Chemical Chaperones Help Increase Deficient Enzyme Activity in Gaucher Disease

Scientists at The Scripps Research Institute have discovered that certain chemical chaperones help increase the activity of various types of glucocerebrosidase, the enzyme lacking in patients with Gaucher (go-SHAY) disease. This discovery suggests that the active levels of glucocerebrosidase can be improved through the use of select site-directed small molecules or chemical chaperones, which bind and stabilize proteins and prevent their degradation. These findings could lead to the development of first-in-class drugs for the treatment of the disease.

The new study, published in the current issue of Chemical Biology, was led by Jeffery W. Kelly, Ph.D. Kelly is the Lita Annenberg Hazen Professor of Chemistry, a member of The Skaggs Institute for Chemical Biology, and vice president of academic affairs at Scripps Research.

He conducted the research with a team of Scripps Research scientists including Anu R. Sawkar, Sara L. Adamski-Werner, Wei-Chieh Cheng, Chi-Huey Wong of the Department of Chemistry and The Skaggs Institute for Chemical Biology; Ernest Beutler of the Department of Molecular and Experimental Medicine; and Klaus-Peter Zimmer of the Universita"tskinderklinik, Munster, Germany.

First identified in 1882, Gaucher disease is the most common lipid-storage disorder, the result of a genetic mutation passed from both parents. It is the most common genetic disease among the Ashkenazi Jewish population of Eastern European ancestry. The lack of the specific enzyme, glucoerebrosidase, which helps cells break down the fat molecule glucocerebroside, produces a buildup of fatty deposits primarily in the spleen, liver, and bone marrow. The most common symptoms of Gaucher disease are liver and spleen enlargement, anemia, and bone pain. In a small number of patients with the disease, however, glucocerebroside also accumulates in the central nervous system, leading to neurological damage.

Gaucher disease Definition
Gaucher disease is an inherited deficiency of the enzyme -glucosidase, which results in the buildup of a toxic substance (glucosylceramide) in different parts of the body, such as the spleen, liver, and bones.

Causes, incidence, and risk factors

Gaucher Disease is a rare, inherited, potentially fatal disorder. Deficiency of the enzyme -glucocerebrosidase leads to an accumulation of glucosylceramide in storage compartments (lysosomes) of certain cells in the body.

It is the most common type of a group of diseases known as lysosomal storage diseases. Lysosomes are cell compartments in which substances are broken down by specific enzymes. This is analogous to a machine breakdown at an assembly plant causing a huge pileup of unfinished products.
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