Heparan sulfate

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Structure formula of a heparan sulfate subunit


The major cell membrane HSPGs are the transmembrane syndecans and the glycosylphosphatidylinositol (GPI) anchored glypicans. Other minor forms of membrane HSPG include betaglycan[3] and the V-3 isoform of CD44 present on keratinocytes and activated monocytes.[4]


Possible role in Alzheimer's disease and Parkinson's disease[edit]


HS structure and differences from heparin[edit]





  • GlcA = β-D-glucuronic acid
  • IdoA = α-L-iduronic acid

HS biosynthesis[edit]


In the 1980s, Prof. Jeffrey Esko was the first to isolate and characterize animal cell mutants altered in the assembly of heparan sulfate.[7] Many of these enzymes have now been purified, molecularly cloned and their expression patterns studied. From this and early work on the fundamental stages of HS/heparin biosynthesis using a mouse mastocytoma cell free system a lot is known about the order of enzyme reactions and specificity.[8]

Chain initiation[edit]





Chain elongation[edit]



Chain modification[edit]




Generation of GlcNH2[edit]


Epimerisation and 2-O-sulfation[edit]





Currently seven glucosaminyl 3-O-sulfotransferases (3OSTs) are known to exist in mammals (eight in zebrafish).[13][14] The 3OST enzymes create a number of possible 3-O-sulfated disaccharides, including GlcA-GlcNS(3S±6S) (modified by 3OST1 and 3OST5), IdoA(2S)-GlcNH2(3S±6S)(modified by 3OST3a, 3OST3b, 3OST5 and 3OST6) and GlcA/IdoA(2S)-GlcNS(3S) (modified by 3OST2 and 3OST4).[15][16][17][18] As with all other HS sulfotransferases, the 3OSTs use 3'-phosphoadenosine-5'-phosphosulfate (PAPS) as a sulfate donor. Despite being the largest family of HS modification enzymes, the 3OSTs produce the rarest HS modification, the 3-O-sulfation of specific glucosamine residues at the C3-OH moiety.[19]

The 3OSTs are divided into two functional subcategories, those that generate an antithrombin III binding site (3OST1 and 3OST5) and those that generate a herpes simplex virus 1 glycoprotein D (HSV-1 gD) binding site (3OST2, 3OST3a, 3OST3b, 3OST4, 3OST5 and 3OST6).[15][16][17][18][20][21][22][23][24][25][26] As the 3OSTs are the largest family of HS modification enzymes and their actions are rate-limiting, substrate specific and produce rare modifications, it has been hypothesized that 3OST modified HS plays an important regulatory role in biological processes.[18][21][21]

Ligand binding[edit]




Heparan sulfate analogue[edit]

Heparan sulfate analogues are thought to display identical properties as heparan sulfate with exception of being stable in a proteolytic environment like a wound.[28][29] Because heparan sulfate is broken down in chronic wounds by heparanase, the analogues only bind sites where natural heparan sulfate is absent and cannot be broken down by any known heparanases and glycanases.[30] Also the function of the heparan sulfate analogues is the same as heparan sulfate, protecting a variety of protein ligands such as growth factors and cytokines. By holding them in place, the tissue can then use the different protein ligands for proliferation.

For more information see:Heparan sulfate analogue


  3. ^ Andres, J. L. et al. (1992). "Binding of two growth factor families to separate domains of the proteoglycan betaglycan". J. Biol. Chem. 267 (9): 5927–30. PMID 1556106. 
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  7. ^ Esko, J.D.,Stewart, T.E., and Taylor, W.H. (1985) Animal cell mutants defective inglycosaminoglycan biosynthesis. Proc.Natl. Acad. Sci. USA 85:3197-3201. PMID 3858816
  10. ^ Carlsson P, Presto J. et al. (2008). "Heparin/Heparan Sulfate Biosynthesis: Processive formation of N-sulfated domains". J. Biol. Chem. 283 (29): 20008–20014. doi:10.1074/jbc.M801652200. PMID 18487608. 
  11. ^ Höök, M. et al. (1975). "Biosynthesis of heparin. Studies on the microsomal sulfation process". J. Biol. Chem. 250 (15): 6065–71. PMID 807579. 
  12. ^ Toida, T. et al. (1 January 1997). "Structural differences and the presence of unsubstituted amino groups in heparan sulphates from different tissues and species". Biochem. J. 322(Pt2) (Pt 2): 499–506. PMC 1218218. PMID 9065769. 
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