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Protein Structure Provides Clue to Long Life
By Nancy Touchette

People who drink red wine and consume a low calorie diet tend to live longer. This may be due, at least in part, to a family of proteins called sirtuins. Now researchers have obtained a detailed view of the structure of one of these proteins from yeast.

The finding may help researchers understand the molecular basis of longevity and could lead to new drugs to improve health and increase lifespan.

“It's important to understand the details of how these proteins work,” says Ronen Marmostein of the Wistar Institute in Philadelphia, Pennsylvania, who led the research. “Now we are in a better position to design molecules to stimulate sirtuin activity.”

The dream of a fountain of youth has transcended human history. In 1546 Lucas Cranach depicted his version in The Fountain of Youth. Oil on canvas. Staatliche Museen zu Berlin, Gemaldegalerie, Berlin, Germany.

Such molecules may mimic the effects of a low calorie diet and improve health, he says. Low calorie diets increase the lifespan of many organisms, including yeast, worms, mice, and humans. This increase in longevity depends on sirtuins.

Recently, researchers found that organic compounds abundant in grapes, red wine, apples, olives, and other plants activate human and yeast sirtuin proteins and extend the life span of yeast cells. The finding has led many to believe that the proteins may play a key role in delaying the effects of aging.

Sirtuins remove a chemical tag known as an acetyl group from several types of proteins important in cell function. The new study provides a detailed view of the part of the sirtuin that carries out the action.

By determining the structure of three molecules involved in the reaction—a sirtuin, a common cell metabolite called NAD, and a second protein—the researchers were able to figure out how sirtuins go about the process of removing the tag from the protein.

NAD is important in the breaking down food in the body. Researchers have speculated that a low-calorie diet may free NAD so it is available to help sirtuins do their job—altering proteins that somehow affect the aging process.

The researchers still don't know how organic compounds such as resveratol, found in wine, activate sirtuin enzymes. The next step, says Marmorstein, is to determine how sirtuin interacts with molecules that activate or inhibit it.

“Once we are able to visualize the structure of sirtuin with a bound activator or inhibitor, we can better understand how it works and do a better job of designing potential new drugs,” he says.

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Zhao, K. et al. Structure of the yeast Hst2 protein deacetylase in ternary complex with 2'-O-acetyl ADP ribose and histone peptide. Structure 11, 1403-1411 (2003).


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