Genetic Defect Linked to Structural Defect

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'Scientists at the Weizmann Institute in Israel, together with an American team based at the Scripps Research Institute in California, have succeeded for the first time to link the specific structural genetic mutations in Gaucher disease to the resulting mechanical dysfunction of the enzyme glucocerebrosidase', says Prof Anthony Futerman

As a result of the research, the Israeli and American teams have been able to locate and characterize a specific structural defect in a genetic mutation that prevents the enzyme from performing its function to break down certain fatty molecules which then accumulate and result in the disease. The paper describing this work was published in The Journal of Biological Chemistry and was selected as the Journal's "Paper of the Week" which was ranked in the top 1% of some 6,600 annual publications in this journal.

In close collaboration with colleagues at the Scripps Research Institute in La Jolla, California, an interdisciplinary team at the Weizmann Institute which included, in addition to Prof Futerman, Prof Joel Sussman and Prof Israel Silman looked at the crystal structure of the enzyme for clues about its defective functionality.

Working with a small molecule that binds to and inhibits the enzyme's action, post-doctoral fellow Dr Lakshmanane Premkumar of the Weizmann Institute noticed that this inhibitor caused movements in the same area of the enzyme's structure where some mutations causing Gaucher disease were known to occur. This raised a red flag and led the team to perform a closer examination of the enzyme's structure in this specific area. The defect was thus revealed.

One of the genetic mutations associated with Gaucher disease affects the way the enzyme molecule curls and folds forming a constricted opening too small for the fatty molecule to fit through. This mutation prevents the molecule from entering the enzyme and thus it does not get broken down. The unprocessed fatty molecules then accumulate in the body and cause the symptoms of Gaucher disease.

Gaucher disease was the first disease treated by enzyme replacement therapy, in which a form of glucocerebrosidase known as Cerezyme is given to the patients. This treatment, although effective, is costly. The researchers hope that their findings will lead either to improvements in the efficiency of the existing therapy or prompt exploration of new therapeutic approaches such as enhancing the enzyme's mechanical flexibility and capacity to process the fatty molecules.

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Source: Gauchers News December 2005.
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