Elusive inhibitors of sugar transferases created
June 10, 2012 § Leave a comment
Scientists can now better tinker with the sugar molecules in cells. A group at The Scripps Research Institute has developed inhibitors that choke the activity of two major classes of sugar enzymes, sialyltransferases and fucosyltransferases. These inhibitors can help scientists better understand the role of various sugar molecules in cell signaling and immunity as well as explore new ways to treat chronic inflammation, autoimmune diseases and cancer.
Glycobiology is an important area of investigation to understand the roles of various sugars both in normal and disease states. (As an example, check out my post on Sanfilippo syndrome.)
One challenge in studying sugars and their complexes is to understand how the 250 different enzymes called glycosyltransferases do their jobs in creating complex sugar structures. The field has been hindered by the lack of a tool: inhibitors that can work in cell cultures and in animal models on glycosyltransferases.
A team led by James C. Paulson and his graduate student Cory Rillahan at Scripps has now developed inhibitors of transferases of sialic acid and fucose, two important sugars that are found at the tips of complex sugar structures and that mediate important interactions with other proteins. In their study published in Nature Chemical Biology, the authors describe inhibitors that can cross the cell membrane to enter cells and confuse the sialyltransferases and fucosyltransferases into binding to these inhibitors instead of their normal sugar substrates. The enzymes get throttled into silence by these inhibitors.
However, these inhibitors do more than just inhibit. They also cause the cells to stop making functional fucose and sialic acid building blocks. As a result, cells exposed to the inhibitors lose almost all of their fucoses and sialic acids from their sugar complexes.
This affects one critical complex called Sialyl-Lewis X. It’s expressed on activated white blood cells, and its overexpression has been linked to chronic inflammation and various cancers. When the investigators treated cells with their inhibitors, they found that the fucoses and sialic acids disappeared from the Sialyl-Lewis X within a few days. This, in turn, meant that the cells were less likely to cause inflammation or cancer metastases.
The investigators now are working to extend their work on these enzyme-inhibiting analogs in laboratory mice. “We want to show that these compounds can be used to alter glycans on cells that contribute to inflammation, autoimmunity and cancer but without harming the animals,” says Paulson.