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Information on EC 2.8.2.8 - [heparan sulfate]-glucosamine N-sulfotransferase and Organism(s) Homo sapiens
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2.8.2.8 [heparan sulfate]-glucosamine N-sulfotransferaseIUBMB Comments
The enzyme also catalyses the sulfation of chondroitin 4-sulfate and dermatan sulfate, but to a much more limited extent.
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Word Map
- 2.8.2.8
- proteoglycans
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n-sulfation
- glycosaminoglycans
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n-deacetylation
-
sulfotransferases
- 5'-phosphosulfate
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ndsts
- 3'-phosphoadenosine
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2-o-sulfation
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2-o-sulfotransferase
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n-unsubstituted
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sulfuryl
- 3'-phosphoadenosine-5'-phosphosulfate
- hs3st1
- medicine
- diagnostics
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Synonyms
ndst1, ndst-1, ndst2, ndst3, ndst-2, ndst4, n-deacetylase/n-sulfotransferase-1, n-deacetylase/n-sulfotransferase, n-deacetylase/n-sulfotransferase 1, heparan sulfate n-deacetylase/n-sulfotransferase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
3'-phosphoadenylyl-sulfate:heparitin N-sulfotransferase
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3'-phosphoadenylylsulfate:N-desulfoheparin N-sulfotransferase
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3'-phosphoadenylylsulfate:N-desulfoheparin sulfotransferase
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desulfoheparin sulfotransferase
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heparan sulfate 2-N-sulfotransferase
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heparan sulfate N-deacetylase/N-sulfotransferase
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heparan sulfate N-sulfotransferase
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heparan sulfate sulfotransferase
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heparin N-sulfotransferase
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heparitin sulfotransferase
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N-deacetylase/N-sulfotransferase
N-desulfoheparin sulfotransferase
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N-heparan sulfate sulfotransferase
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N-HSST
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NDST
Ndst1
NDST2
PAPS:DSH sulfotransferase
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PAPS:N-desulfoheparin sulfotransferase
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sulfotransferase, desulfoheparin
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine = adenosine 3',5'-bisphosphate + [heparan sulfate]-N-sulfoglucosamine
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine = adenosine 3',5'-bisphosphate + [heparan sulfate]-N-sulfoglucosamine
binding mechanism, interaction scheme, sulfuryl transfer mechanism
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3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine = adenosine 3',5'-bisphosphate + [heparan sulfate]-N-sulfoglucosamine
residues 558-882 provide the sulfotransferase domain of the bifunctional enzyme, with Lys614 as a catalytically important conserved residue
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3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine = adenosine 3',5'-bisphosphate + [heparan sulfate]-N-sulfoglucosamine
important residue are Glu642, Lys614, Lys883, with possible involvement of Thr617 and Thr618, in binding 3'-phosphoadenosine 5'-phosphosulfate
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3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine = adenosine 3',5'-bisphosphate + [heparan sulfate]-N-sulfoglucosamine
5'-phosphate binding and active site structure
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3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine = adenosine 3',5'-bisphosphate + [heparan sulfate]-N-sulfoglucosamine
comparison of catalytic mechanism aspects of the NDST isozymes, overview
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine = adenosine 3',5'-bisphosphate + [heparan sulfate]-N-sulfoglucosamine
complex mechanism of GAG biosynthesis, mechanism of forward motion and hydrogen bond network analysis, overview
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
sulfate group transfer
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PATHWAY SOURCE
PATHWAYS
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SYSTEMATIC NAME
IUBMB Comments
3'-phosphoadenylyl-sulfate:[heparan sulfate]-glucosamine N-sulfotransferase
The enzyme also catalyses the sulfation of chondroitin 4-sulfate and dermatan sulfate, but to a much more limited extent.
CAS REGISTRY NUMBER
COMMENTARY
9026-75-9
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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
3'-phosphoadenylyl sulfate + GlcA-GlcNAc-GlcA-GlcNS-GlcA-pNP
adenosine 3',5'-bisphosphate + ?
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-
-
?
3'-phosphoadenylyl sulfate + heparosan
adenosine 3',5'-bisphosphate + heparosan sulfate
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-
-
?
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine
adenosine 3',5'-bisphosphate + [heparan sulfate]-N-sulfoglucosamine
3'-phosphoadenylylsulfate + N,O-desulfated heparan sulfate
adenosine 3',5'-bisphosphate + O-desulfated heparan sulfate
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no activity with
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?
3'-phosphoadenylylsulfate + N-acetylated heparan sulfate
?
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no activity with
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?
3'-phosphoadenylylsulfate + N-desulfated heparan sulfate
adenosine 3',5'-bisphosphate + heparan sulfate
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best substrate
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?
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine
adenosine 3',5'-bisphosphate + [heparan sulfate]-N-sulfoglucosamine
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-
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?
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine
adenosine 3',5'-bisphosphate + [heparan sulfate]-N-sulfoglucosamine
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-
?
