Abstract
The sugar residues in most polysaccharides are incorporated as their
corresponding monomers during polymerization. Here we summarize the
three known exceptions to this rule, involving the biosynthesis of
alginate, and the glycosaminoglycans, heparin/heparan sulfate and
dermatan sulfate. Alginate is synthesized by brown seaweeds and certain
bacteria, while glycosaminoglycans are produced by most animal species.
In all cases one of the incorporated sugar monomers are being C5-epimerized
at the polymer level, from D-mannuronic acid to L-guluronic acid
in alginate, and from D-glucuronic acid to L-iduronic acid in glycosaminoglycans.
Alginate epimerization modulates the mechanical properties of seaweed
tissues, whereas in bacteria it seems to serve a wide range of purposes.
The conformational flexibility of iduronic acid units in glycosaminoglycans
promotes apposition to, and thus functional interactions with a variety
of proteins at cell surfaces and in the extracellular matrix. In
the bacterium Azotobacter vinelandii the alginates are being epimerized
at the cell surface or in the extracellular environment by a family
of evolutionary strongly related modular type and Ca(2+)-dependent
epimerases (AlgE1-7). Each of these enzymes introduces a specific
distribution pattern of guluronic acid residues along the polymer
chains, explaining the wide structural variability observed in alginates
isolated from nature. Glycosaminoglycans are synthesized in the Golgi
system, through a series of reactions that include the C5-epimerization
reaction along with extensive sulfation of the polymers. The single,
Ca(2+)-independent, epimerase in heparin/heparan sulfate biosynthesis
and the Ca(2+)-dependent dermatan sulfate epimerase(s) also generate
variable epimerization patterns, depending on other polymer-modification
reactions. The alginate and heparin epimerases appear unrelated at
the amino acid sequence level, and have probably evolved through
independent evolutionary pathways; however, hydrophobic cluster analysis
indicates limited similarity. Seaweed alginates are widely used in
industry, while heparin is well established in the clinic as an anticoagulant.
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