MINI-REVIEW Glycosaminoglycan polysaccharide biosynthesis and production: today and tomorrow Paul L. DeAngelis Received: 2 November 2011 / Revised: 29 November 2011 / Accepted: 1 December 2011 / Published online: 6 March 2012 # Springer-Verlag 2012 Abstract Glycosaminoglycans [GAGs] are essential heter- opolysaccharides in vertebrate tissues that are also, in certain cases, employed as virulence factors by microbes. Hyaluronan [HA], heparin, and chondroitin sulfate [CS] are GAGs cur- rently used in various medical applications and together are multi-billion dollar products thus targets for production by animal-free manufacture. By using bacteria as the source of GAGs, the pathogen’ s sword may be converted into a plow- share to help avoid potential liabilities springing from the use of animal-derived GAGs including adventitious agents (e.g., prions, pathogens), antigenicity, degradation of the environ- ment, and depletion of endangered species. HA from microbes, which have a chemical structure identical to human HA, has already been commercialized and sold at the ton- scale. Substantial progress towards microbial heparin and CS has been made, but these vertebrate polymers are more com- plicated structurally than the unsulfated bacterial polysaccha- ride precursors thus require additional processing steps. This review provides an overview of GAG structure, medical applications, microbial biosynthesis, and the state of bacterial GAG production systems. Representatives of all glycosyl- transferase enzymes that polymerize the sugar chains of the three main GAGs have been identified and serve as the core technology to harness, but the proteins involved in sugar precursor formation and chain export steps of biosynthesis are also essential to the GAG production process. In addition, this review discusses future directions and potential important issues. Overall, this area is poised to make great headway to produce safer (both increased purity and more secure supply chains) non-animal GAG-based therapeutics. Keywords Polysaccharide . Capsule . Synthase . Glycosyltransferase . Hyaluronan . Heparin . Chondroitin Glycosaminoglycan structures and sources Glycosaminogly- cans [GAGs] are sugar heteropolysaccharides that contain a hexosamine (typically GlcNAc or GalNAc) as part of their repeating structure (Laurent and Fraser 1992; Esko and Lindahl 2001; DeAngelis 2002a; Silbert and Sugumaran 2002). The GAGs found in vertebrate tissues have been well studied due to their medical applications. Studies of various knockout organism systems deem that hyaluronan [HA], heparan sulfate/heparin, and chondroitin sulfate are essential for mammals. These three polymers are based on a repeating disaccharide unit (Table 1); this is in contrast to some of the most common natural polysaccharides such as cellulose, starch, and chitin that are based on a single monosaccharide unit. GAGs are very hydrophilic, anionic polymers. In mam- mals, these long polysaccharides are composed of hundreds to thousands of repeats depending on the source tissue and organism. Also, in chondroitin sulfate and heparan/sulfate heparin (but not HA), there are post-polymerization modifi- cations of the polysaccharide backbone (sulfation and/or epi- merization) that vary depending on the tissue and developmental stage (Esko and Lindahl 2001; Silbert and Sugumaran 2002; Sugahara and Kitagawa 2002). In the body, most chondroitin sulfate and heparan sulfate (but not HA) is attached covalently to a protein during synthesis, but for current medical applications, the free GAG chains are employed. Certain pathogenic bacteria also produce the virtually identical or similar GAG backbones to enhance infection P. L. DeAngelis (*) Department of Biochemistry and Molecular Biology, Oklahoma Center for Medical Glycobiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73126, USA e-mail: paul-deangelis@ouhsc.edu Appl Microbiol Biotechnol (2012) 94:295–305 DOI 10.1007/s00253-011-3801-6