January 2010

Anne-Frances Miller: Spinning Toward Success


Anne-Frances Miller believes enzymes are catalysts extraordinaire. Consider the following: The industrial process used to make the vast quantities of fertilizer necessary to support agriculture worldwide involves exposing nitrogen gas (N2) to temperatures in excess of 400 degrees Celsius at 200 atmospheres of pressure. This illustrates the difficulty of breaking the triple bond in dinitrogen (second in strength only to that of carbon monoxide). Meanwhile, in the roots of leguminous plants, bacterial enzymes are carrying out the same chemical conversion at room temperature under standard pressure.

Anne-Frances Miller in front of one of her NMR machines.

This is the reason that Miller will never cease to be fascinated by enzymes. “Their ability to speed up chemical reactions by factors of millions, billions or more gives biology access to chemistry that would be useless at uncatalyzed rates,” she says.

However, Miller, an associate professor of chemistry at the Uni­versity of Kentucky and director of the university’s nuclear magnetic resonance spectroscopy facility, is quick to point out that proteins should not get all of the glory. “Many of the most marvelous enzymes subcontract out the dirty work,” she says. “The most difficult chemistry is actually being executed by metal ions or organic cofactors. What the protein does is help select the proper substrate, focus the reactivity on the desired reaction and coordinate the reaction with other aspects of metabolism.”

That partnership between the protein and its cofactor forms the basis of Miller’s research interests. Using spectroscopic tools like NMR and electron paramagnetic resonance, which can reveal the details of the molecular interactions occurring at the interface of the protein and cofactor, Miller seeks to understand the mechanistic basis behind enzyme catalysis, particularly oxidation-reduction reactions.

And, by answering questions about, for example, how proteins guide the specificity of broadly reactive cofactors like metal ions or how a flavin’s chemical properties change when it becomes associated with a protein, Miller hopes to figure out one of the most enduring mysteries in enzymology: how proteins can both activate and control such powerful chemical reactions.

“Take dioxygen, for example,” Miller says. “Molecular oxygen is an extremely reactive molecule thermodynamically, but it also has a large kinetic barrier for activation. This is why it has accumulated to about 20 percent of our atmosphere. Because of that barrier, dioxygen holds a huge reservoir of potential energy.”

“Then, look at proteins,” she adds. “As reagents, they’re pretty mild-mannered— we even eat them for breakfast. How can proteins catalyze reactions with oxygen and not get burned up?”

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Fascinating! - Eric B



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