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US team reveals mechanism of drug breakdown enzyme

Researchers reveal atomic level structural details of an enzyme system which aids in the breakdown of drugs and toxins in the human body, a development which could lead to safer drugs in the future

Researchers at the University of Michigan have revealed atomic level structural details of an enzyme system which aids in the breakdown of many drugs and toxins in the human body.

The work could lead to the development of safer drugs in the future.

Research published in the online US journal BBA Biomembranes has shown that two proteins work cooperatively to rid the body of toxic chemicals. Cytochrome P450 is mainly involved, but only when its action is boosted by a second protein, cytochrome b5.

Both proteins interact only when they are bound to a cell membrane, which renders traditional techniques, such as X-ray crystallography, ineffective at highlighting the structural details of the interaction.

Crystallography is currently used to determine protein structures, but in order to do this the molecules must be separated from their membrane environment, says Ayyalusamy Ramamoorthy, head of the research group and associate professor of chemistry and biophysics.

As cytochrome b5 adheres to the cell membrane, separations break the molecule from its adherence point on the membrane, the structure of which controls its interaction with cytochrome P450. Thus, crystallography cannot provide insights into the mechanism of the interaction between P450 and b5.

To resolve this problem, Ramamoorthy's team used solid state NMR spectroscopy, which can produce detailed images of proteins in the membrane environment and reveal molecular structure. The technique also shows how a particular protein joins to the cell membrane.

More work is in progress to determine the detailed high-resolution structures of these two proteins, as well as other membrane-associated proteins which include many biologically important molecules.

Ramamoorthy said: "These proteins are involved in all major diseases, everywhere in the body, and are therefore primary targets for pharmaceutical applications. In my opinion, solving the structures of membrane proteins should be the highest priority for structural biologists in the coming years."

Ramamoorthy added that the research at the University of Minnesota will expand through plans to set up a high magnetic field solid-state NMR spectrometer facility and an NIH-funded programme.

17th September 2007

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