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine
adenosine 3',5'-bisphosphate + [heparan sulfate]-N-sulfoglucosamine
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-
-
-
?
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine
adenosine 3',5'-bisphosphate + [heparan sulfate]-N-sulfoglucosamine
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-
?
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine
adenosine 3',5'-bisphosphate + [heparan sulfate]-N-sulfoglucosamine
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-
?
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine
adenosine 3',5'-bisphosphate + [heparan sulfate]-N-sulfoglucosamine
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-
-
?
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine
adenosine 3',5'-bisphosphate + [heparan sulfate]-N-sulfoglucosamine
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-
-
?
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine
adenosine 3',5'-bisphosphate + [heparan sulfate]-N-sulfoglucosamine
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-
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?
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine
adenosine 3',5'-bisphosphate + [heparan sulfate]-N-sulfoglucosamine
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substrate needs to be deacetylated
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?
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine
adenosine 3',5'-bisphosphate + [heparan sulfate]-N-sulfoglucosamine
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NDST1 is able to partially sulfate exogenous substrate in the absence of NDST2 but not vice versa
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?
additional information
?
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NDST1 and NDST2 have no redundant activities but rather have complementary activities in making N-sulfated heparan sulfate motifs with cyclophilin B-binding properties. Synthesis of heparan sulfate with cyclophilin B-binding properties is determined by cell type-specific expression of sulfotransferases
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?
additional information
?
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NDST-1 is a bifunctional enzyme that displays N-deacetylase and N-sulfotransferase activities to convert an N-acetylated glucosamine residue to an N-sulfoglucosamine residue
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?
additional information
?
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substrate specificity of recombinant NDST-1 (rNDST-1), full-length enzyme and individual N-deacetylase and N-sulfotransferase domains, with model oligosaccharides, detailed overview. Saccharides N-sulfated by NDST-1 are highly ordered, alternately containing N-S domains and N-Ac domains. Domain cooperation plays an essential role in NDST-1 production of HS with specific structures, and N-deacetylation is the limiting step. Recombinant NDST-1 clearly displayed bifunctional activity, it shows N-deacetylase and N-sulfotransferase activity, and the minimum-sized substrate for the bifunctional activity is a hexasaccharide
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additional information
?
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substrate specificity of recombinant NDST-1 (rNDST-1), full-length enzyme and individual N-deacetylase and N-sulfotransferase domains, with model oligosaccharides, detailed overview. Saccharides N-sulfated by NDST-1 are highly ordered, alternately containing N-S domains and N-Ac domains. Domain cooperation plays an essential role in NDST-1 production of HS with specific structures, and N-deacetylation is the limiting step. Recombinant NDST-1 clearly displayed bifunctional activity, it shows N-deacetylase and N-sulfotransferase activity, and the minimum-sized substrate for the bifunctional activity is a hexasaccharide
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additional information
?
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substrate specificity of recombinant NDST-1 (rNDST-1), full-length enzyme and individual N-deacetylase and N-sulfotransferase domains, with model oligosaccharides, detailed overview. Saccharides N-sulfated by NDST-1 are highly ordered, alternately containing N-S domains and N-Ac domains. Domain cooperation plays an essential role in NDST-1 production of HS with specific structures, and N-deacetylation is the limiting step. Recombinant NDST-1 clearly displayed bifunctional activity, it shows N-deacetylase and N-sulfotransferase activity, and the minimum-sized substrate for the bifunctional activity is a hexasaccharide
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additional information
?
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substrate specificity of recombinant NDST-4 (rNDST-4) with model oligosaccharides, detailed overview. Full-length rNDST-4 lacks obvious N-deacetylase activity, and displays only N-sulfotransferase activity. NDST-4 does not show directional N-sulfotransferase activity and the N-deacetylase domain is inactive. rNDST-4 modified heparosan only contained below 5% disaccharide units with the structure of GlcA-GlcNS. rNDST-4 displays low N-deacetylase activity toward polysaccharide. rNDST-4 is not active with a heptasaccharide substrate or smaller
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additional information
?
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substrate specificity of recombinant NDST-4 (rNDST-4) with model oligosaccharides, detailed overview. Full-length rNDST-4 lacks obvious N-deacetylase activity, and displays only N-sulfotransferase activity. NDST-4 does not show directional N-sulfotransferase activity and the N-deacetylase domain is inactive. rNDST-4 modified heparosan only contained below 5% disaccharide units with the structure of GlcA-GlcNS. rNDST-4 displays low N-deacetylase activity toward polysaccharide. rNDST-4 is not active with a heptasaccharide substrate or smaller
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additional information
?
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substrate specificity of recombinant NDST-4 (rNDST-4) with model oligosaccharides, detailed overview. Full-length rNDST-4 lacks obvious N-deacetylase activity, and displays only N-sulfotransferase activity. NDST-4 does not show directional N-sulfotransferase activity and the N-deacetylase domain is inactive. rNDST-4 modified heparosan only contained below 5% disaccharide units with the structure of GlcA-GlcNS. rNDST-4 displays low N-deacetylase activity toward polysaccharide. rNDST-4 is not active with a heptasaccharide substrate or smaller
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additional information
?
