Examination of the mechanism of human brain aspartoacylase through the binding of an intermediate analogue.

[canavan disease]

Canavan disease is a fatal neurological disorder caused by the malfunctioning of a single metabolic enzyme , aspartoacylase , that catalyzes the deacetylation of N-acetyl-L-aspartate to produce L-aspartate and acetate . The structure of human brain aspartoacylase has been determined in complex with a stable tetrahedral intermediate analogue , N-phosphonomethyl-L-aspartate . This potent inhibitor forms multiple interactions between each of its heteroatoms and the substrate binding groups arrayed within the active site . The binding of the catalytic intermediate analogue induces the conformational ordering of several substrate binding groups , thereby setting up the active site for catalysis . The highly ordered binding of this inhibitor has allowed assignments to be made for substrate binding groups and provides strong support for a carboxypeptidase-type mechanism for the hydrolysis of the amide bond of the substrate , N-acetyl- l-aspartate .