Abstract
Heparan sulfates are sulfated glycosaminoglycans distributed on the cell surfaces and in the extracellular matrices of most tissues. The structurally related polysaccharide heparin is a highly sulfated variant of heparan sulfate that is exclusively produced by connective tissue mast cells. Heparan sulfate and heparin are synthesized as proteoglycans, and their biosynthesis is initiated by formation of a tetrasaccharide linkage region attached to a serine residue in the core protein (GlcAβ1-3Galβ1-3Galβ1- 4Xylβ1-O-Ser). After addition of a single α-GlcNAc residue, elongation proceeds by the action of glycosyltransferases, which add β1,4-GlcA and α1,4-GlcNAc units in alternating sequence to the nonreducing end of the growing polymer. Bifunctional glycosyltransferases, denoted EXT1 and EXT2, are believed to be involved in the sequential addition of GlcA and GlcNAc. Concomitant with chain elongation, further modifications occur through several enzymatic steps that generate a complex polysaccharide containing N-acetylated and N-sulfated GlcN residues, GlcA and IdoA acid units, and O-sulfate groups in various positions.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Bellaiche Y, The I, Perrimon N (1998) Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion. Nature 394:85–88
Forsee WT, Rodén L (1981) Biosynthesis of heparin: transfer of N-acetylglucosamine to heparan sulfate oligosaccharides. J Biol Chem 256:7240–7247
Helting T, Lindahl U (1971) Occurrence and biosynthesis of β-glucuronidic linkages in heparin. J Biol Chem 246:5442–5447
Helting T, Lindahl U (1972) Biosynthesis of heparin: transfer of N-acetylglucosamine and glucuronic acid to low-molecular weight heparin fragments. Acta Chem Scand 26:3515–3523
Kitagawa H, Shimakawa H, Sugahara K (1999) The tumor suppressor EXT-like gene EXTL2 encodes an α1,-N-acetylhexosaminyltransferase that transfers N-acetylgalactosamine and N-acetylglucosamine to the common glycosaminoglycan-protein linkage region: the key enzyme for the chain initiation of heparan sulfate. J Biol Chem 274:13933–13937
Kobayashi S-i, Morimoto K-i, Shimizu T, Takahashi M, Kurosawa H, Shirasawa T (2000) Association of EXT1 and EXT2, hereditary multiple exostoses gene products, in Golgi apparatus. Biochem Biophys Res Commun 268:860–867
Lidholt K, Lindahl U (1992) Biosynthesis of heparin: the D-glucuronosyl-and N-acetyl-D-glucosaminyltransferase reactions and their relation to polymer modification. Biochem J 289:21–29
Lidholt K, Kjellén L, Lindahl U (1989) Biosynthesis of heparin: relationship between the polymerization and sulphation processes. Biochem J 261:999–1007
Lidholt K, Weinke JL, Kiser CS, Lugemwa FN, Bame KJ, Cheifetz S, Massagué J, Lindahl U, Esko JD (1992) A single mutation affects both N-acetylglucosaminyltransferase and glucuronosyltransferase activities in a Chinese hamster ovary cell mutant defective in heparan sulfate biosynthesis. Proc Natl Acad Sci USA 89:2267–2271
Lind T, Lindahl U, Lidholt K (1993) Biosynthesis of heparin/heparan sulfate: identification of a 70-kDa protein catalyzing both the D-glucuronosyl-and the N-acetyl-D-glucosaminyltransferase reactions. J Biol Chem 268:20705–20708
Lind T, Tufaro F, McCormick C, Lindahl U, Lidholt K (1998) The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate. J Biol Chem 273:26265–26268
McCormick C, Duncan G, Goutsos KT, Tufaro F (2000) The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate. Proc Natl Acad Sci USA 97:668–673
McCormick C, Leduc Y, Martindale D, Mattison K, Esford L, Dyer A, Tufaro F (1998) The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate. Nat Genet 19:158–161
Senay C, Lind T, Muguruma K, Tone Y, Kitagawa H, Sugahara K, Lidholt K, Lindahl U, Kusche-Gullberg M (2000) The EXT1/EXT2 tumor suppressors; catalytic activies and role in heparan sulfate biosynthesis. EMBO Reports 1:282–286
Silbert JE (1963) Incorporation of 14C and 3H from nucleotide sugars into a polysaccharide in the presence of a cell-free preparation from mouse mast cell tumors. J Biol Chem 238:3542–3546
Stickens D, Evans G (1998) A sugar fix for bone tumours? Nat Genet 19:110–111
The I, Bellaiche Y, Perrimon N (1999) Hedgehog movement is regulated through tout velu-dependent synthesis of a heparan sulfate proteoglycan. Mol Cell 4:633–639
Toyoda H, Kinoshita-Toyoda A, Selleck SB (2000) Structural analysis of glycosaminogly-cans in Drosophila and Caenorhabditis elegans and demonstration that tout-velu, a Drosophila gene related to EXT tumor suppressors, affects heparan sulfate in vivo. J Biol Chem 275:2269–2275
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2002 Springer Japan
About this chapter
Cite this chapter
Kusche-Gullberg, M., Lindahl, U. (2002). Heparan Sulfate GlcA/GlcNAc Transferase. In: Taniguchi, N., et al. Handbook of Glycosyltransferases and Related Genes. Springer, Tokyo. https://doi.org/10.1007/978-4-431-67877-9_56
Download citation
DOI: https://doi.org/10.1007/978-4-431-67877-9_56
Publisher Name: Springer, Tokyo
Print ISBN: 978-4-431-67996-7
Online ISBN: 978-4-431-67877-9
eBook Packages: Springer Book Archive