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PDBsum entry 2o4h
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References listed in PDB file
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Key reference
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Title
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Examination of the mechanism of human brain aspartoacylase through the binding of an intermediate analogue.
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Authors
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J.Le coq,
A.Pavlovsky,
R.Malik,
R.Sanishvili,
C.Xu,
R.E.Viola.
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Ref.
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Biochemistry, 2008,
47,
3484-3492.
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PubMed id
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Abstract
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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.
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