Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Enzyme structure holds key to cocaine, heroin metabolism

08.04.2003


Implications for treatment, defense against chemical weapons



A study led by scientists at the University of North Carolina at Chapel Hill offers the first molecular explanation of how the body metabolizes and detoxifies cocaine and heroin. "We show for the first time how humans initiate the breakdown and clearance of these dangerous narcotics," said Dr. Matthew R. Redinbo, assistant professor in the department of chemistry, and in the School of Medicine’s department of biochemistry and biophysics.

"This work also has two potential applications. First, our results can be used to generate an efficient treatment for cocaine overdose. Second, the same system we describe can be engineered to detoxify chemical weapons, including sarin, soman, tabun and VX gases."


A report of the study, published online Monday (April 7) in Nature Structural Biology, presents the first crystal structure of the protein human carboxylesterase 1, or hCE1.

The 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.

In their report, Redinbo and his group describe 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 the enzyme could bind to two cocaine molecules simultaneously, but that it specifically generates the primary metabolic breakdown product (metabolite) of cocaine. This indicates that the enzyme holds "significant promise in the treatment of acute cocaine overdose," the report said.

"We need to engineer a more active form of the enzyme that is specific for cocaine. We can do this by generating a small number of changes in the amino acid sequence that would increase the metabolic efficiency," Redinbo said.

When injected into an overdose 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 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 a close collaboration with Dr. Philip Potter, an associate member at St. Jude Children’s Research Hospital in Memphis, Tenn.


School of Medicine contact: Leslie Lang, (919) 843-9687 or llang@med.unc.edu

Leslie H. Lang | EurekAlert!
Further information:
http://www.med.unc.edu/

More articles from Life Sciences:

nachricht Topologische Quantenchemie
21.07.2017 | Max-Planck-Institut für Chemische Physik fester Stoffe

nachricht Topological Quantum Chemistry
21.07.2017 | Max-Planck-Institut für Chemische Physik fester Stoffe

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Manipulating Electron Spins Without Loss of Information

Physicists have developed a new technique that uses electrical voltages to control the electron spin on a chip. The newly-developed method provides protection from spin decay, meaning that the contained information can be maintained and transmitted over comparatively large distances, as has been demonstrated by a team from the University of Basel’s Department of Physics and the Swiss Nanoscience Institute. The results have been published in Physical Review X.

For several years, researchers have been trying to use the spin of an electron to store and transmit information. The spin of each electron is always coupled...

Im Focus: The proton precisely weighted

What is the mass of a proton? Scientists from Germany and Japan successfully did an important step towards the most exact knowledge of this fundamental constant. By means of precision measurements on a single proton, they could improve the precision by a factor of three and also correct the existing value.

To determine the mass of a single proton still more accurate – a group of physicists led by Klaus Blaum and Sven Sturm of the Max Planck Institute for Nuclear...

Im Focus: On the way to a biological alternative

A bacterial enzyme enables reactions that open up alternatives to key industrial chemical processes

The research team of Prof. Dr. Oliver Einsle at the University of Freiburg's Institute of Biochemistry has long been exploring the functioning of nitrogenase....

Im Focus: The 1 trillion tonne iceberg

Larsen C Ice Shelf rift finally breaks through

A one trillion tonne iceberg - one of the biggest ever recorded -- has calved away from the Larsen C Ice Shelf in Antarctica, after a rift in the ice,...

Im Focus: Laser-cooled ions contribute to better understanding of friction

Physics supports biology: Researchers from PTB have developed a model system to investigate friction phenomena with atomic precision

Friction: what you want from car brakes, otherwise rather a nuisance. In any case, it is useful to know as precisely as possible how friction phenomena arise –...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Closing the Sustainability Circle: Protection of Food with Biobased Materials

21.07.2017 | Event News

»We are bringing Additive Manufacturing to SMEs«

19.07.2017 | Event News

The technology with a feel for feelings

12.07.2017 | Event News

 
Latest News

NASA looks to solar eclipse to help understand Earth's energy system

21.07.2017 | Earth Sciences

Stanford researchers develop a new type of soft, growing robot

21.07.2017 | Power and Electrical Engineering

Vortex photons from electrons in circular motion

21.07.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>