Sugar has been called “evil,” “toxic,” and “poison.” But the body needs sugars, too. Sugar molecules help cells recognize and fight viruses and bacteria, shuttle proteins from cell to cell, and make sure those proteins function. Too much or too little can contribute to a range of maladies, including neurodegenerative diseases like Alzheimer’s, inflammation, diabetes, and even cancer.
About 85 percent of proteins, including those associated with Alzheimer’s and Parkinson’s, are beyond the reach of current drugs. One critical and abundant sugar (O-GlcNAc, pronounced o-glick-nack) is found on more than 5,000 proteins, many of them considered “undruggable.” But now, researchers at Harvard have designed a new, highly selectiveO-GlcNAc pencil and eraser — tools that can add or remove the sugar from a protein with no off-target effects — to examine exactly what these sugars are doing and, eventually, engineer them into new treatments for the undruggable.
“We can now start studying particular proteins and see what happens when you add or remove the sugar,” said Daniel Ramirez, a co-author on the paper published in Nature Chemical Biology and a Ph.D. candidate in biological and biomedical sciences in the Graduate School of Arts and Sciences. “This is turning out to be very important for a lot of chronic diseases, like cancer and diabetes and Alzheimer’s.”
Ramirez designed the original O-GlcNAc pencil, which was reported in ACS Chemical Biology.
All cells carry a multitude of sugars (called glycans), but they’re notoriously hard to study. Current tools provide either a wide-lens view (turning on or off all the O-GlcNAcs in a cell) or an ultra-zoomed-in view (turning on or off a single sugar on one amino acid on one protein). Neither of these perspectives can show the crucial insight that would enable researchers to connect the dots from O-GlcNAc to disease: what O-GlcNAc molecules are doing to a protein as a whole.
“With the protein-level approach, we’re filling in an important piece that was missing,” said Christina Woo, an associate professor of chemistry and chemical biology, who led the study. Her lab’s tool is like Goldilocks’ lukewarm bowl of porridge: Not too broad, not too specific. Just right.
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