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 New technique unveils 'matrix' inside tissues and tumors
29.06.2017 | University of Copenhagen The Faculty of Health and Medical Sciences

nachricht Designed proteins to treat muscular dystrophy
29.06.2017 | Universität Basel

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Making Waves

Computer scientists use wave packet theory to develop realistic, detailed water wave simulations in real time. Their results will be presented at this year’s SIGGRAPH conference.

Think about the last time you were at a lake, river, or the ocean. Remember the ripples of the water, the waves crashing against the rocks, the wake following...

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Nanostructures taste the rainbow

29.06.2017 | Physics and Astronomy

New technique unveils 'matrix' inside tissues and tumors

29.06.2017 | Life Sciences

Cystic fibrosis alters the structure of mucus in airways

29.06.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>