胰岛素降解酶将β-淀粉样肽水解为既无神经毒性也不会沉积在淀粉样斑块上的产物。
Insulysin hydrolyzes amyloid beta peptides to products that are neither neurotoxic nor deposit on amyloid plaques.
作者信息
Mukherjee A, Song E, Kihiko-Ehmann M, Goodman J P, Pyrek J S, Estus S, Hersh L B
机构信息
Department of Biochemistry, Department of Physiology and Sanders-Brown Center on Aging, and Mass Spectrometry Facility, University of Kentucky, Lexington, Kentucky 40536-0298, USA.
出版信息
J Neurosci. 2000 Dec 1;20(23):8745-9. doi: 10.1523/JNEUROSCI.20-23-08745.2000.
Insulysin (EC. 3.4.22.11) has been implicated in the clearance of beta amyloid peptides through hydrolytic cleavage. To further study the action of insulysin on Abeta peptides recombinant rat insulysin was used. Cleavage of both Abeta(1-40) and Abeta(1-42) by the recombinant enzyme was shown to initially occur at the His(13)-His(14), His(14)-Gln(15), and Phe(19)-Phe(20) bonds. This was followed by a slower cleavage at the Lys(28)-Gly(29), Val(18)-Phe(19), and Phe(20)-Ala(21) positions. None of the products appeared to be further metabolized by insulysin. Using a rat cortical cell system, the action of insulysin on Abeta(1-40) and Abeta(1-42) was shown to eliminate the neurotoxic effects of these peptides. Insulysin was further shown to prevent the deposition of Abeta(1-40) onto a synthetic amyloid. Taken together these results suggest that the use of insulysin to hydrolyze Abeta peptides represents an alternative gene therapeutic approach to the treatment of Alzheimer's disease.
胰岛素降解酶（EC. 3.4.22.11）已被证明通过水解作用参与β淀粉样肽的清除。为了进一步研究胰岛素降解酶对β淀粉样肽的作用，使用了重组大鼠胰岛素降解酶。重组酶对β淀粉样肽（1 - 40）和β淀粉样肽（1 - 42）的切割最初发生在组氨酸（13）-组氨酸（14）、组氨酸（14）-谷氨酰胺（15）和苯丙氨酸（19）-苯丙氨酸（20）键处。随后在赖氨酸（28）-甘氨酸（29）、缬氨酸（18）-苯丙氨酸（19）和苯丙氨酸（20）-丙氨酸（21）位置的切割速度较慢。胰岛素降解酶似乎不会使任何产物进一步代谢。在大鼠皮质细胞系统中，胰岛素降解酶对β淀粉样肽（1 - 40）和β淀粉样肽（1 - 42）的作用表明可消除这些肽的神经毒性作用。进一步研究表明胰岛素降解酶可阻止β淀粉样肽（1 - 40）在合成淀粉样物质上的沉积。综合这些结果表明，使用胰岛素降解酶水解β淀粉样肽代表了一种治疗阿尔茨海默病的替代基因治疗方法。
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