A team of Vanderbilt University biochemists and pharmaceutical industry researchers have caught a "molecular snapshot" of the first step in an important biochemical reaction involved in pain, inflammation and even cancer.
The findings by the team from Vanderbilt and Searle/Monsanto Company are described in the May 4 issue of the journal Nature. Their work provides insights that may help guide future drug development.
Using a technology called X-ray crystallography, the researchers determined the three-dimensional structure of the enzyme cyclooxygenase-2 (COX-2) with arachidonic acid -- its "substrate," or the starting material for the reaction -- bound to it. This binding is the first step in a series of chemical reactions that result in production of a number of hormone-like prostaglandins that contribute to pain and inflammation. Elevated levels of COX-2 have also been linked to tumor development; and tumor growth has, in turn, been blocked in the laboratory with agents that block COX-2's action.
"This results from a long line of research to understand how COX-2 interacts with its substrates and inhibitors," said Lawrence J. Marnett, Ph.D., Mary Geddes Stahlman Professor of Cancer Research, Professor of Biochemistry, and Associate Director of Basic Research Programs for the Vanderbilt-Ingram Cancer Center. "It helps us to understand in very specific terms how arachidonic acid is bound on the enzyme. This kind of information helps in identifying and developing new inhibitors."
Until now, work to develop drugs that inhibit the action of COX-2 has been based on scientifically grounded hypotheses about how arachidonic acid fits into the enzyme. But no one knew for certain where it bound onto COX-2 and the precise shape of the "pocket" into which it fits. The goal would be to use this information to design drug molecules that more precisely mimic that fit.
The "snapshot" also caught the initial product of the reaction, prostaglandin G2, still bound
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Contact: Cynthia Manley
cynthia.manley@mcmail.vanderbilt.edu
615-322-4747
Vanderbilt University Medical Center
3-May-2000