Bioengineered production of glycosaminoglycans and their analogues.

Glycosaminoglycans (GAGs) are a class of linear polysaccharides, consisting of alternating disaccharide sequences of uronic acid and hexosamines (or galactose) with and without sulfation. They can interact with various proteins, such as growth factors, receptors and cell adhesion molecules, endowing these with various biological and pharmacological activities. Such activities make GAGs useful in health care products and medicines. Currently, all GAGs, with the exception of hyaluronan, are produced by extraction from animal tissues. However, limited availability, poor control of animal tissues, impurities, viruses, prions, endotoxins, contamination and other problems have increased the interest in new approaches for GAG production. These new approaches include GAGs production by chemical synthesis, chemoenzymatic synthesis and metabolic engineering. One chemically synthesized heparin pentasaccharide, fondaparinux sodium, is in clinical use. Mostly, hyaluronan today is prepared by microbial fermentation, largely replacing hyaluronan from rooster comb. The recent gram scale chemoenzymatic synthesis of a heparin dodecasaccharide suggests its potential to replace currently used animal-sourced low molecular weight heparin (LMWH). Despite these considerable successes, such high-tech approaches still cannot meet worldwide demands for GAGs. This review gives a brief introduction on the manufacturing of unfractionated and low molecular weight heparins, the chemical synthesis and chemoenzymatic synthesis of GAGs and focuses on the progress in the bioengineered preparation of GAGs, particularly heparin.