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the enzyme NDST removes the acetyl group from the GlcNAc residue and transfers a sulfate group to the primary amine forming a GlcNS substitute
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additional information
?
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the enzyme NDST removes the acetyl group from the GlcNAc residue and transfers a sulfate group to the primary amine forming a GlcNS substitute
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additional information
?
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the enzyme NDST removes the acetyl group from the GlcNAc residue and transfers a sulfate group to the primary amine forming a GlcNS substitute
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additional information
?
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the enzyme NDST removes the acetyl group from the GlcNAc residue and transfers a sulfate group to the primary amine forming a GlcNS substitute
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additional information
?
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the enzyme NDST removes the acetyl group from the GlcNAc residue and transfers a sulfate group to the primary amine forming a GlcNS substitute. Isozyme NDST3 has relatively higher N-deacetylase activity and lower sulfotransferase activity
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additional information
?
-
the enzyme NDST removes the acetyl group from the GlcNAc residue and transfers a sulfate group to the primary amine forming a GlcNS substitute. Isozyme NDST3 has relatively higher N-deacetylase activity and lower sulfotransferase activity
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-
-
additional information
?
-
the enzyme NDST removes the acetyl group from the GlcNAc residue and transfers a sulfate group to the primary amine forming a GlcNS substitute. Isozyme NDST3 has relatively higher N-deacetylase activity and lower sulfotransferase activity
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-
additional information
?
-
the enzyme NDST removes the acetyl group from the GlcNAc residue and transfers a sulfate group to the primary amine forming a GlcNS substitute. Isozyme NDST3 has relatively higher N-deacetylase activity and lower sulfotransferase activity
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-
additional information
?
-
the enzyme NDST removes the acetyl group from the GlcNAc residue and transfers a sulfate group to the primary amine forming a GlcNS substitute. Isozyme NDST4 has relatively higher sulfotransferase activity and lower N-deacetylase activity
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additional information
?
-
the enzyme NDST removes the acetyl group from the GlcNAc residue and transfers a sulfate group to the primary amine forming a GlcNS substitute. Isozyme NDST4 has relatively higher sulfotransferase activity and lower N-deacetylase activity
-
-
-
additional information
?
-
the enzyme NDST removes the acetyl group from the GlcNAc residue and transfers a sulfate group to the primary amine forming a GlcNS substitute. Isozyme NDST4 has relatively higher sulfotransferase activity and lower N-deacetylase activity
-
-
-
additional information
?
-
the enzyme NDST removes the acetyl group from the GlcNAc residue and transfers a sulfate group to the primary amine forming a GlcNS substitute. Isozyme NDST4 has relatively higher sulfotransferase activity and lower N-deacetylase activity
-
-
-
additional information
?
-
the enzyme NDST removes the acetyl group from the GlcNAc residue and transfers a sulfate group to the primary amine forming a GlcNS substitute. The catalytic mechanism of NDST1 is responsible for determining the distribution of GlcNS residues in the heparan sulfate (HS) chains. NDST1 binds to its substrates in a random manner, but the processes catalyzed by this enzyme are nonrandom, leading to the formation of specific products in different regions of the chains. During this process, NDST1 can bind to any of the internal GlcNAc residues on the chain. Once the sulfation process has been initiated, NDST1 can then convert the GlcNAc residues to GlcNS residues in sequence from the nonreducing to the reducing end of the chain until it reaches a GlcNS residue located five units away from the reducing end. The establishment of this catalytic model for NDST1 provides direct proof that NDST1 plays a decisive role in the distribution of GlcNS residues
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additional information
?
-
the enzyme NDST removes the acetyl group from the GlcNAc residue and transfers a sulfate group to the primary amine forming a GlcNS substitute. The catalytic mechanism of NDST1 is responsible for determining the distribution of GlcNS residues in the heparan sulfate (HS) chains. NDST1 binds to its substrates in a random manner, but the processes catalyzed by this enzyme are nonrandom, leading to the formation of specific products in different regions of the chains. During this process, NDST1 can bind to any of the internal GlcNAc residues on the chain. Once the sulfation process has been initiated, NDST1 can then convert the GlcNAc residues to GlcNS residues in sequence from the nonreducing to the reducing end of the chain until it reaches a GlcNS residue located five units away from the reducing end. The establishment of this catalytic model for NDST1 provides direct proof that NDST1 plays a decisive role in the distribution of GlcNS residues
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additional information
?
-
the enzyme NDST removes the acetyl group from the GlcNAc residue and transfers a sulfate group to the primary amine forming a GlcNS substitute. The catalytic mechanism of NDST1 is responsible for determining the distribution of GlcNS residues in the heparan sulfate (HS) chains. NDST1 binds to its substrates in a random manner, but the processes catalyzed by this enzyme are nonrandom, leading to the formation of specific products in different regions of the chains. During this process, NDST1 can bind to any of the internal GlcNAc residues on the chain. Once the sulfation process has been initiated, NDST1 can then convert the GlcNAc residues to GlcNS residues in sequence from the nonreducing to the reducing end of the chain until it reaches a GlcNS residue located five units away from the reducing end. The establishment of this catalytic model for NDST1 provides direct proof that NDST1 plays a decisive role in the distribution of GlcNS residues
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-
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additional information
?
