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The newly evolved enzyme developed by Thorson and colleagues Gavin. J.
Williams and Changsheng Zhang, according to Thorson, is akin to a
"Swiss Army enzyme," a catalyst that can decorate many different
chemical molecules with all sorts of sugars to alter their biological
effects.
Enzymes are proteins that act as catalysts across biology, from
single-celled organisms to humans. They promote chemical reactions in
cells and are used widely in industry for everything from making beer
and cheese to producing paper and biofuel.
They are also important for making so-called natural drugs,
therapeutic agents based on the blueprints of chemicals produced in
nature by plants and microorganisms. Such natural sugar-bearing
chemicals are the basis for some of medicine's most potent antibiotics
and anticancer drugs as exemplified by the antibiotic erythromycin and
the anticancer drug doxorubicin.
Important chemical features of such drugs are natural sugars,
molecules that often determine a chemical compound's biological
effects. Although scientists can sometimes manipulate how sugars are
added or subtracted to a chemical molecule to alter its therapeutic
properties, it is difficult and not always possible to routinely
modify them to enhance their beneficial effects.
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
new 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.
"We're transferring the sugar to a beacon," Thorson explains. "When
you attach a sugar, you shut off the fluorescence."
The development of the screen, according to Thorson, 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. The ability to rapidly evolve
these enzymes has opened a lot of doors."
The range of potential therapeutic agents that might be generated with
the new technology includes important anti-inflammatory and
anti-cancer compounds, and antibiotics.
What's more, the work could lead to the creation of a "super bug," an
engineered bacterium that can perform the entire process in a
laboratory dish: "There's no doubt that this is going to work in
vivo," says Thorson. "We can create a bug where you feed it sugars and
the compounds you want to hang those sugars on" to arrive at new
medicines.
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