Welcome to …(drumroll here)… Acetyl Tag, the new game that goes beyond the cellular nucleus to the cytoplasm, to a place where few would guess finding — let alone imagine — masses of acetylated metabolic enzymes.
“We have discovered an entirely new layer of control of metabolism,” says Yue Xiong, Ph.D., professor of biochemistry and biophysics and a member of the UNC Lineberger Comprehensive Cancer Center.
Xiong points out that almost all previous studies on acetylation have focused on proteins in the nucleus, where acetyl tags on proteins regulate how tightly the DNA’s genetic code is packaged. It’s known that protein acetylation plays a key role in gene expression.
But Xiong along with study co-leader Kun-Liang Guan, professor of pharmacology at the University of California, San Diego, wanted to determine if acetylation also plays a role in the other half of the cell, the cytoplasm.
After separating the nucleus and the cytoplasm of human primary liver cells, the study team used mass spectroscopy to take a chemical census of the cytoplasm’s contents .
And to their surprise, they identified approximately a thousand new proteins that are acetylated, greatly expanding the previously recognized repertoire of fewer than one hundred. Nearly every metabolic enzyme was acetylated, presumably because their starting material was liver, an organ rich in metabolic activity.
In addition, the researchers discovered that blocking acetylation chemically or genetically affected these metabolic enzymes in a number of different ways, either by stimulating its activity, inhibiting it, or degrading the protein itself. They suspect that acetylation is important for coordinating not only the players within a metabolic pathway but also between different pathways.
The next step is to take their finding in normal cells and see how it can inform their study of tumor cells. The researchers are in the process of looking at each metabolic enzyme, one-by-one, to see which one displays the most disparate acetylation patterns between normal and cancer cells. They will then try to use the very same proteins that tack on or pull off those acetyl groups – called acetylases or deacetylases, respectively — to modify acetylation and thwart cancer development.
“If we can identify which enzyme or enzymes are responsible for the difference in metabolism between normal and tumor cells, then we may have have new targets for the treating cancer patients,” says Xiong.
The study appears in the February 19 issue of Science.