-
the enzyme NDST removes the acetyl group from the GlcNAc residue and transfers a sulfate group to the primary amine forming a GlcNS substitute. The catalytic mechanism of NDST1 is responsible for determining the distribution of GlcNS residues in the heparan sulfate (HS) chains. NDST1 binds to its substrates in a random manner, but the processes catalyzed by this enzyme are nonrandom, leading to the formation of specific products in different regions of the chains. During this process, NDST1 can bind to any of the internal GlcNAc residues on the chain. Once the sulfation process has been initiated, NDST1 can then convert the GlcNAc residues to GlcNS residues in sequence from the nonreducing to the reducing end of the chain until it reaches a GlcNS residue located five units away from the reducing end. The establishment of this catalytic model for NDST1 provides direct proof that NDST1 plays a decisive role in the distribution of GlcNS residues
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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
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine
adenosine 3',5'-bisphosphate + [heparan sulfate]-N-sulfoglucosamine
additional information
?
-
-
NDST1 and NDST2 have no redundant activities but rather have complementary activities in making N-sulfated heparan sulfate motifs with cyclophilin B-binding properties. Synthesis of heparan sulfate with cyclophilin B-binding properties is determined by cell type-specific expression of sulfotransferases
-
-
?
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine
adenosine 3',5'-bisphosphate + [heparan sulfate]-N-sulfoglucosamine
-
-
-
-
?
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine
adenosine 3',5'-bisphosphate + [heparan sulfate]-N-sulfoglucosamine
-
-
-
?
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine
adenosine 3',5'-bisphosphate + [heparan sulfate]-N-sulfoglucosamine
-
-
-
?
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine
adenosine 3',5'-bisphosphate + [heparan sulfate]-N-sulfoglucosamine
-
-
-
?
3'-phosphoadenylyl sulfate + [heparan sulfate]-glucosamine
adenosine 3',5'-bisphosphate + [heparan sulfate]-N-sulfoglucosamine
-
NDST1 is able to partially sulfate exogenous substrate in the absence of NDST2 but not vice versa
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
divalent metal ions are not required for N-sulfotransferase activity of NDST-1
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
-
binding kinetics, ligand-binding free energy calculations, modeling
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
231
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purified recombinant sulfotransferase domain, substrate is at all positions completely desulfated heparin
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
bifunctional enzyme possessing heparan sulfate N-deacetylase and N-sulfotransferase activity
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crystal structure of sulfotransferase domain, Protein Data Bank: 1NST
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enzyme form NDST3, bifunctional enzyme possessing heparan sulfate N-deacetylase and N-sulfotransferase activity
SwissProt
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
high expression level of isozyme NDST2. The expression of NDST2 in monocytes is modified following cell activation or maturation, although the same treatment has no significant effect on the level of mRNAencoding NDST1
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CD4+ cells, high expression level of isozyme NDST2. NDST1 is barely detected in naive T-lymphocytes by comparison with memory and activated CD4 T cells, whereas no notable variation in the expression of NDST2 can be distinguished between T cell subsets
EXT1, NDST1, and NDST2 differentially regulate heparan sulfate biosynthesis in human tooth germ
additional information
additional information
-
NDST1 and NDST2 are widely expressed in all the tissues analyzed, overview. Synthesis of heparan sulfate with cyclophilin B-binding properties is determined by cell type-specific expression of sulfotransferases
additional information
NDST3 and NDST4 are predominantly expressed during embryonic development, although NDST3 is also found in adult heart and brain tissues, whereas NDST4 is only present at low levels in adult brain tissue
additional information
NDST3 and NDST4 are predominantly expressed during embryonic development, although NDST3 is also found in adult heart and brain tissues, whereas NDST4 is only present at low levels in adult brain tissue
additional information
NDST3 and NDST4 are predominantly expressed during embryonic development, although NDST3 is also found in adult heart and brain tissues, whereas NDST4 is only present at low levels in adult brain tissue
additional information
NDST3 and NDST4 are predominantly expressed during embryonic development, although NDST3 is also found in adult heart and brain tissues, whereas NDST4 is only present at low levels in adult brain tissue
additional information
the mRNAs of NDST1 and NDST2 are transcribed in all embryonic and adult tissues, but at different levels during the different stages of development, as well as different organs. NDST1 is widely distributed in the body
additional information
the mRNAs of NDST1 and NDST2 are transcribed in all embryonic and adult tissues, but at different levels during the different stages of development, as well as different organs. NDST1 is widely distributed in the body
additional information
the mRNAs of NDST1 and NDST2 are transcribed in all embryonic and adult tissues, but at different levels during the different stages of development, as well as different organs. NDST1 is widely distributed in the body
