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 Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory

nachricht How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Argon is not the 'dope' for metallic hydrogen

24.03.2017 | Materials Sciences

Astronomers find unexpected, dust-obscured star formation in distant galaxy

24.03.2017 | Physics and Astronomy

Gravitational wave kicks monster black hole out of galactic core

24.03.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>