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Fig. 2. Heparan sulfate chain biosynthesis. Heparan sulfate (HS) glycosaminoglycan
(GAG) chains are synthesized on a core protein by the sequential action of
individual glycosyltransferases and modification enzymes, in a three-step
process involving chain initiation, polymerization and modification. HS chain
synthesis begins with the assembly of a linkage tetrasaccharide on serine
residues in the core polypeptide. This process is catalyzed by four enzymes
(Xyl transferase, Gal transferase I-II and GlcA transferase I), which add
individual sugar residues sequentially to the non-reducing end of the growing
chain. After the assembly of the linkage region, one or more 
-GlcNAc
transferases add a single 1,4-linked GlcNAc unit to the chain, which
initiates the HS polymerization process. HS chain polymerization then takes
place by the addition of alternating GlcA and GlcNAc residues, which is
catalyzed by the EXT family proteins. As the chain polymerizes, it undergoes a
series of modifications that include GlcNAc N-deacetylation and N-sulfation,
C5 epimerization of GlcA to IdoA, and variable O-sulfation at C2 of
IdoA and GlcA, at C6 of GlcNAc and GlcNS units, and, occasionally, at C3 of
GlcN residues. The HS GAG chains are 
100 or more sugar units long and
have numerous structural heterogeneities. Four Drosophila enzymes,
including Botv, Ttv, Sotv and Sfl, which are homologs of vertebrate EXTL3,
EXT1, EXT2 and N-deacetylase/N-sulfotransferase, respectively, are highlighted
in red. Gal, galactose; GlcNAc, N-acetylglucosamine; GlcA, glucuronic acid;
GlcNS, N-sulfoglucosamine; IdoA, iduronic acid.
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