Identification and Expression in Mouse of Two Heparan Sulfate Glucosaminyl N-Deacetylase/N-Sulfotransferase Genes

Kusche-Gullberg, Marion; Eriksson, Inger; Pikas, Dagmar Sandbäck; Kjellén, Lena

doi:10.1074/jbc.273.19.11902

Cited by 84 publications

(65 citation statements)

References 23 publications

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“…In mice, targeted disruption of NDST1 results in neonatal lethality due to pulmonary hypoplasia and respiratory distress (15,16). Liver heparan sulfate is also affected in composition, consistent with the widespread expression of NDST1 (10,11). NDST2 mRNA is also highly expressed in most tissues (10,11).…”

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confidence: 69%

“…Liver heparan sulfate is also affected in composition, consistent with the widespread expression of NDST1 (10,11). NDST2 mRNA is also highly expressed in most tissues (10,11). However, mice lacking NDST2 develop and reproduce normally but show fewer connective tissue-type mast cells.…”

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confidence: 76%

“…Three NDST isozymes have been identified in vertebrates, whereas only single orthologs are known in Drosophila melanogaster and Caenorhabditis elegans (3)(4)(5)(6)(7)(8)(9)(10)(11). Mutations in these genes can have profound effects on development.…”

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Multiple Isozymes of Heparan Sulfate/Heparin GlcNAcN-Deacetylase/GlcN N-Sulfotransferase

Aikawa

Grobe

Tsujimoto

et al. 2001

Journal of Biological Chemistry

203

161

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We report the cloning and partial characterization of the fourth member of the vertebrate heparan sulfate/ heparin: GlcNAc N-deacetylase/GlcN N-sulfotransferase family, which we designate NDST4. Full-length cDNA clones containing the entire coding region of 872 amino acids were obtained from human and mouse cDNA libraries. The deduced amino acid sequence of NDST4 showed high sequence identity to NDST1, NDST2, and NDST3 in both species. NDST4 maps to human chromosome 4q25-26, very close to NDST3, located at 4q26 -27. These observations, taken together with phylogenetic data, suggest that the four NDSTs evolved from a common ancestral gene, which diverged to give rise to two subtypes, NDST3/4 and NDST1/2. Reverse transcriptionpolymerase chain reaction analysis of various mouse tissues revealed a restricted pattern of NDST4 mRNA expression when compared with NDST1 and NDST2, which are abundantly and ubiquitously expressed. Comparison of the enzymatic properties of the four murine NDSTs revealed striking differences in N-deacetylation and N-sulfation activities; NDST4 had weak deacetylase activity but high sulfotransferase, whereas NDST3 had the opposite properties. Molecular modeling of the sulfotransferase domains of the murine and human NDSTs showed varying surface charge distributions within the substrate binding cleft, suggesting that the differences in activity may reflect preferences for different substrates. An iterative model of heparan sulfate biosynthesis is suggested in which some NDST isozymes initiate the N-deacetylation and N-sulfation of the chains, whereas others bind to previously modified segments to fill in or extend the section of modified residues.Heparan sulfate and heparin bind a variety of growth factors, enzymes, and extracellular matrix proteins (1). These interactions depend on specific arrangements of variably sulfated glucosaminyl residues (GlcNAc, GlcN, 1 and GlcNS) and glucuronic (GlcA) and iduronic acids. The assembly of these sequences proceeds in a stepwise manner as follows. (i) The chains initiate by formation of the linkage tetrasaccharide, GlcA␤1,3Gal␤1,3Gal␤1,4Xyl␤, on serine residues of core proteins; (ii) the chains elongate by alternating the additions of GlcNAc␣1,4 and GlcA␤1,4 residues; (iii) the chains are modified initially by N-deacetylation and N-sulfation of subsets of GlcNAc residues, (iv) adjacent D-GlcA residues undergo C5-epimerization to L-iduronic acid, and (v) sulfation occurs at C2 of the uronic acid residues and at C6 and C3 of glucosaminyl residues. In this scheme, GlcNAc N-deacetylation and N-sulfation creates the prerequisite substrate needed for the later modification reactions (reviewed by Rodén (2)). These reactions are catalyzed by a family of enzymes designated the GlcNAc N-deacetylase/N-sulfotransferases (NDSTs).Three NDST isozymes have been identified in vertebrates, whereas only single orthologs are known in Drosophila melanogaster and Caenorhabditis elegans (3-11). Mutations in these genes can have profound effects on development. In D. melanogas...

