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February 24, 2003
Volume 81, Number 8
CENEAR 81 8 p. 4
ISSN 0009-2347


Enzymatic product supports subsequent steps in multistep reaction


In a study to determine how an enzyme with only a single active site catalyzes a multistep DNA-repair process, chemistry professor Gregory L. Verdine and coworkers at Harvard University have revealed what may be the first reported example of product-assisted enzymatic catalysis [Nat. Struct. Biol., published online Feb. 18,].

HELPER 8-Oxoguanine product (oxoG), released from damaged DNA in the first step of a DNA-repair process, assists in subsequent steps, leading to DNA strand cleavage.
The study shows that "the enzyme performs a reaction on a substrate, holds captive the reaction product, and exploits its functionality to catalyze the remaining steps of the reaction," Verdine explains.

The paper "is very interesting and unique," comments assistant professor of biochemistry and molecular biophysics Nancy C. Horton of the University of Arizona College of Medicine, whose research interests include enzymology and DNA repair. "I don't know of any other enzyme reaction that uses a product of one of its reactions in a multistep reaction to catalyze subsequent steps." Verdine and coworkers "have made a very strong case for this activity," Horton says.

In the study, Verdine's group determined the mechanism of ac-tion by which a key DNA repair enzyme--human 8-oxoguanine DNA glycosylase/lyase--catalyzes removal of the mutagen 8-oxoguanine from DNA. The researchers found that the enzyme catalyzes cleavage of 8-oxoguanine from its mooring on the DNA backbone, captures the oxoguanine product upon its release from DNA, and then uses it as a cofactor to perform acid-base chemistry on the DNA substrate. The process ultimately splits the DNA backbone.

"Most enzymes come equipped with all of the functional groups that they need to perform a reaction," Verdine says. But the process catalyzed by 8-oxoguanine DNA glycosylase/lyase represents a unique case in which product assistance is required if the enzyme is to complete its catalytic mission. Substrate-assisted enzymatic catalysis has been observed previously, Verdine notes, but not the corresponding product-assisted process.

The study helps explain "how a single enzyme active site can catalyze five or six different reaction steps in series during multistep processing of a substrate," Verdine says. "It takes millions, if not billions, of years of evolution to produce an enzyme that carries out just one reaction efficiently. What kind of strategy can an enzyme use to reduce the difficulty and complexity inherently associated with serial catalysis? Our findings show one elegant solution to this problem."


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Copyright © 2003 American Chemical Society

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