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BIOCHEMISTRY
Although ribozymes capable of performing a wide range of reactions have been evolved in the lab, only a handful of classes of these RNA-based catalysts are found in nature. Now, a new type of ribozyme that senses the presence of a key metabolite in bacteria and regulates gene expression in response has been discovered by researchers at Yale University [Nature, 428, 281 (2004)].
The Yale team discovered the new ribozyme while sifting through natural mRNAs for short spans of RNA that can sense the presence of small-molecule metabolites like nucleotides or sugars. Upon binding a specific metabolite, these so-called "riboswitches" change shape to block the mRNA's translation into protein. Before Breaker's lab began examining the first riboswitches a few years ago, biologists had assumed that only proteins could regulate gene activity in response to environmental signals. By proving the existence of a number of prokaryotic riboswitches--including ones capable of sensing coenzyme B-12, lysine, adenine, and guanine--Breaker's lab has proven that metabolite-responsive gene regulation can be accomplished with RNA, not just proteins. The new ribozyme is also a kind of riboswitch, Breaker notes. The difference is that binding of GlcN6P causes the ribozyme to catalyze its own cleavage, whereas metabolite binding in previously discovered riboswitches triggers no catalytic activity, just a change in shape. It remains unclear, however, how ribozyme self-cleavage shuts down production of the amidotransferase. Breaker points out that the cut isn't made in the part of the RNA that actually codes for the enzyme, but rather some distance upstream of this region, within the ribozyme itself. "The fine details of the gene-control mechanism remain to be established," he acknowledges. Previously, several groups, including Breaker's, have designed artificial ribozymes that cleave themselves upon binding a specific small molecule. "These findings might have prompted some to wonder why nature failed to use, or perhaps to retain, such an elegant mechanism," writes biochemist and Howard Hughes Medical Institute President Thomas R. Cech in an accompanying Nature commentary. "But it's clear now that this perhaps-ancient talent of RNA is alive and well," he adds. It remains to be seen whether such ribozymes are widely used. Still, "it's exciting to speculate that some of the highly conserved untranslated regions in eukaryotic messenger RNAs could in fact be playing such roles," says biochemist Jennifer A. Doudna of the University of California, Berkeley. Breaker's team is now hunting for similar ribozymes in higher organisms.
COURTESY OF BENJAMIN BOESE FLIP THE SWITCH Breaker's team found the new ribozyme at one end of the messenger RNA that codes for an amidotransferase enzyme. When the mRNA is translated into protein, the enzyme produced makes glucosamine-6-phosphate (GlcN6P). At high levels, the sugar binds to the ribozyme, causing the ribozyme to cleave itself. Cleavage halts production of the amidotransferase and decreases GlcN6P levels. |
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