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confidence: 76%

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Multiple Isozymes of Heparan Sulfate/Heparin GlcNAcN-Deacetylase/GlcN N-Sulfotransferase

Aikawa

Grobe

Tsujimoto

et al. 2001

Journal of Biological Chemistry

203

161

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“…NDST1 and NDST2 both have N-deacetylase as well as N-sulfotransferase activities and are co-expressed in most tissues and cell types (42). Therefore, the restricted phenotype of the NDST2 Ϫ/Ϫ mice, where only connective tissue type MCs were affected, was surprising (32,33).…”

Section: Discussionmentioning

confidence: 99%

“…In control MCs, much more NDST2 than NDST1 is expressed (Fig. 1C) (42), and NDST2 will therefore be the dominating isoform in the GAGosomes, despite its lower preference for GAGosome incorporation. Because the level of NDST enzymes is higher in MCs than in liver cells, the polysaccharide produced will have a high content of sulfate groups.…”

Section: Discussionmentioning

confidence: 99%

Lowered Expression of Heparan Sulfate/Heparin Biosynthesis Enzyme N-Deacetylase/N-Sulfotransferase 1 Results in Increased Sulfation of Mast Cell Heparin

Dagälv

Holmborn

Kjellén³

et al. 2011

Journal of Biological Chemistry

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Background: NDST1 and 2 are isoenzymes taking part in heparan sulfate and heparin N-sulfation during biosynthesis. Results: NDST1ϩ/Ϫ and NDST1 Ϫ/Ϫ mast cells synthesize heparin with increased degree of sulfation. Conclusion:Tentatively, the Golgi enzyme complex, "the GAGosome," responsible for heparin biosynthesis, is more efficient when containing only NDST2. Significance: Learning how biosynthesis is regulated is crucial to understanding the biological functions of heparin/heparan sulfate.Deficiency of the heparan sulfate biosynthesis enzyme N-deacetylase/N-sulfotransferase 1 (NDST1) in mice causes severely disturbed heparan sulfate biosynthesis in all organs, whereas lack of NDST2 only affects heparin biosynthesis in mast cells (MCs). To investigate the individual and combined roles of NDST1 and NDST2 during MC development, in vitro differentiated MCs derived from mouse embryos and embryonic stem cells, respectively, have been studied. Whereas MC development will not occur in the absence of both NDST1 and NDST2, lack of NDST2 alone results in the generation of defective MCs. Surprisingly, the relative amount of heparin produced in NDST1 ؉/؊ and NDST1 ؊/؊ MCs is higher (≈30%) than in control MCs where ≈95% of the 35 S-labeled glycosaminoglycans produced is chondroitin sulfate. Lowered expression of NDST1 also results in a higher sulfate content of the heparin synthesized and is accompanied by increased levels of stored MC proteases. A model of the GAGosome, a hypothetical Golgi enzyme complex, is used to explain the results.

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Glycosylation of Proteins in the Golgi Apparatus

Desko

Kohler

2008

Wiley Encyclopedia of Chemical Biology

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Oligosaccharides are essential for interactions of cells with their environments. These complex carbohydrates are often found covalently attached to proteins embedded in eukaryotic cell membranes. Protein glycosylation is heterogeneous; this heterogeneity stems from the biosynthesis of these polymers. As proteins destined for secretion or cell‐surface presentation traffic through the endoplasmic reticulum and the Golgi apparatus, they are modified with sugars in a stepwise fashion by enzymes called glycosyltransferases. The differential expression of these enzymes leads to a multiplicity of specific oligosaccharides both among and within cells because not all cells contain all enzymes and because not all substrate proteins will encounter every enzyme. Although myriad oligosaccharides are found attached to proteins, most of these diverse structures can be grouped into several classes of glycans. In this article, we will discuss some of the most common forms of Golgi protein glycosylation: mucin‐type O ‐linked glycosylation, N ‐linked glycosylation, and the formation of glycosaminoglycans. In addition, we will briefly consider some less common, but essential, forms of glycosylation.

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Identification and Expression in Mouse of Two Heparan Sulfate Glucosaminyl N-Deacetylase/N-Sulfotransferase Genes

Cited by 84 publications

References 23 publications

Multiple Isozymes of Heparan Sulfate/Heparin GlcNAcN-Deacetylase/GlcN N-Sulfotransferase

Multiple Isozymes of Heparan Sulfate/Heparin GlcNAcN-Deacetylase/GlcN N-Sulfotransferase

Lowered Expression of Heparan Sulfate/Heparin Biosynthesis Enzyme N-Deacetylase/N-Sulfotransferase 1 Results in Increased Sulfation of Mast Cell Heparin

Glycosylation of Proteins in the Golgi Apparatus

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