens (Q93063), Homo sapiens
Manually annotated by BRENDA team
Wu, Z.; Wang, Y.; Wang, J.; Chen, Y.; Guo, Y.
The role of EXT1 gene mutation and its high expression of calcitonin gene-related peptide in the development of multiple exostosis
Biochem. Biophys. Res. Commun.
505
959-965
2018
Homo sapiens (Q16394)
Manually annotated by BRENDA team
Sembajwe, L.; Katta, K.; Gronning, M.; Kusche-Gullberg, M.
The exostosin family of glycosyltransferases MRNA expression profiles and heparan sulphate structure in human breast carcinoma cell lines
Biosci. Rep.
38
1-12
2018
Homo sapiens (Q16394), Homo sapiens (Q93063), Homo sapiens
Manually annotated by BRENDA team
Kero, D.; Bilandzija, T.; Arapovic, L.; Vukojevic, K.; Saraga-Babic, M.
Syndecans and enzymes involved in heparan sulfate biosynthesis and degradation are differentially expressed during human dontogenesis
Front. Physiol.
9
732
2018
Homo sapiens (Q16394)
Manually annotated by BRENDA team
Okolicsanyi, R.K.; Bluhm, J.; Miller, C.; Griffiths, L.R.; Haupt, L.M.
An investigation of genetic polymorphisms in heparan sulfate proteoglycan core proteins and key modification enzymes in an Australian Caucasian multiple sclerosis population
Hum. Genomics
14
18
2020
Homo sapiens (Q16394)
Manually annotated by BRENDA team
Ushakov, V.; Tsidulko, A.; De La Bourdonnaye, G.; Kazanskaya, G.; Volkov, A.; Kiselev, R.; Kobozev, V.; Kostromskaya, D.; Gaytan, A.; Krivoshapkin, A.; Aidagulova, S.; Grigorieva, E.
Heparan sulfate biosynthetic system is inhibited in human glioma due to EXT1/2 and HS6ST1/2 down-regulation
Int. J. Mol. Sci.
18
2301
2017
Homo sapiens (Q16394), Homo sapiens (Q93063)
Manually annotated by BRENDA team
Wang, X.; Cornelis, F.M.F.; Lories, R.J.; Monteagudo, S.
Exostosin-1 enhances canonical Wnt signaling activity during chondrogenic differentiation
Osteoarthritis Cartilage
27
1702-1710
2019
Homo sapiens (Q16394)
Manually annotated by BRENDA team