Bioengineering and Metabolic Engineering

Glycoengineering

Heparin, a highly sulfated glycosaminoglycan (GAG), is used extensively as an anticoagulant. It consists of repeating disaccharide units, containing iduronic acid (or glucuronic acid) and glucosamine, exhibiting variable degrees of sulfation. Heparin, and its analogues, are used during surgery and dialysis, and are often used to coat indwelling catheters and other devices where the vascular system is exposed. Administered parenterally, often continuously due to its short half-life, over 0.5 billion doses are required per year. The annual sales of pharmaceutical heparin are over $3 billion and it is prepared in 100 metric ton amounts annually. Currently obtained from mucosal tissue of meat animals, mainly porcine intestine, and to a lesser extent bovine lung, its early stage production is poorly controlled, due to the source of the material. This problem came into sharp focus in 2008 when the presence of contaminating over-sulfated chondroitin sulfate in heparin, sourced from pigs, resulted in 81 deaths in the USA. This, coupled with the fact that only two doses are obtained per animal means that the demand for an alternative and more controlled sources of heparin is high.

To this end the Glycoengineering subgroup consists of two sections: Bioengineering and Metabolic Engineering. The bioengineering section involves the use of microbial, mainly bacterial, processes to generate and modify GAGs, using a combination of fermentation and chemo-enzymatic modification. The metabolic engineering section involves the manipulation of the natural metabolic processes of mammalian cells to generate and modify GAGs, intracellulary

Projects

Bioengineered Heparin Project

A biosynthetic pathway was designed that began with bacterial synthesis of the backbone structure, N-acetyl heparosan, with the aim of producing a bioengineered heparin product. N-Acetyl heparosan is synthesized by E. coli K5 as a capsular polysaccharide and is shed into the growth media.

Metabolic Engineering Project

Heparin, a natural product of mast cells, is stored in mast cell granules and is released with histamine on type-1 allergic response leading to mast cell degranulation. Metabolic engineering offers a potential approach to prepare heparin by fermentation. The metabolic engineering of bacterial cells is relatively straightforward since most of the biosynthetic pathways are relatively simple and well known, but while bacteria are both easy and inexpensive to engineer and to grow, they are not compartmentalized, lack a Golgi and thus are incapable of making all but the simplest glycoproteins.

The Linhardt Research Labs

Center for Biotechnology and Interdisciplinary Studies

110 8th St., BT 4211 Troy, NY 12180

(518) 423-6893

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