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Enzyme structure holds key to cocaine, heroin metabolism

dose victim, the enzyme could help metabolize the cocaine before it became toxic, he said.

Heroin poses another problem. It has no activity on its own. "It needs to be broken down a little in the body to make morphine," Redinbo said. "It's morphine's activity, hitting opioid receptors in the brain, that provides the feeling of complacency and peace associated with heroin use."

In terms of using hCE1 against chemical weapons, Redinbo said the U.S. military is aggressively seeking to develop the enzyme as a battlefield prophylactic that could be used to detoxify sarin, soman, tabun and VX gases. Chemically, these nerve agents are organophosphate poisons, similar in structure to agricultural weed control chemicals.

"Without the crystal structure, they have been making educated guesses as to where to make changes in the enzyme that would increase its efficiency in detoxifying these agents," said Redinbo. "Now, knowledge of the crystal structure takes much of the guesswork out of identifying the most effective modifications."

The military's idea is to inject its people with protective enzymes prior to battle, he said; these enzymes have a long serum half-life and could offer several days of protection.

"These chemical weapons kill by impacting nerve endings throughout the body, including in the respiratory system. One could inject or inhale the protectant, and it's not likely to cause an immune reaction because it's a human protein," Redinbo said.

It also appears that the enzyme plays a role in cholesterol metabolism - namely, cholesterol transport into and out of the liver. "Its primary evolutionary role may be this function," said study lead author Sompop Bencharit, a chemistry graduate student in Redinbo's laboratory.

"Our crystal structures of hCE1 will enable the development of highly selective and efficient forms of the enzyme for use in a variety of civilian and military settings," the report said. "The engineering of novel hCE
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Contact: Leslie H. Lang
llang@med.unc.edu
919-843-9687
University of North Carolina School of Medicine
8-Apr-2003


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