additional information
the mRNAs of NDST1 and NDST2 are transcribed in all embryonic and adult tissues, but at different levels during the different stages of development, as well as different organs. NDST1 is widely distributed in the body
additional information
the mRNAs of NDST1 and NDST2 are transcribed in all embryonic and adult tissues, but at different levels during the different stages of development, as well as different organs. NDST2 is only expressed in connective tissue-type mast cells, which produce heparin in vivo
additional information
the mRNAs of NDST1 and NDST2 are transcribed in all embryonic and adult tissues, but at different levels during the different stages of development, as well as different organs. NDST2 is only expressed in connective tissue-type mast cells, which produce heparin in vivo
additional information
the mRNAs of NDST1 and NDST2 are transcribed in all embryonic and adult tissues, but at different levels during the different stages of development, as well as different organs. NDST2 is only expressed in connective tissue-type mast cells, which produce heparin in vivo
additional information
the mRNAs of NDST1 and NDST2 are transcribed in all embryonic and adult tissues, but at different levels during the different stages of development, as well as different organs. NDST2 is only expressed in connective tissue-type mast cells, which produce heparin in vivo
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
NDST isozymes are all type II membrane proteins. They have a short cytoplasmic tail (12 to 18 amino acids), transmembrane and stem regions consisting of about 40 amino acids and a catalytic domain responsible for their independent N-deacetylation and N-sulfation activities
NDST isozymes are all type II membrane proteins. They have have a short cytoplasmic tail (12 to 18 amino acids), transmembrane and stem regions consisting of about 40 amino acids and a catalytic domain responsible for their independent N-deacetylation and N-sulfation activities
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
physiological function
additional information
evolution
four NDST isoforms are present in humans
evolution
four NDST isoforms are present in the human. NDST-1 is the most widely distributed isoform in tissues and organisms, and is considered to exhibit profound physiological functions during all stages of human development
malfunction
a complete lack of NDST1 results in an inability to synthesize HS glycan chains, which is ultimately lethal
malfunction
-
heparan sulfate (HS) is a sulfated polysaccharide that plays a key role in morphogenesis, physiology and pathogenesis. The biosynthesis of HS takes place in the Golgi apparatus by a group of enzymes that polymerize, epimerize and sulfate the sugar chain. This biosynthetic process introduces varying degrees of sulfate substitution, which are tightly regulated and directly dictate binding specificity to different cytokines, morphogens and growth factors. Molecular dynamics simulations to investigate the dynamics of substrate recognition of two glycosaminoglycan (GAG) sulfotransferases, N-deacetylase-N-sulfotransferase and 2-O-sulfotransferaseto the HS chain during the biosynthetic process. Fine-tuned complex mechanism of GAG biosynthesis
metabolism
-
in the general scheme of heparan sulfate biosynthesis, GlcNAc N-deacetylation and N-sulfation by NDSTs create the prerequisite substrate needed for the next enzymatic modifications
metabolism
the enzymes is involved in heparan sulfate biosynthesis. EXT1, NDST1, and NDST2 differentially regulate heparan sulfate biosynthesis in human tooth germ
physiological function
-
NDST1 is required for initiation of N-sulfation of the nascent precursor, whereas NDST2 may fill in or extend the sections of N-sulfated residues in heparin and highly sulfated heparan sulfate species
physiological function
the enzyme is involved in heparan sulfate biosynthesis
physiological function
heparan sulfate (HS) is widely distributed in mammalian tissues in the form of HS proteoglycans, which play essential roles in various physiological and pathological processes. In contrast to the template-guided processes involved in the synthesis of DNA and proteins, HS biosynthesis is not believed to involve a template. But the final structure of HS chains is strictly regulated. Two major steps, namely coding and decoding steps, are involved in the biosynthesis of HS, which strictly regulate its chemical structure and biological activity. The coding process in this context is based on the distribution of sulfate moieties on the amino groups of the glucosamine residues in the HS chains. The sulfation of these amine groups is catalyzed by N-deacetylase/N-sulfotransferase, which has four isozymes. The composition and distribution of sulfate groups and iduronic acid residues on the glycan chains of HS are determined by several other modification enzymes, which can recognize these coding sequences (i.e. the decoding process). The degree and pattern of the sulfation and epimerization in the HS chains determines the extent of their interactions with several different protein factors, which further influences their biological activity. Mammalian cells can regulate the expression of the four different NDST isozymes as required during the different stages of their development and spatial orientation. In this way, the cells can make use of the different catalytic modes of activity of the NDSTs to adjust the length of the GlcNS clusters on the HS side chains, as well as the ratio of GlcNS to GlcNH2 residues
physiological function
-
