Glycobiology-Glycosaminoglycans and Polysaccharides

By: Vicki Caligur, BioFiles 2008, 3.10, 3.

BioFiles 2008, 3.10, 3.

Vicki Caligur
Product Manager, Specialty Biochemistry
vicki.caligur@sial.com


Polysaccharides are structural components of plant, animal, and bacterial cells. As a group, polysaccharides, such as starch, glycogen, and cellulose, are ubiquitous and common. However, when specific classes of polysaccharides are examined, it is clear they have great variation based on origin, structure, and function. In this Glycobiology issue of BioFiles, we have focused on two specific types of polysaccharides: glycosaminoglycans and dextran.

Even within the specific class of glycosaminoglycans, the diversity of function is so extensive that a comprehensive review is not possible. Glycosaminoglycans are primarily found in animal tissue, and their function was initially thought to be solely that of space-occupying components of the extracellular matrix. We now know that glycosaminoglycans contribute to the functionality of proteoglycans and participate in cellular signaling, neuron development, lipoprotein metabolism, inflammation, and bacterial infection.

The structural complexity of glycosaminoglycans is necessary for functionality but also makes structure confirmation extremely difficult, as demonstrated by the heparin contamination crisis in early 2008.

In the early 20th century, heparin was isolated and found to act as an anticoagulant, and it has been used medically for over 70 years. Low molecular weight heparin modified by various techniques has been developed for use as an anticoagulant to reduce heparin-induced thrombocytopenia. In 1983, the pentasaccharide sequence within heparin that possesses the ability to block factor Xa and antithrombin activity was identified.1 The pentasaccharide fondaparinux is now commercially synthesized and has been approved for medical use in the United States and Europe as an anticoagulant under the trade name ARIXTRA®. Although these alternatives are available, heparin from natural sources continues to be widely used clinically.

In the spring of 2008, at least 20 patient deaths were associated with contaminated heparin that was not detected by routine analysis. An international team of researchers identified the impurity as a variant of chondroitin sulfate, a different glycosaminoglycan found in cartilage, which had been modified with sulfate groups in an unnatural pattern. The conclusive identification required multiple techniques, including multidimensional NMR spectroscopy supported by enzymatic digestion and HPLC analysis and was validated by chemical synthesis of an oversulfated chondroitin that matched the unknown contaminant.2 As a result of this exhaustive analysis, capillary electrophoresis and NMR spectroscopy are now required by the United States FDA to screen heparin for similar contamination.


Dextran, a glucose polymer isolated from the bacteria Leuconostoc mesenteroides was first applied to medical use as a plasma volume expander and an antithrombotic during World War II. The structural features and applications of dextran, dextran sulfate, and pullulan are reviewed in this issue.

Finally, the GlycoProfile™ β-Elimination Kit is Sigma®’s newest product for removing glycans from glycoproteins. Unlike other chemical deglycosylation techniques, β-elimination allows researchers to recover both the glycan pool and the protein core for downstream analysis and application. The GlycoProfile β-Elimination Kit allows for complete glycoproteomic analysis of O-linked glycoproteins as never before possible.

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References

  1. Petitou, M., Casu, B., and Lindahl, U., 1976-1983, a critical period in the history of heparin: the discovery of the antithrombin binding site. Biochimie, 85, 83-89 (2003).
  2. Guerrini, M., Beccati, D., Shriver, Z., Naggi, A., Viswanathan, K., Bisio, A., Capila, I., Lansing, J.C., Guglieri, S., Fraser, B., Al-Hakim, A., Gunay, N.S., Zhang, Z., Robinson, L., Buhse, L., Nasr, M., Woodcock, J., Langer, R., Venkataraman, G., Linhardt, R.J., Casu, B., Torri, G., and Sasisekharan, R. Oversulfated chondroitin sulfate is a contaminant in heparin associated with adverse clinical events. Nat. Biotechnol., 26, 669-75 (2008).

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