Riddle Solved in Studying Critical Complex Carbohydrate

Riddle Solved in Studying Critical Complex Carbohydrate

Sep 3, 2008 9:30 AM

A carbohydrate molecule that plays a critical role in human development, health and disease—but whose function had been impossible to study in model organisms—now can be examined because of a breakthrough led by a University of Utah College of Pharmacy researcher.

The discovery, published online in the Journal of Biological Chemistry (http://www.jbc.org/cgi/reprint/M805939200v1), opens new ways to study proteoglycans—molecules comprising proteins and highly sulfated carbohydrate chains—which can shed light on disease and health problems ranging from Alzheimer’s and diabetes to heart disease and cancer, according to Kuberan Balagurunathan, Ph.D., assistant professor of medicinal chemistry and senior author of the study.

“Now we can define this molecule’s role in development,” Balagurunathan said. “We can better understand its role in the cardiovascular system, brain, and other biological systems.”

Proteoglycans are found throughout the body and have many roles in human biology, such as helping to guide the wiring of developing brains, preventing blood from clotting, preventing neurons from regenerating, and promoting tumor cell growth, invasion, and migration. Chondroitin sulfate, which comprises part of proteoglycans, helps cartilage retain its spongy property to protect bones in the joints, such as in the knees and shoulders, and is taken as a dietary supplement by many people who claim it eases the pain of osteoarthritis. Heparan sulfate, also part of proteoglycans, is linked with metabolism, changes in diabetes, and cancer.

Proteoglycans, one of the most important types of carbohydrates known as glycoconjugates, are made (biosynthesized) by nearly two dozen enzymes inside a cell. To study the function of proteoglycans, researchers need to examine what happens in cells when proteoglycans aren’t produced. Until now, the only way to do that was by using Chlorate, a bleaching agent, and Brefeldin, a fungal metabolite. Though these small molecules prevent the biosynthesis of proteoglycans, both are toxic to the cells, preventing researchers from studying proteoglycan functions in animal models. 

Balagurunathan and his colleagues prevented proteoglycans from being made, without harming other proteins, glycoconjugates, and the cellular machinery, by using small molecules that mimic carbohydrates and truncate the carbohydrate chains that make proteoglycans. When these chains are stopped from growing, proteoglycans can’t be biosynthesized, but the other cellular processes are not affected. Researchers then can observe what effects the lack of proteoglycans have on numerous biological processes.

“Now there is a tool to define the role of these molecules,” Balagurunathan said. “We can block one aspect of the biological pathway in a very mild, elegant way.”

Balagurunathan and his colleagues plan to conduct their research with zebrafish, tiny fish that make excellent biological models for studying developmental roles and physiological functions of heparan sulfate proteoglycans that are relevant to human health and disease. But their discovery can be used to study other animal models and biological questions as well, he said.

This work is supported by the National Institute of General Medical Sciences and Human Frontiers Science Program.

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