Jan. 7, 2003 Scientists from Johns Hopkins and the University of Wisconsin have discovered that a protein called Sir2, which is found in nearly all living cells, has a new function that might help explain how calorie restriction can increase lifespans for some animals, the scientists say. Their report appeared in the Dec. 20 issue of Science.
A number of laboratories have shown that restricting total calorie intake extends the lifespans of organisms ranging from yeast to laboratory animals. Others have shown that this effect requires Sir2's protein family, called sirtuins, and increased cellular respiration, which is the process of using oxygen to convert calories into energy.
Studying bacteria, the Johns Hopkins-Wisconsin team has discovered that sirtuin controls the enzyme that converts acetate, a source of calories, into acetyl-CoA, a key component of cellular respiration.
"Sirtuins are highly conserved across species, but this is a never-before-described ability of the protein," says Jef Boeke, Ph.D., professor of molecular biology and genetics at Johns Hopkins' Institute for Basic Biomedical Sciences. "If sirtuins modify this enzyme in other organisms, turning on production of acetyl-CoA, it could help explain why restricting regular sources of calories -- sugars and fats -- leads to extended lifespan in many kinds of organisms."
Identified in all living creatures, including single-celled organisms like bacteria and yeast, sirtuin proteins previously were known to play an important role in keeping regions of chromosomes turned off. By modifying the histone proteins that keep DNA tightly coiled, sirtuins prevent certain regions of chromosomes from being exposed to cells' DNA-reading machinery.
Sirtuin's new role in bacteria involves the same modification as its interaction with histone -- removing an acetyl group, a "decoration" added to a protein's sequence (like phosphate) -- but the targeted protein is involved in producing energy, not controlling chromosomes.
Normally, cells can survive by using many different molecules as sources of energy -- potent sources like fats or sugars, or even relatively energy-poor molecules like acetate.
However, Jorge Escalante-Semerena and Vincent Starai of the University of Wisconsin created a strain of bacteria missing its sirtuin protein and noticed that it couldn't live on acetate. Boeke had previously noticed that yeast without sirtuin had the same problem, so the researchers dug deeper.
They discovered that the sirtuin protein in bacteria is a crucial modifier of an enzyme known as acetyl-CoA synthetase, which converts acetate into acetyl-CoA in a two-step process. Acetyl-CoA then can directly fuel the citric acid cycle, the central energy-producing step in cellular respiration.
"This is a completely new target for the sirtuin protein," says Boeke, who has been studying "transcriptional silencing" -- sirtuin's previously known role -- for some time. "Converting acetate isn't the cell's only way of making acetyl-CoA, but when acetate is the major energy source, it's crucial. Now we have to check for this role in other organisms."
The Wisconsin researchers found that sirtuin activates the first step of acetate's conversion, and Boeke and Johns Hopkins' Robert Cole and Ivana Celic figured out that sirtuin does so by removing an acetyl group from a lysine in the enzyme's active site.
While bacteria and yeast are both single-celled critters, yeast are much more closely related to animals, including humans, than are bacteria. If the yeast version of sirtuin also modifies the newly identified target, that would more likely reflect the protein's role in animals and would more formally link the protein to lifespan extension, at least for yeast. The effect of calorie restriction on the lifespan of bacteria has not been established.
### The studies were funded by the National Institutes of Health, and the Jerome Stefaniak and Pfizer Predoctoral Fellowships (to Starai). The Johns Hopkins Mass Spectrometry facility is funded by the National Center for Research Resources, the Johns Hopkins Fund for Medical Discovery, and the Johns Hopkins Institute for Cell Engineering. Authors on the paper are Starai and Escalante-Semerena of Wisconsin; and Celic, Cole and Boeke of the Johns Hopkins School of Medicine.
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