Structure of Glucocerebrosidase May Lead to Gaucher Treatment

A new study describes the three-dimensional structure of the enzyme glucocerebrosidase, which due to mutation fails to function in the lipid storage syndrome known as Gaucher disease.

Gaucher disease is an inherited metabolic disorder in which harmful quantities of glucocerebroside accumulate in the spleen, liver, lungs, bone marrow, and, in rare cases, the brain. Three clinical forms of Gaucher disease are commonly recognized, but in all of them, patients exhibit a deficiency of glucocerebrosidase, which catalyzes the first step in the biodegradation of glucocerebroside. Except for the brain, glucocerebroside arises mainly from the biodegradation of old red and white blood cells. In the brain, glucocerebroside arises from the turnover of complex lipids during brain development and the formation of the myelin sheath of nerves.

Investigators at the Weizmann Institute of Science (Rehovot, Israel) used x-ray crystallography to map the structure of glucocerebrosidase to a resolution of two angstroms. They found that the catalytic domain consisted of a TIM barrel, as expected for a member of the glucosidase hydrolase A clan. The distance between the catalytic residues E235 and E340 was consistent with a catalytic mechanism of retention. N370 was located on the longest alpha-helix (helix 7). Helix 7 was at the interface between the TIM barrel and a separate immunoglobulin-like domain on which L444 was located, suggesting an important regulatory or structural role for this noncatalytic domain.

The authors hope that their findings, published June 3, 2003, in the online edition of the European Molecular Biology Organization (EMBO) Reports, will provide the possibility of engineering improved glucocerebrosidase for enzyme-replacement therapy, and for designing structure-based drugs aimed at restoring the activity of defective glucocerebrosidase.





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