Enzyme structure has implications for defense against chemical weapons. (EH Update).

A report in the journal Nature Structural Biology offers the first molecular explanation of how the body metabolizes and detoxifies cocaine and heroin. This work, whose lead author is Sompop Bencharit, a graduate student in the laboratory of Dr. Matthew R. Redimbo of the University of North Carolina at Chapel Hill, also suggests a system that can be engineered to detoxify chemical weapons, including sarin, soman, tabun, and VX gases.

The report, which received advance online publication on April 7, presents the first crystal structure of the protein human car-boxylesterase 1, or hCE1. This protein, an enzyme, is a broad-spectrum bioscavenger found throughout the body--in the liver, small intestine, kidney, lungs, testes, and scavenger cells. It also circulates to a lesser extent in human blood plasma. The report describes how hCE1 is responsible for metabolizing the first step of cocaine breakdown in the body and the first two steps of heroin breakdown. The researchers determined the crystal structure of the enzyme in complexes with analogues of cocaine and heroin. They found that the enzyme could bind to two cocaine molecules simultaneously, but that it specifically generates the primary metabolic breakdown product (metabolite) of cocaine. This finding, the report concludes, indicates that the enzyme holds "significant promise in the treatment of acute cocaine overdose."

Redinbo said the U.S. military is aggressively seeking to develop hCE1 as a battlefield prophylactic. It might be used to detoxify sarin, soman, tabun, and VX gases, which are organophosphate poisons, similar in structure to agricultural weed control chemicals. The military's idea is to inject its people with protective enzymes prior to battle; the enzymes have a long serum half-life and could offer several days of protection.

According to Redimbo, "These chemical weapons kill by affecting 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."

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 Sompop Bencharit.

The report adds that "the engineering of novel hCE1 enzymes with improved catalytic power toward cocaine or organophosphate poisons is currently in progress.

The National Cancer Institute, a component of the National Institutes of Health, supported the research, which involved close collaboration with Dr. Philip Potter, an associate member at St. Jude Children's Research Hospital in Memphis, Tennessee.