Rensselaer Research Review Winter 2010-11
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Scientists Sequence the First Carbohydrate Biopolymer

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Structure of the bikunin. The portion on the left corresponds to the sugar part of the molecule, the sequence of which was determined in the new study. The portion on the right corresponds to the protein part of bikunin.

DNA and protein sequencing have forever transformed science, medicine, and society. Understanding the structure of these complex biomolecules has revolutionized drug development, medical diagnostics, forensic science, and our understanding of evolution and development. But, one major molecule in the biological triumvirate has remained largely uncharted: carbohydrate biopolymers.

Recently, for the first time ever, a team of researchers led by Robert Linhardt of Rensselaer Polytechnic Institute announced in the October 9 Online Publication edition of the journal Nature Chemical Biology the sequence of a complete complex carbohydrate biopolymer. The surprising discovery provides the scientific and medical communities with an important and fundamental new view of these vital biomolecules, which play a role in everything from cell structure and development to disease pathology and blood clotting.

The paper is titled “The proteoglycan bikunin has a defined sequence.”

“Carbohydrate biopolymers, known as glycosaminoglycans, appear to be really important in how cells interact in higher organisms and could explain evolutionary differences and how development is driven. We also know that carbohydrate chains respond to disease, injury, and changes in the environment,” said Linhardt, who is the Ann and John H. Broadbent Jr. ’59 Senior Constellation Professor of Biocatalysis and Metabolic Engineering at Rensselaer. “In order to understand how and why this all happens, we first need to know their structure. And today, at least for the simplest glycosaminoglycan structure, we can now do this.”

The first glycosaminoglycan sequenced was obtained from bikunin. Bikunin is a proteoglycan, a protein to which a single glycosaminoglycan chain is attached. Unlike less sophisticated carbohydrate biopolymers, such as starch and cellulose, the proteoglycans are decorated with structurally complex carbohydrates that enable them to perform more sophisticated and defined roles in the body. Bikunin, for example, is a natural anti-inflammatory that is used as a drug for the treatment of acute pancreatitis in Japan. It has the simplest chemical structure of any proteoglycan. Linhardt views the discovery of the structure of bikuin as the first step on the ladder to the discovery of the structure of more complex proteoglycans.

Using the Top-Down Approach: Picturing the Full Puzzle Intact

“The first genome sequences of DNA were on the simplest organisms such as bacteria. Once the technology was developed it ultimately led to the sequencing of the human genome,” he said. “In our efforts to sequence carbohydrate biopolymers we don’t yet know if the defined structure we observe for this simple protoglycan will hold for much more complex proteoglycans.” But, looking for structure in more complex proteoglycans will be among the next steps in the research for Linhardt and his team. The search for structure could help put to rest a long-running debate in the scientific community as to whether complex carbohydrate biopolymers require a defined structure to function.

To uncover the entire structure, Linhardt and his team, which was led by his doctoral student Mellisa Ly, borrowed a technique from the field of protein research called the proteomics top-down approach. As opposed to the bottom-up approach that first breaks apart a complex biopolymer into pieces and then rebuilds it piece by piece like a jigsaw puzzle, the top-down approach used by Linhardt and colleagues allows the researcher to picture the whole intact puzzle. This can only be accomplished with some of the most sophisticated technology available to the scientific community today, including very high-powered mass spectrometers.

Linhardt used a mass spectrometer located in the Rensselaer Center for Biotechnology and Interdisciplinary Studies (CBIS) to make his initial discoveries, and had these results independently confirmed on a separate and higher-level spectrometer at the University of Georgia. Mass spectrometers break down a molecule into separate charged particles or ions. These ions can then be categorized and analyzed based on their mass-to-charge ratio. These ratios then allow for sequencing of the entire molecule.

The research is funded by the National Institutes of Health.

Linhardt and Ly were joined in the research by Tatiana Laremore of Rensselaer; Franklin Leach and Jonathan Amster of the University of Georgia; and Toshihiko Toida of Chiba University in Japan.

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“Uncharted Territory”
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