Hexuronyl C5-epimerases in alginate and glycosaminoglycan biosynthesis

The sugar residues in most polysaccharides are incorporated as their corres ponding monomers during polymerization. Here we summarize the three known e xceptions to this rule, involving the biosynthesis of alginate, and the gly cosaminoglycans, heparin/heparan sulfate and dematan sulfate. Alginate is s ynthesized 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-mannuro nic acid to L-guluronic acid in alginate, and from D-glucuronic acid to L-i duronic acid in glycosaminoglycans. Alginate epimerization modulates the me chanical properties of seaweed tissues, whereas in bacteria it seems to ser ve a wide range of purposes. The conformational flexibility of iduronic aci d units in glycosaminoglycans promotes apposition to, and thus functional i nteractions with a variety of proteins at cell surfaces and in the extracel lular matrix. In the bacterium Azotobacter vinelandii the alginates are bei ng epimerized at the cell surface or in the extracellular environment by a family of evolutionary strongly related modular type and Ca2+-dependent epi merases (AlgEl-7). Each of these enzymes introduces a specific distribution pattern of guluronic acid residues along the polymer chains, explaining th e wide structural variability observed in alginates isolated from nature. G lycosaminoglycans are synthesized in the Golgi system, through a series of reactions that include the C5-epimerization reaction along with extensive s ulfation of the polymers. The single, Ca2+-independent, epimerase in hepari n/heparan sulfate biosynthesis and the Ca2+-dependent dermatan sulfate epim erase(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 throu gh independent evolutionary pathways; however, hydrophobic cluster analysis indicates limited similarity. Seaweed alginates are widely used in industr y, while heparin is well established in the clinic as an anticoagulant. (C) 2001 Societe francaise de biochimie et biologic moleculaire/Editions scien tifiques et medicales Elsevier SAS. All rights reserved.