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Researchers crack the code of the complex sugar molecule

CAMBRIDGE, Mass.--MIT researchers report in a recent issue of the Journal of the American Chemical Society that their new analytical method unravels the structure of heparan sulfate, a sugar molecule on the surface of all cells in the body, and heparin, a commercial drug used to prevent clotting.

Researchers have been able to determine the structure of proteins and DNA quickly and cheaply for decades. But it has been very difficult to do the same for sugars (polysaccharides), because these molecules are so much more complex and structurally variable.

Heparan sulfate is particularly interesting to researchers because it is involved in normal physiological functions such as tissue regeneration, and also disease-related functions such as developmental disorders and tumor growth.

The new method was developed by MIT Professor of Biology Robert D. Rosenberg and postdoctoral associates Kuberan Balagurunathan and Zhengliang L. Wu, technical associate Miroslaw Lech, research affiliate Lijuan Zhang and research scientist David Beeler.

In 2000, using different methods, MIT researchers led by Ram Sasisekharan, associate professor of biological engineering, also developed a technique for determining the overall structure of polysaccharides and applied it to a key heparin fragment. However, Rosenberg and others in his lab have developed a new technique for identifying the key areas on the molecule critical for biological action. This method uses different labels to identify critical areas on the molecule required for biological action.

Thirty years ago, Rosenberg, then at Harvard Medical School, demonstrated that heparin works as a blood thinner by binding to its target, a blood-coagulation protein called antithrombin, through sugar groups in one of its key sections. This causes the antithrombin molecule to increase the rate at which it inhibits blood coagulation enzymes. The end result of this action is to inhibit blood coagulation and function as an anticoagulant drug.

The new technique, which is unusual because it combines liquid chromatography with mass spectrometry, can separate heparin and heparan sulfate oligosaccharides that are three to four times larger than what was possible previously.

"No one has been able to figure out the critical structural parameters responsible for the biological activity of these compounds," Rosenberg said. "Development of newer techniques for heparan sulfate oligosaccharide analysis is greatly needed in the postgenome era as attention shifts to the functional implications of proteins and carbohydrates in general and heparan sulfate in particular."

This work is funded by the National Institutes of Health.

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