NEW RIBOZYME MAKES THE CUT | March 22, 2004 Issue - Vol. 82 Issue 12 | Chemical & Engineering News
Volume 82 Issue 12 | p. 6 | News of The Week
Issue Date: March 22, 2004

NEW RIBOZYME MAKES THE CUT

Biochemistry: Natural RNA enzyme alters gene expression, usually a job for proteins
Department: Science & Technology

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)].

Breaker
Credit: Michael Marsland/Yale University
8212NOTW_Breaker
 
Breaker
Credit: Michael Marsland/Yale University

The new ribozyme--discovered by Yale molecular, cellular, and developmental biology professor Ronald R. Breaker, postdoc Wade C. Winkler, graduate student Ali Nahvi, and coworkers--acts as a metabolite-responsive genetic switch in certain bacteria. Known as glmS, the ribozyme is located at one end of the messenger RNA (mRNA) that encodes the amidotransferase enzyme responsible for synthesizing glucosamine-6-phosphate (GlcN6P), a simple sugar critical for cell-wall biosynthesis. When levels of this sugar get too high, GlcN6P binds to the ribozyme. This binding event triggers the ribozyme to cleave itself in two, shutting down production of the amidotransferase and preventing it from making any more GlcN6P.

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.

[+]Enlarge
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.
Credit: Benjamin Boese
8212notw3aa.ce
 
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.
Credit: Benjamin Boese

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.

 
Chemical & Engineering News
ISSN 0009-2347
Copyright © American Chemical Society

Leave A Comment

*Required to comment