NDST, the first modifying enzyme, removes the acetyl group from GlcNAc and adds a sulfate group, generating N-sulfoglucosamine (GlcNS). The generation of GlcNS introduces N-sulfated (NS) domains along the HS chain. When these NS domains are flanked by unmodified N-acetylated domains (NA domains) NA/NS domains are generated. This organization specifies different protein-binding motifs, overview
physiological function
NDSTs are potential bifunctional enzymes that contain two independent catalytic domains: the N-deacetylase domain removes the acetyl group from GlcNAc to form GlcNH2, and the N-sulfo-transferase domain transfers a sulfo group to the GlcNH2 residue to form GlcNS. The enzyme is involved in the synthesis of heparan sulfate (HS), a highly sulfated linear glycosaminoglycan polysaccharide, consisting of a disaccharide repeating unit of sulfated derivatives of glucosamine and glucuronic acid (GlcA) or iduronic acid (IdoA) residues. HS is widely present in proteoglycan saccharide chains in mammalian tissues and the extracellular matrix. The final structure of HS chains is strictly regulated in vivo, though the biosynthesis is not guided by a template process. N-Deacetylase/N-sulfotransferase (NDST) is the first modification enzyme in the HS biosynthetic pathway. The N-sulfo groups introduced by NDST are reportedly involved in determination of the susceptibility to subsequent processes catalyzed by C5-epimerse and 3-O-sulfotranferases. NDST-4 plays a limited role in heparan sulfate biosynthesis
physiological function
NDSTs are potential bifunctional enzymes that contain two independent catalytic domains: the N-deacetylase domain removes the acetyl group from GlcNAc to form GlcNH2, and the N-sulfo-transferase domain transfers a sulfo group to the GlcNH2 residue to form GlcNS. The enzyme is involved in the synthesis of heparan sulfate (HS), a highly sulfated linear glycosaminoglycan polysaccharide, consisting of a disaccharide repeating unit of sulfated derivatives of glucosamine and glucuronic acid (GlcA) or iduronic acid (IdoA) residues. HS is widely present in proteoglycan saccharide chains in mammalian tissues and the extracellular matrix. The final structure of HS chains is strictly regulated in vivo, though the biosynthesis is not guided by a template process. N-Deacetylase/N-sulfotransferase (NDST) is the first modification enzyme in the HS biosynthetic pathway. The N-sulfo groups introduced by NDST are reportedly involved in determination of the susceptibility to subsequent processes catalyzed by C5-epimerse and 3-O-sulfotranferases
additional information
-
sulfotransferases contain a conserved interspaced positively charged amino acid residues that form a patch which controls the protein-GAG binding equilibrium. The amphipathic random coil positions the putative charged active site residue side chains of Glu641 and Glu642 toward the center of the cleft, while the opposing region of the cleft contains side chains of residues required for binding, His716, Gln717 and His720, molecular dynamics simulations
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). NDST1_HUMAN
882
1
100868
Swiss-Prot
Secretory Pathway (Reliability: 2)
NDST2_HUMAN
883
1
100875
Swiss-Prot
Secretory Pathway (Reliability: 2)
NDST3_HUMAN
873
1
100902
Swiss-Prot
Secretory Pathway (Reliability: 2)
NDST4_HUMAN
872
1
100716
Swiss-Prot
Secretory Pathway (Reliability: 2)
A8K8T3_HUMAN
882
1
100838
TrEMBL
Secretory Pathway (Reliability: 2)
A8K0V5_HUMAN
872
1
100689
TrEMBL
Secretory Pathway (Reliability: 2)
B4E139_HUMAN
760
0
87573
TrEMBL
other Location (Reliability: 3)
S4R438_HUMAN
815
1
92872
TrEMBL
Secretory Pathway (Reliability: 2)
Q59GK2_HUMAN
698
0
80402
TrEMBL
other Location (Reliability: 2)
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
-
computational modeling of the structure of crystallized N-sulfotransferase domain, residues 580-880 with 3'-phosphoadenosine 5'-phosphate bound, and of residues 587-602 and 664-671, which are missing from the crystal structure
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
four potential N-glycosylation sites are present in NDST-4, making the glycosylation become one potential reason why recombinant NDST-4 lacks N-deacetylase activity. The baculovirus expression system is capable of transferring N-linked oligosaccharide side chains to the same sites in recombinant proteins as in the native protein in mammalian cells
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
18 mg/ml, 0.1 M Tris-HCl, pH 8.3, 0.1 M NaCl, 4 mM 3'-phosphoadenosine 5'-phosphate, reservoir solution: Bis-Tris-propane, pH 7.0, 0.2 M NaCl, 30% PEG 3000, room temperature, X-ray diffraction structure determination and analysis
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
K614A
-
site-directed mutagenesis of the sulfotransferase domain of the bifunctional enzyme, complete loss of N-sulfotransferase activity
additional information
additional information
-
lack of NDST1 affects heparan sulfate structure in all tissues tested, with a dramatic reduction in N- and O-sulfation of the polysaccharide. Silencing the expression of NDST1, NDST2, 2-OST, and 3-OST3 by RNA interference efficiently decreases binding and activity of cyclophilin B
additional information
overexpression of NDST1 or NDST2 in recombinant human embryonic kidney 293 cells gives rise to different heparan sulfate (HS) N-sulfation patterns. The HS produced in cells transfected with NDST1 and NDST2 typically shows increased levels of N-sulfation. However, compared with cells overexpressing NDST1, the HS generated by cells overexpressing NDST2 has longer N-sulfation regions and a higher degree of N-sulfation
additional information
overexpression of NDST1 or NDST2 in recombinant human embryonic kidney 293 cells gives rise to different heparan sulfate (HS) N-sulfation patterns. The HS produced in cells transfected with NDST1 and NDST2 typically shows increased levels of N-sulfation. However, compared with cells overexpressing NDST1, the HS generated by cells overexpressing NDST2 has longer N-sulfation regions and a higher degree of N-sulfation
