Mutational analysis of aspartoacylase: implications for Canavan disease.
Mutational analysis of aspartoacylase: implications for Canavan disease.
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天冬氨酸酰化酶的突变分析：对卡纳万病的影响。
DOI：
10.1016/j.brainres.2007.02.069
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发表时间：
2007
期刊：
影响因子：
2.9
通讯作者：
Namboodiri,MAAryan
中科院分区：
文献类型：
--
作者：
Hershfield,JeremyR;Pattabiraman,Nagarajan;Madhavarao,ChikkathurN;Namboodiri,MAAryan
Mutations that result in near undetectable activity of aspartoacylase, which catalyzes the deacetylation of N-acetyl-l-aspartate, correlate with Canavan Disease, a neurodegenerative disorder usually fatal during childhood. The underlying biochemical mechanisms of how these mutations ablate activity are poorly understood. Therefore, we developed and tested a three-dimensional homology model of aspartoacylase based on zinc dependent carboxypeptidase A. Mutations of the putative zinc-binding residues (H21G, E24D/G, and H116G), the general proton donor (E178A), and mutants designed to switch the order of the zinc-binding residues (H21E/E24H and E24H/H116E) yielded wild-type aspartoacylase protein levels and undetectable ASPA activity. Mutations that affect substrate carboxyl binding (R71N) and transition state stabilization (R63N) also yielded wild-type aspartoacylase protein levels and undetectable aspartoacylase activity. Alanine substitutions of Cys124 and Cys152, residues indicated by homology modeling to be in close proximity and in the proper orientation for disulfide bonding, yielded reduced ASPA protein and activity levels. Finally, expression of several previously tested (E24G, D68A, C152W, E214X, D249V, E285A, and A305E) and untested (H21P, A57T, I143T, P183H, M195R, K213E/G274R, G274R, and F295S) Canavan Disease mutations resulted in undetectable enzyme activity, and only E285A and P183H showed wild-type aspartoacylase protein levels. These results show that aspartoacylase is a member of the caboxypeptidase A family and offer novel explanations for most loss-of-function aspartoacylase mutations associated with Canavan Disease.
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影响因子：
158.5
作者：
FORREST, WH;BROWN, BW;TEUTSCH, G
通讯作者：
TEUTSCH, G
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影响因子：
168.9
作者：
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镰状细胞病患者的精神病理学。
影响因子：
3.4
作者：
S. Leavell;C. V. Ford
通讯作者：
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影响因子：
168.9
作者：
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DOI：
10.1056/nejm198412133112409
发表时间：
1984
期刊：
The New England journal of medicine
影响因子：
--
作者：
S. Chien
通讯作者：
S. Chien