Weizmann Institute scientists have deciphered the three-dimensional spatial structure of the enzyme whose mutations cause Gaucher's disease
Different graphic configurations of the enzyme glucocerebrosides
A multidisciplinary team of scientists from the Weizmann Institute of Science recently deciphered the three-dimensional spatial structure of the enzyme glucocerebrosides. Some of the mutations that occur in this enzyme are the cause of Gaucher's disease, which is a genetic disease that mainly attacks Ashkenazi Jews. This discovery may lead to the development of several types of effective drugs to treat the disease.
Gaucher's disease was discovered in 1882 by the French doctor Philippe Gaucher. The signs of the disease are a swollen and enlarged spleen and liver, to the point of impairing their functions. In a relatively rare version of the disease, it also affects the brain. In the 20s, it became clear that the cause of the disease is an excessive accumulation of
Fat-like molecules called glucosylceramide lipids.
In the 60s, it became clear that the cause of the accumulation of lipids is a malfunction of a certain enzyme, whose function is to break down the lipids and control their amount. In the 80s, the gene responsible for the production of the disintegrating enzyme was discovered, and it became clear that mutations occurring in this gene are what cause damage to the enzyme's function, thus causing Gaucher's disease. In the early 90s, the "Ganzyme" company from the USA began to produce the correct enzyme from sorghum, and then developed a way to produce it using genetic engineering techniques, in cell cultures. Today, thousands of patients with Gaucher's disease are treated with the injection of a normal enzyme produced in this way, called "replacement enzyme therapy", or ERT for short.
The cost of treatment with this technique is between 100 thousand and 300 thousand dollars per patient, per year.
From this the importance of the possibility, arising from the current research of Weizmann Institute scientists, to develop different types of effective drugs for the disease is clear.
The team of scientists from the Weizmann Institute who set out to decipher the structure of the enzyme, whose mutations cause the disease, included Prof. Tony Futterman from the Department of Biological Chemistry, Prof. Yoel Sussman from the Department of Structural Biology, and Prof. Israel Silman from the Department of Neurobiology. Dr. Michal Harel, Lili Toker, and research student Hai Dvir, all from the Weizmann Institute of Science, also participated in the study.
In order to decipher the three-dimensional spatial structure of the enzyme, crystals must be produced from it.
Many scientists, all over the world, have been trying for a decade to face this challenge. The institute's scientists tried - and recently even succeeded - to solve this difficulty by means of a certain shortening of sugar branches that are part of the enzyme.
After they succeeded in formulating the enzyme, the researchers used a research technique called X-ray ("X-ray") crystallography. With this method, the crystals are irradiated with X-rays, and by measuring the radiation scattered from the crystal, it is possible to learn about the three-dimensional spatial structure of the molecules that make it up. In this case, the researchers used radiation from a synchrotron, which is a special accelerator that produces X-rays. The process was carried out at the European Synchrotron - ESRF - in Grenoble, France (Israel is a full member of the organization that operates this facility).
The discovery of the structure of the normal enzyme may lead to the development of different drugs to treat Gaucher's disease. First, this information may help design a more effective enzyme that will be injected into patients and replace the defective enzyme molecules in their bodies. This is about improving the efficiency of the enzyme compared to the alternative enzyme that is currently used as a medicine to treat patients with Gaucher's disease. This is an ERT method that has already been approved by the US Food and Drug Administration (FDA, and therefore it seems that it may be an effective temporary substitute until, in the distant future, genetic therapy for the disease may be developed (as we know, the attempts to develop genetic therapies have recently encountered difficulties). Another type of Medicines that can be developed thanks to the new research is the design of small molecules that will complement the damaged enzymes in the patient's body, and return them to normal activity.
The "Yade" company, which is engaged in promoting industrial applications based on the results of the research of Weizmann Institute of Science scientists, submitted an application for registration of patents for medical uses of these findings.
