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Sep 10, 2007

Investigators Create Novel Glycosylation Enzyme

  • A team of researchers from the UW-Madison School of Pharmacy report that they discovered a new enzyme capable of changing the chemical properties of existing drugs and small molecules to make new agents to treat cancer and fight infection.

    The newly evolved enzyme is akin to a Swiss Army enzyme, a catalyst that can decorate many different chemical molecules with sugars to alter their biological effects, according to the scientists.

    Important chemical features of some drugs are natural sugars, which often determine a compound’s biological effects. Although scientists can sometimes manipulate how sugars are added or subtracted to a molecule to alter its therapeutic properties, it is difficult and not always a matter of routine.

    The new enzyme was created by generating random mutations in genes that make a naturally occurring enzyme. The altered genes were then put into a bacterium, which fabricated a series of randomly mutated enzymes. These enzyme variants were then tested in a high-throughput screen where chemical molecules engineered to fluoresce stop glowing when a sugar is successfully attached.

    The development of the screen, according to the investigators, was critical, overcoming a key limitation in the glycosyltransferase field. “We’re assaying hundreds of very interesting drug-like molecules now with newly evolved glycosyltransferases,” notes Jon Thorson, Ph.D., a University of Wisconsin-Madison professor of pharmaceutical sciences. “The ability to rapidly evolve these enzymes has opened a lot of doors.”

    The study is published in the September issue of Nature Chemical Biology.



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