additional information
overexpression of NDST1 or NDST2 in recombinant human embryonic kidney 293 cells gives rise to different heparan sulfate (HS) N-sulfation patterns. The HS produced in cells transfected with NDST1 and NDST2 typically shows increased levels of N-sulfation. However, compared with cells overexpressing NDST1, the HS generated by cells overexpressing NDST2 has longer N-sulfation regions and a higher degree of N-sulfation
additional information
overexpression of NDST1 or NDST2 in recombinant human embryonic kidney 293 cells gives rise to different heparan sulfate (HS) N-sulfation patterns. The HS produced in cells transfected with NDST1 and NDST2 typically shows increased levels of N-sulfation. However, compared with cells overexpressing NDST1, the HS generated by cells overexpressing NDST2 has longer N-sulfation regions and a higher degree of N-sulfation
additional information
overexpression of NDST1 or NDST2 in recombinant human embryonic kidney 293 cells gives rise to different heparan sulfate (HS) N-sulfation patterns. The HS produced in cells transfected with NDST1 and NDST2 typically shows increased levels of N-sulfation. However, compared with cells overexpressing NDST1, the HS generated by cells overexpressing NDST2 has longer N-sulfation regions and a higher degree of N-sulfation. Furthermore, the transfection of NDST-deficient COS cells with NDST1 results in the formation of HS with a high affinity for FGF. In contrast, the overexpression of NDST1 in wild-type COS cells has very little effect on the N-acetylation to N-sulfation ratio of HS
additional information
overexpression of NDST1 or NDST2 in recombinant human embryonic kidney 293 cells gives rise to different heparan sulfate (HS) N-sulfation patterns. The HS produced in cells transfected with NDST1 and NDST2 typically shows increased levels of N-sulfation. However, compared with cells overexpressing NDST1, the HS generated by cells overexpressing NDST2 has longer N-sulfation regions and a higher degree of N-sulfation. Furthermore, the transfection of NDST-deficient COS cells with NDST1 results in the formation of HS with a high affinity for FGF. In contrast, the overexpression of NDST1 in wild-type COS cells has very little effect on the N-acetylation to N-sulfation ratio of HS
additional information
overexpression of NDST1 or NDST2 in recombinant human embryonic kidney 293 cells gives rise to different heparan sulfate (HS) N-sulfation patterns. The HS produced in cells transfected with NDST1 and NDST2 typically shows increased levels of N-sulfation. However, compared with cells overexpressing NDST1, the HS generated by cells overexpressing NDST2 has longer N-sulfation regions and a higher degree of N-sulfation. Furthermore, the transfection of NDST-deficient COS cells with NDST1 results in the formation of HS with a high affinity for FGF. In contrast, the overexpression of NDST1 in wild-type COS cells has very little effect on the N-acetylation to N-sulfation ratio of HS
additional information
overexpression of NDST1 or NDST2 in recombinant human embryonic kidney 293 cells gives rise to different heparan sulfate (HS) N-sulfation patterns. The HS produced in cells transfected with NDST1 and NDST2 typically shows increased levels of N-sulfation. However, compared with cells overexpressing NDST1, the HS generated by cells overexpressing NDST2 has longer N-sulfation regions and a higher degree of N-sulfation. Furthermore, the transfection of NDST-deficient COS cells with NDST1 results in the formation of HS with a high affinity for FGF. In contrast, the overexpression of NDST1 in wild-type COS cells has very little effect on the N-acetylation to N-sulfation ratio of HS
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
heparin-Toyopearl column chromatography and nickel-agarose column chromatography
recombinant fusion tagged sulfotransferase domain from Escherichia coli BL21 cells by affinity chromatography
-
recombinant His6-tagged NDST-4 by nickel affinity and heparin affinity chromatography
recombinant sulfotransferase domain NST1 from Escherichia coli strain B834 (DE3)
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
construction of a chimeric enzyme consisiting of a soluble enzyme form NDST3 N-terminally fused to a protein A fragment, expression in COS-7 cells
DNA sequence determination, analysis, and expression of the wild-type and mutated sulfotransferase domain of the bifunctional enzyme in Escherichia coli BL21 cells as fusion tagged protein
-
expression of the selenomethionyl sulfotransferase domain NST1 in methionine auxotrophic Escherichia coli strain B834 (DE3)
-
gene NDST1, recombinant expression in yeast cells, recombinant overexpression of NDST1 in HEK-293 cells
gene NDST4, recombinant expression of C-terminally His6-tagged full-length NDST-4 and of luminal domain of NDST4 (Ser35-Arg872) in Spodoptera frugiperda Sf9 cells using the insect baculovirus transfection system
isozyme NDST4, DNA sequence determination and analysis, chromosomal localization
recombinant overexpression of NDST2 in HEK-293 cells
the N-terminal domain (A66-P604) of the bifunctional enzyme heparan sulfate N-deacetylase/N-sulfotransferase 2 is cloned as a (His)6-fusion protein, expression in Escherichia coli. The N-terminal domain contains functional N-deacetylase activity
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
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
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Sueyoshi, T.; Kakuta, Y.; Pedersen, L.C.; Wall, F.E.; Pedersen, L.G.; Negishi, M.
