A natural substance derived from a common plant (Galanthus nivalis), may form a basis for the development of improved drugs for Alzheimer's disease
From the right: Prof. Yoel Sussman, Dr. Gitai Krieger, and Prof. Israel Silman. Spatial structure
A natural substance derived from a common plant (Galanthus nivalis), may form a basis for the development of improved drugs for Alzheimer's disease. This possibility emerges from a study carried out by a team of researchers from the Weizmann Institute of Science, led by Professors Yoel Sussman and Israel Silman, and with the participation of Dr. Zvi Greenblatt and Dr. Gitai Krieger. The scientists showed exactly how the natural substance succeeds in inhibiting the activity of the acetylcholine-esterase enzyme, which breaks down the neurotransmitter acetylcholine at the communication junctions in the brain.
Alzheimer's disease is caused by the weakening of the nerve communication in the brain, which is mediated by the neurotransmitter acetylcholine. This weakening may be caused by the death of nerve cells that produce acetylcholine, which reduces the amount of the neurotransmitter in the brain. To re-strengthen neural communication, the amount of the neurotransmitter in the communication nodes in the brain must be increased. The only practical way to do this is based on slowing down the breakdown processes of the neurotransmitter. This breakdown is carried out by the enzyme acetylcholine-esterase, which works very efficiently: one molecule of enzyme breaks down 20,000 molecules of neurotransmitter in one second. The ability to inhibit Alzheimer's disease depends, therefore, on the ability to inhibit the activity of the acetylcholine-esterase enzyme. Several existing medicines for the disease already work in this way, but now the institute's scientists have discovered exactly how a substance called galantamine that comes from the plant (Galanthus nivalis) does it. These findings were published in the scientific journal FEBS Letters.
Dr. Greenblatt says that in addition to inhibiting the breakdown enzyme, galantamine binds to the acetylcholine receptors displayed on the membranes of the nerve cells, thereby increasing the efficiency of nerve communication. Galantamine's dual activity, together with the fact that it causes fewer negative side effects, make it a promising candidate to serve as a basis for the development of improved drugs to treat patients with Alzheimer's disease.
The scientists revealed the spatial structure of a molecular coupling involving the acetylcholine-esterase enzyme molecule with the molecule of the inhibitor substance, galantamine. In this way, it became clear in which sites of the enzyme, exactly, the molecule of the inhibitory substance works. This information may form the basis for the efforts of scientists who will seek to develop a more effective and precise inhibitory drug.
The breaking moments
Jonathan Swift, author of Gulliver's Travels, said that vision is the ability to see the unseen. If we treat this definition as simple, it seems that the scientists of the Weizmann Institute of Science have recently succeeded in turning a vision into reality. They succeeded - for the first time in the world - to "photograph" the moment of the breaking of chemical bonds in a protein molecule exposed to a flux of X-ray radiation originating from a synchrotron. These findings were recently published as the cover story in the scientific journal PNAS (Proceeding of the National Academy of Science), and they can help improve our ability to know the chemical properties that cause various biological macromolecules to be sensitive to radiation, something that may help in the development of medicinal substances to prevent radiation damage.
The research team of Weizmann Institute scientists included Dr. Gitai Krieger, Dr. Michal Harel and Prof. Yoel Sussman from the Department of Structural Biology, and Prof. Israel Silman from the Department of Neurobiology. They collaborated with Dr. Martin Wick, Dr. Maria Rabez, Dr. Piet Gross and Prof. Jan Kroon, from the Center for Biomolecular Research in Utrecht, the Netherlands, and with Dr. Raymond Rowley and Dr. Sian McSweeney from the European Laboratory of Molecular Biology in Grenoble, France.
"The surprising results awaited us in a narrow alley that branched off from the broad stream of research, which we turned to, in fact, by chance," says Dr. Krieger. The scientists set out to investigate how the acetylcholine esterase enzyme, which plays a key role in learning and memory processes in the brain, reacts in "real time". To do this, they exposed crystals of the enzyme to a strong beam of X-rays ("x-rays") originating from a synchrotron. For this, they used the European Union's synchrotron facility in Grenoble, France. This scientific cooperation was made possible thanks to the fact that Israel recently became a member of the group of countries that operate this facility.
The acetylcholine esterase works at an enormous speed, and the scientists hoped to obtain a series of "photographs" that would describe the different stages of its activity through a sequence of fast and short bursts of radiation. But when they examined the "photographs" they received, the scientists realized that instead of documenting the various stages of the chemical reaction of the enzyme with other molecules, they were able, for the first time in the world, to document the various stages of breaking a chemical bond in the three-dimensional spatial structure of a protein molecule, as a result of its exposure to the flux of radiation. "We received a clear sequence of 'animation' describing the breaking of the chemical bond between the two parts of the molecule - something that has never been seen before," says Prof. Sussman.
The scientists discovered that a certain chemical bond (disulfide), which is quite common in protein molecules, is particularly sensitive to X-ray radiation. This discovery may teach a lot about the way radiation can harm animals and humans. Now the scientists of the Weizmann Institute, together with their colleagues from Europe, intend to use this technique to investigate and accurately test the ability of various materials to moderate and perhaps even block the damage of radiation.
The breaking moments of the acetylcholine-esterase molecule
