An interdisciplinary team of Weizmann Institute scientists has solved the 3-D structure of an enzyme involved in Gaucher's disease, a genetic illness that mainly affects Ashkenazi Jews. The study, published in EMBO Reports, may lead to the design of effective new therapies.
Gaucher's disease is characterized by swelling and enlargement of the spleen and liver and disruption in the function of these organs; in rare cases, it may also affect the brain. It is caused by the accumulation of a fatty substance, or lipid, called glucosylceramide. Accumulation occurs due to a defect in the enzyme charged with breaking down this lipid and regulating its amount.
Today thousands of Gaucher's patients are treated by injections of this enzyme, in an approach called enzyme replacement therapy, or ERT. The annual cost of the therapy is approximately $100,000 to $300,000 per patient. More affordable alternatives, such as the ones that may emerge from the Weizmann Institute study, are urgently needed.
The Institute team included Prof. Tony Futerman of the Biological Chemistry Department, Prof. Joel Sussman of the Structural Biology Department and Prof. Israel Silman of the Neurobiology Department, as well as Dr. Michal Harel, Lilly Toker and graduate student Hay Dvir.The solved enzyme structure may help in the design of a more effective enzyme that would improve today's ERT. It may also make possible the design of small molecules that will supplement the damaged enzyme in the patient's body, thereby restoring its normal functioning.
Prof. Futerman's research was supported by the Estate of Ernst and Anni Deutsch-Promotor Stiftung, Switzerland; the Paul Godfrey Foundation; the Buddy Taub Foundation; the Sir Siegmund Warburg's Weizmann Trust; and the Estate of Louis Uger, Canada. He is the incumbent of the Joseph Meyerhoff Professorial Chair of Biochemistry.
Prof. Silman's research was supported by the Nella and Leon Benoziyo Center for Neurosciences; the Charles A. Dana Foundation; the Carl and Micaela Einhorn-Dominic Brain Research Institute; and the Helen & Milton A. Kimmelman Center for Biomolecular Structure & Assembly. He is the incumbent of the Bernstein-Mason Professorial Chair of Neurochemistry
Prof. Sussman's research was supported by the Charles A. Dana Foundation; the Jean and Jula Goldwurm Memorial Foundation; Mr. Yossi Hollander, Israel; the Helen & Milton A. Kimmelman Center for Biomolecular Structure & Assembly; the Joseph and Ceil Mazer Center for Structural Biology; the late Sally Schnitzer; and the Kalman & Ida Wolens Foundation. He is the incumbent of the Morton and Gladys Pickman Chair in Structural Biology.
The research utilized infrastructure provided by the Kekst Family Center for Medical Genetics.
The Slick Joint
Mimicking key design elements of this biolubrication system, physicist Prof. Jacob Klein of the Materials and Interfaces Department has recently created a synthetic lubricant that cuts friction a thousand-fold or more. The study, published in Nature, could lead to a range of applications - from longer-lasting micro-machines to biomedical products.
Previous studies had suggested that biolubrication systems, such as those in joints and eyes, maycontain hyaluronan molecules that coat the rubbing surfaces, shielding them from mechanical damage. Hyaluronan was also known to be strongly attracted to water.
Klein and his colleagues suspected that in joints, hyaluronan may be attached to a thin cartilage layer covering the bone. Parts of the long, chain-like hyaluronan molecule stick out into the synovial fluid between the bones, resembling bristles on a brush.
The team developed a synthetic model that mimicked a double-brush system, anchoring two charged molecules (polyelectrolytes) to opposite-facing ceramic surfaces. The resulting system showed extremely effective friction resistance, particularly when exposed to a water-based solution. “The brushes strongly try to avoid each other, resisting contact even when an external force is applied to press them closer. This enables them to easily slide past one another,” says Klein.
The synthetic brushes were designed to imitate the electrically charged nature of biolubricants. The negative charge on the bristle tips then attracted water molecules - which in fact explains why the brushes performed most effectively in a water-based solution. “The water molecules are tightly bound by the charges, causing them to act like molecular ball bearings,” Klein explains.
Prof. Klein is the incumbent of the Hermann Mark Professorial Chair of Polymer Physics.