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Anti-aging Enzyme's Secrets Revealed

April 1, 2005
Johns Hopkins Medical Institutions
Johns Hopkins researchers have determined how a tiny molecule normally squelches the activity of an enzyme that otherwise could help yeast, worms and flies live longer.

Johns Hopkins researchers have determined how a tiny molecule normally squelches the activity of an enzyme that otherwise could help yeast, worms and flies live longer.

The structural secrets they found, which are described in the March 18 issue of Molecular Cell, are likely to help efforts to design molecules that increase or decrease the enzyme's normal activity. The idea isn't to create a fountain of youth, say the researchers, but to help treat diabetes, inflammation, cancer or other conditions in which the enzyme plays a role. The enzyme, called Sir2 or sirtuin, turns on or off certain proteins by removing "decorations" called acetyl groups.

"Some of the proteins the enzyme turns on or off are already known to be involved in disease, and new ones are being identified all the time," says Cynthia Wolberger, Ph.D., professor of biophysics and a Howard Hughes Medical Institute investigator in Johns Hopkins' Institute for Basic Biomedical Sciences. "The idea is that specifically and carefully altering the activity of sirtuins could help fix those conditions by restoring appropriate activity levels of the specific protein involved."

For example, Johns Hopkins scientist Pere Puigserver reported just last month that the human equivalent of Sir2 is intimately involved in controlling whether the liver produces sugar when food is scarce. In people with diabetes, sugar production in the liver is constant, and targeting this sirtuin might help restore control.

One key controller of the enzyme's activity is a small, naturally occurring molecule called nicotinamide (nick-oh-TIN-ah-mid), itself a product of the enzyme's complex chemistry. Already, scientists knew that this molecule fine-tunes sirtuin's activity by reducing its ability to remove the acetyl groups from proteins.

But exactly how nicotinamide interfered with sirtuin's activity was unknown. One idea was that there might be two places where nicotinamide could sit in the enzyme -- one spot where it's created, and another where it just blocks the enzyme from doing its job.

"Our structures of the protein and nicotinamide show that this is clearly not the case," says Wolberger, whose research focuses on understanding proteins' functions by determining what they look like. "Instead, nicotinamide binds in only one spot in the enzyme."

Jose Avalos, then a graduate student, found the answer by determining the three-dimensional structure of the nicotinamide and sirtuin bound together. The structure literally shows the molecule sitting in a pocket of the enzyme and also reveals how its presence prevents sirtuin from doing its thing. Based on this picture, the researchers altered a single component of that pocket, which made the enzyme sensitive to a different molecule.

"Things don't usually work out so cleanly," says Wolberger. "But in this case we made a prediction based on the structure, and we were able to prove that prediction true."

Wolberger and Avalos used sirtuin from bacteria to create their structures, but the human version of the enzyme responds to nicotinamide in the same way. Avalos's structures clearly identify which building blocks of the sirtuin protein are involved in binding nicotinamide.

"Understanding the interaction in such detail can help in the design of new compounds that could inhibit sirtuin's activity or increase it," says Avalos, now a postdoctoral fellow with Nobel laureate Rod MacKinnon at The Rockefeller University. "Which one you'd want to do depends on the ailment being addressed."

Molecules that mimic nicotinamide and block sirtuin's activity might be useful in treating diabetes, based on Puigserver's recent discoveries. Or the structural clues could be used to do the opposite, to turn up sirtuin's activity, which might restart a tumor suppressor gene called p53 that is erroneously shut off in many cancers. But those are just two examples.

"In the last two or three years, there's been an explosion in the number of known implications of sirtuin enzymes in biology and human health," notes Avalos.

Wolberger's goal isn't developing drugs, but understanding the details of how sirtuin works and how it's controlled, in part by understanding how various inhibitors and stimulators of sirtuin activity interact with the enzyme.

The research was funded by the Howard Hughes Medical Institute and the National Institute of General Medical Sciences, part of the National Institutes of Health. Authors on the paper are Avalos, Wolberger and Katherine Bever.

Story Source:

The above story is based on materials provided by Johns Hopkins Medical Institutions. Note: Materials may be edited for content and length.

Cite This Page:

Johns Hopkins Medical Institutions. "Anti-aging Enzyme's Secrets Revealed." ScienceDaily. ScienceDaily, 1 April 2005. <www.sciencedaily.com/releases/2005/03/050329144030.htm>.
Johns Hopkins Medical Institutions. (2005, April 1). Anti-aging Enzyme's Secrets Revealed. ScienceDaily. Retrieved September 22, 2014 from www.sciencedaily.com/releases/2005/03/050329144030.htm
Johns Hopkins Medical Institutions. "Anti-aging Enzyme's Secrets Revealed." ScienceDaily. www.sciencedaily.com/releases/2005/03/050329144030.htm (accessed September 22, 2014).

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