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Discovery might improve design, effectiveness of anti-cancer drugs

19.10.2004


Working with an enzyme that degrades anti-cancer drugs in humans, University of North Carolina at Chapel Hill biochemists and colleagues have made a discovery that they believe eventually could help improve such drugs’ design and effectiveness.



The scientists have shown that the enzyme protein can be made to "fly through the vapor phase" -- from which solvent water is totally absent -- without changing its structure.

When a solution containing the enzyme was introduced as a fine spray into a vacuum created in a mass spectrometer in the laboratory, normal solvent molecules were completely evaporated, leaving bare, charged molecules known as ions, the researchers said. The protein ions were trapped in the extremely high vacuum for seconds, but in the new experiments, a single water molecule remained undisturbed, which was a surprise since no one ever saw that before. "This suggests how we might change an inhibitor molecule to make it fit the enzyme more perfectly and hence be more effective in blocking that enzyme’s action in destroying anticancer drugs," said Dr. Richard V. Wolfenden, Alumni Distinguished professor of biochemistry and biophysics at the UNC School of Medicine.


The experiments involving the enzyme cytidine deaminase, which is derived from bacteria and many other sources, mark the first time that scientists have detected a water molecule inside a protein molecule by mass spectrometry, he said. A report on the research appears in the latest issue of the Proceedings of the National Academy of Sciences. Besides Wolfenden, UNC participants include lead author Dr. Christoph H. Borchers, assistant professor of biochemistry and biophysics and faculty director of the UNC Michael Hooker Proteomics Core Facility, and doctoral student Gottfried K. Schroeder. Wolfenden and Borchers are members of UNC’s Lineberger Comprehensive Cancer Center.

"When the active site of this enzyme binds to what is called the active site of a well-fitting inhibitor molecule, it also binds a single water molecule, which appears to be trapped in a small gap left by the inhibitor," Wolfenden said. "The sequestering of the water molecule from its surroundings is evident from the fact that this protein ‘water bottle’ flies for many seconds through a nearly perfect vacuum into which the water molecule would evaporate instantly if it were exposed to the surroundings."

Inside the mass spectrometer manufactured by Bruker Daltronics, Inc., the vacuum was comparable to the vacuum found in intergalactic space, he said. Wolfenden said the presence of the water-filled gap hints at how an inhibitor might be improved further -- by expanding it to fill the gap -- which is important in designing drugs. "Moreover, this specific enzyme is known to inactivate the anticancer agent cytarabine," he said. "That inactivation limits the effectiveness of cytarabine in cancer tissue such as in non-Hodgkins lymphoma, several forms of leukemia and other cancers. By protecting cytarabine against degradation, a powerful inhibitor of the enzyme cytidine deaminase might be used in combination with cytarabine for cancer chemotherapy." The UNC scientists are now exploring that possibility in further laboratory studies, Wolfenden said.

Since it is highly sensitive and accurate, mass spectrometry is a major analytical tool capable of sequencing peptides and allowing researchers to identify and characterize proteins at their physiological level. The instrument in which the experiments were performed is located at the North American headquarters of Bruker Daltonics in Billerica, Mass.

The Michael Hooker Proteomics Core Facility will soon acquire one of the sophisticated mass spectrometers, said Borchers, also a member of UNC’s Center of Environmental Health and Susceptibility.

Other authors of the new paper are Dr. Victor E. Marquez of the National Cancer Institute, Dr. Steven A. Short of GlaxoSmithKline, Dr. Mark J. Snider of the College of Wooster, and Dr. J. Paul Speir of Bruker Daltonics.

The National Institutes of Health supported the research.

David Williamson | EurekAlert!
Further information:
http://www.med.unc.edu

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