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Eliminate Data Analysis Bottlenecks in Drug Discovery

like its sirtuin relatives, is best known for removing molecular "decorations" on proteins that help organize DNA and restrict access to genes. It turns out that sirtuin1 also removes these decorations from PGC1, and then remains bound to PGC1 as it starts up the sugar-making process, the researchers found.

"Because both proteins are required for the liver to make sugar, targeting sirtuin1 in a very specific way might help control sugar production in people with diabetes," says Puigserver. "Sirtuin1 interacts with many different proteins, and it's just this one interaction you would want to prevent."

But, he says, PGC1 has an unusually close relationship with sirtuin1 that may make for relatively easy picking. PGC1, unlike the vast majority of proteins, only uses sirtuin1 to remove its "decorations," called acetyl groups. Most other proteins can have the groups plucked off by a number of different enzymes.

"PGC1 is a 'clean' target for sirtuin1," says Puigserver. "If sirtuin1 isn't available, PGC1 becomes covered in acetyl groups, and the acetyl-covered PGC1 can't make sugar."

In their experiments, graduate student Joseph Rodgers also discovered that the livers of fasted mice first developed high levels of a chemical called pyruvate, which is a starting material for making glucose, and then accumulated high levels of sirtuin1 protein. (Rodgers will receive the Nupur Dinesh Thekdi Research Award on April 14 for this work as part of the School of Medicine's 28th annual Young Investigators' Day celebration.)

"When there's no incoming food, muscles make lactate and alanine and send them to the liver to be converted into pyruvate and glucose," says Puigserver. "It appears, from our work, as though the pyruvate then triggers increased production of sirtuin1, which in turn lets PGC1 start converting the pyruvate into the glucose the body needs to survive."

The relationship between sirtuin1 and PGC1 also connects processes in
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