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Biological Chemistry

Arthur C. Cope Scholar Award: John A. Gerlt

Recipients are honored for contributions of major significance to chemistry

by Stu Borman
February 22, 2010 | A version of this story appeared in Volume 88, Issue 8

Credit: Courtesy of John Gerlt
Credit: Courtesy of John Gerlt

Research that has led to a deeper understanding of how enzymes accelerate a wide range of reactions and develop different mechanisms has earned John A. Gerlt of the University of Illinois, Urbana-Champaign, one of this year’s Cope Scholar Awards.

From in-depth investigations of enzymatic proton abstraction to identifying substrates for enzymes of unknown function and characterizing evolutionary relationships in enzyme families, “Gerlt’s work is characterized by chemical rigor, keen recognition of new concepts, creativity, and early use of genomic tools,” chemistry and biology professor JoAnne Stubbe of Massachusetts Institute of Technology says.

Gerlt’s work has included pioneering studies of how enzymes such as mandelate racemase abstract protons from extremely weak acids to generate carbanion intermediates. Gerlt and coworkers, in collaboration with the late University of Minnesota chemistry professor Paul G. Gassman, suggested that electrophilic catalysis and strong hydrogen bonding were key factors in making such difficult reactions proceed at reasonable rates. These studies have led to a better appreciation for the sophisticated tools enzymes can use to accelerate reactions.

Observations that mandelate racemase and muconate lactonizing enzyme resemble one another structurally but catalyze different reactions provided an entry point for Gerlt and coworkers into the study of enzyme superfamilies. They found that the two enzymes are members of a common group, the enolase superfamily, because they stabilize similar transition states via a conserved set of active-site residues.

Gerlt’s group subsequently predicted and experimentally verified 17 different reactions catalyzed by enolase superfamily enzymes. The researchers also used directed evolution to explore the ways in which such enzymes can achieve mechanistic diversity. One of their major achievements was use of a single mutation to redesign an epimerase to catalyze a dehydration reaction.

“The importance of chemistry in the evolution of new catalytic functions from a common scaffold was a revolutionary new idea that has had a profound influence on enzymology and studies of enzyme evolution,” Stubbe says.

Gerlt and coworkers have combined experimental studies of enzyme structure, function, and mechanism with computational studies—such as homology modeling, in silico ligand docking, and bioinformatics—to predict functions of uncharacterized enzymes. And they have used their mechanistic understanding of these enzymes to redesign them to catalyze new reactions.

They also are studying the orotidine 5´-phosphate decarboxylase family of enzymes, which catalyze different reactions with distinct mechanisms, and they have made progress in revealing the structural basis and evolution of this type of mechanistic plasticity. Their work could provide important insights into the way similar active-site residues can be used to catalyze reactions with completely different mechanisms.

Gerlt, 62, earned a bachelor’s degree in biochemistry from Michigan State University and a Ph.D. in biochemistry from Harvard University. He did a fellowship at the National Institutes of Health in the mid-1970s and joined the chemistry faculty of Yale University and then the University of Maryland before moving to the University of Illinois in 1994, where he is currently Gutgsell Chair in Chemistry. Since 2004, he has served as associate editor of Biochemistry.



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