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.
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Contact: Joanna Downer
jdowner1@jhmi.edu
410-614-5105
Johns Hopkins Medical Institutions
6-Jan-2003