New insights on sirtuins, involved in gene expression and aging

(PHILADELPHIA) -- In recent years, scientists have become interested in the workings of a family of enzymes called sirtuins, known to play critical roles in a variety of vital life processes, including metabolism, aging, and gene expression. Previous studies, for example, have suggested that low-calorie diets that extend life boost sirtuin activity dramatically, hinting at a link between metabolism and aging through sirtuins. Sirtuins also promote genomic stability, a process that goes awry in cancer and particularly as one ages.

Now, scientists at The Wistar Institute report new findings that further elucidate how sirtuins work and suggest how scientists might identify or design an activator to boost sirtuin activity using a structure-based approach. The research will be published Tuesday, May 18, in the Proceedings of the National Academy of Sciences.

"We know that the Sir2 sirtuin silences gene expression and stabilizes the genome in yeast," says Wistar professor Ronen Marmorstein, Ph.D., senior author of the study. "We also know that sirtuins are highly conserved in humans. The idea researchers are exploring is that if we could activate sirtuins, perhaps we could promote genomic stability and decrease cancer as well as other aging-related problems."

Marmorstein's research team has been focusing on the molecular details of how sirtuins work. Sirtuins are a family of enzymes, proteins that facilitate chemical reactions that involve converting a substrate to a product, forming intermediate substances along the way. Using a yeast sirtuin protein as a model, Marmorstein and his research team captured three-dimensional images of the sirtuin protein in association with a substrate and intermediate mimics, while in previous research his group determined the structure of the protein in association with product. Together, Marmorstein's work provides a comprehensive structural picture of enzymatic activity of sirtuins, an important step toward identifying or designing an activator.

In the structure of the sirtuin protein in complex with the intermediate mimic, Marmorstein's group has found a pocket that appears to be a binding site that, if blocked, would serve to activate the protein. Using virtual libraries of molecules, Marmorstein's research team is identifying molecules with structures that might bind to this pocket and serve as Sir2 activators.

With senior author Marmorstein, the equally contributing lead authors were Kehao Zhao, Ph.D., and Robyn Harshaw, and the other co-author was Xiaomei Chai. Funding for the research was provided by the National Institutes of Health and the Commonwealth Universal Research Enhancement Program, Pennsylvania Department of Health.

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