New Description Of Protein May Be Basis For Regulating Cholesterol

September 18, 1997

Scientists have described the three-dimensional structure and inner workings of a protein that synthesizes a naturally occurring class of complex compounds, one of which is cholesterol. The findings provide the groundwork for understanding how to regulate the creation of cholesterol in the body.

PROVIDENCE, R.I. -- Scientists have described the three-dimensional structure and inner workings of a terpene synthase, a type of protein that synthesizes a naturally occurring class of complex compounds whose members range from the essential oils of herbs, incense and perfumes to the well-known substance cholesterol.

By describing a terpene synthase in three dimensions and offering useful clues as to how it operates, the findings provide the groundwork for understanding how to regulate creation of cholesterol in the body. Other common terpenes include pine resins and the essential oils of myrrh, rosemary and thyme.

Reporting in the current issue of the journal Science, scientists from the University of Pennsylvania and Brown University present the three-dimensional structure of pentalenene synthase, an enzyme responsible for a key step in the formation of a natural antibiotic.

The scientists also explain some of the protein's inner workings. They suggest that pentalenene synthase uses certain amino acids in an internal vessel-like cavity to fold, shape and transform a natural building block - a common plant alcohol derivative - into a particular product. In this case, the product is a terpene molecule that is eventually converted into an antibiotic.

The study's lead author is David W. Christianson, a protein crystallographer at the University of Pennsylvania. Additional authors are Charles A. Lesburg, University of Pennsylvania and Brown's Guangzhi Zhai and David E. Cane. Two other papers in this week's Science describe matching structures and inner workings for proteins that form terpene molecules.

"The processes involved are similar among all three proteins," said Cane, professor of chemistry and biochemistry. "This presents quite a rich view, indicating that hundreds of these compounds have similar origins."

Cane and colleagues are interested in how the protein recognizes, processes and transforms the natural substrate into other products. The scientists used computer models to describe how the substrate might be folded and shaped into an active site in the protein, and identified where those sites were located.

Terpenes can teach scientists about nature's chemical processes, Cane said. For example, the reactions discovered inside the proteins usually don't take place in or around water. Somehow, terpene synthases have devised a way to protect the reactions from surrounding water to make any one of hundreds of possible products, he said.

Describing the protein's structure is a gateway to more probing studies, Cane said. These include engineering proteins in the laboratory to make new products with unique structures. "If we can understand how a particular protein is designed and works and how pieces of its system function, then in principle we can make designer-engineered proteins with particular properties so as to produce new antibiotics," he said.
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Brown University

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