CHAPEL HILL -- Without help from a key enzyme called OMP decarboxylase, 78 million years would be needed at room temperature for a molecule central to all living things to shed half the carbon dioxide attached to it.
When this chemical supercharger does its job, however, the process can occur some 30 times in a single second, University of North Carolina at Chapel Hill biochemists Anna Radzicka and Richard V. Wolfenden reported in 1995. That's the greatest acceleration ever found for a reaction jump-started by an enzyme.
Now, the three-dimensional structure of the enzyme has been determined through a collaboration between Glaxo Wellcome Inc. scientists and UNC-CH researchers. The reaction that the enzyme works on is the last intermediate step in synthesizing UMP -- one of the four letters of the genetic code and is therefore needed by all organisms for growth.
A report on the research appears in Tuesday's (Feb. 29) issue of the Proceedings of the National Academy of Sciences. UNC-CH School of Medicine authors are biochemistry graduate student Brian Miller and Wolfenden, Alumni Distinguished professor of biochemistry and biophysics. Glaxo Wellcome authors are Drs. Steven A. Short, Anne M. Hassell and Michael V. Milburn.
"The molecule's crystal structure, combined with other information, reveals that the enzyme OMP decarboxylase operates by a disarmingly simple and unprecedented mechanism," Wolfenden said. "We were imagining something more elaborate, but what we found was elegant simplicity."
All enzymes work in the body at similar rates and must act pretty much in unison for organisms to survive, he said. What differs from one enzyme to another is that some have much harder jobs than others.
"This one has the hardest job we know about -- changing a reaction that takes a good fraction of the lifetime of the Earth to one that occurs as fast as the shutter release in a single-lens reflex camera," Wolfenden said.
Miller, who is earning his doctorate with the research, said the finding will help explain how all enzymes function. "Once you discover how a particular enzyme works then you can build inhibitors for it," he said. "That's true for many of the drugs on the market today -- including Viagra."
Other enzyme antagonists are used to fight the virus that causes AIDS and to lower blood pressure in patients with stroke and hypertension.
"From our standpoint as basic scientists, this work is really exciting because it increases our understanding of how the enzyme does such a difficult job, something that normally doesn't happen readily in nature," Miller said.
Understanding how enzymes work also is a step toward imitating nature by producing artificial enzymes, Wolfenden said. That possibility also excites researchers, but they have not yet created successful enzyme mimics.
Because it represents an extreme case, biochemists have been so interested in this enzyme that at least four research teams have analyzed its structure independently in four different organisms and are reporting their results almost simultaneously, he said. Two other papers on the structure will appear in the same issue of the Proceedings of the National Academy of Sciences, and a fourth paper has been accepted by the journal Biochemistry.
The late Dr. Mary Ellen Jones, who led UNC-CH's biochemistry department from 1978 to 1989, carried out the most significant early work on the OMP enzyme, he said.
Note: Wolfenden and Miller can be reached at (919) 966-1203.