A role of Lys614 in the sulfotransferase activity of human heparan sulfate N-deacetylase/N-sulfotransferase
FEBS Lett.
433
211-214
1998
Homo sapiens
Kakuta, Y.; Sueyoshi, T.; Negishi, M.; Pedersen, L.C.
Crystal structure of the sulfotransferase domain of human heparan sulfate N-deacetylase/N-sulfotransferase 1
J. Biol. Chem.
274
10673-10676
1999
Homo sapiens
Aikawa, J.; Esko, J.D.
Molecular cloning and expression of a third member of the heparan sulfate/heparin GlcNAc N-deacetylase/N-sulfotransferase family
J. Biol. Chem.
274
2690-2695
1999
Cricetulus griseus, Homo sapiens (O95803), Homo sapiens
Gorokhov, A.; Perera, L.; Darden, T.A.; Negishi, M.; Pedersen, L.C.; Pedersen, L.G.
Heparan sulfate biosynthesis: a theoretical study of the initial sulfation step by N-deacetylase/N-sulfotransferase
Biophys. J.
79
2909-2917
2000
Homo sapiens
Aikawa, J.; Grobe, K.; Tsujimoto, M.; Esko, J.D.
Multiple isozymes of heparan sulfate/heparin GlcNAc N-deacetylase/GlcN N-sulfotransferase. Structure and activity of the fourth member, NDST4
J. Biol. Chem.
276
5876-5882
2001
Homo sapiens (O95803), Homo sapiens (Q9H3R1), Homo sapiens, Mus musculus (P52850), Mus musculus (Q3UHN9), Mus musculus (Q9EQH7), Mus musculus (Q9EQW8), Mus musculus
Grobe, K.; Ledin, J.; Ringvall, M.; Holmborn, K.; Forsberg, E.; Esko, J.D.; Kjellen, L.
Heparan sulfate and development: differential roles of the N-acetylglucosamine N-deacetylase/N-sulfotransferase isozymes
Biochim. Biophys. Acta
1573
209-215
2002
Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Homo sapiens (O95803), Homo sapiens (Q9H3R1), Mus musculus, Mus musculus (Q9EQW8), vertebrata
Duncan, M.B.; Liu, M.; Fox, C.; Liu, J.
Characterization of the N-deacetylase domain from the heparan sulfate N-deacetylase/N-sulfotransferase 2
Biochem. Biophys. Res. Commun.
339
1232-1237
2006
Homo sapiens
Deligny, A.; Denys, A.; Marcant, A.; Melchior, A.; Mazurier, J.; van Kuppevelt, T.H.; Allain, F.
Synthesis of heparan sulfate with cyclophilin B-binding properties is determined by cell type-specific expression of sulfotransferases
J. Biol. Chem.
285
1701-1715
2010
Homo sapiens
Dou, W.; Xu, Y.; Pagadala, V.; Pedersen, L.C.; Liu, J.
Role of deacetylase activity of N-deacetylase/n-sulfotransferase 1 in forming n-sulfated domain in heparan sulfate
J. Biol. Chem.
290
20427-20437
2015
Homo sapiens (P52848)
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 (P52848), Homo sapiens (P52849), Homo sapiens
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 (P52848), Homo sapiens (P52849)
Li, Y.J.; Yin, F.X.; Zhang, X.K.; Yu, J.; Zheng, S.; Song, X.L.; Wang, F.S.; Sheng, J.Z.
Characterization of heparan sulfate N-deacetylase/N-sulfotransferase isoform 4 using synthetic oligosaccharide substrates
Biochim. Biophys. Acta
1862
547-556
2018
Homo sapiens (P52848), Homo sapiens (Q9H3R1), Homo sapiens
Zhang, X.; Wang, F.; Sheng, J.
''Coding'' and ''Decoding'' hypothesis for the regulatory mechanism involved in heparan sulfate biosynthesis
Carbohydr. Res.
428
1-7
2016
Homo sapiens (O95803), Homo sapiens (P52848), Homo sapiens (P52849), Homo sapiens (Q9H3R1)
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