The accumulation of D-isomers of aspartic acid (D-Asp) in proteins during aging has been implicated in the pathogenesis of Alzheimer's disease (AD), cataracts and arteriosclerosis. Here, we identified a specific lactacystin-sensitive endopeptidase that cleaves the D-Asp-containing protein and named it D-aspartyl endopeptidase (DAEP). DAEP has a multi-complex structure (MW: 600 kDa) and is localized in the inner mitochondrial membrane. However, DAEP activity was not detected in E. coli, S. cerevisiae, and C. elegans. A specific inhibitor for DAEP, i-DAEP: (benzoyl-L-Arg-L-His-[D-Asp]-CH(2)Cl; MW: 563.01), was newly synthesized and inhibited DAEP activity (IC(50), 3 microM), a factor of ten greater than lactacystin on DAEP. On the other hand, i-DAEP did not inhibit either the 20S or 26S proteasome. And we identified succinate dehydrogenase and glutamate dehydrogenase 1 as components of DAEP by affinity label using biotinylated i-DAEP. In the long life span of mammals, DAEP may serve as a scavenger against accumulation of racemized proteins in aging. Insights into DAEP will provide the foundation for developing treatments of diseases, such as AD, in which accumulation of D-Asp-containing proteins are implicated.
Isolation and characterization of mammalian D-aspartyl endopeptidase. Publishing Authors By Initials
Isolation and characterization of mammalian D-aspartyl endopeptidase. Journal Published:
PUBLICATION TYPE: Research Support, Non-U.S. Gov
Journal: Amino acids
VOLUME: 32
Page Numbers: 79-85
Journal Abbreviation: Amino Acids
ISSN: 0939-4451
DAY: 6
MONTH: 10
YEAR: 2006
Isolation and characterization of mammalian D-aspartyl endopeptidase. Information
Number of References:
LANGUAGE: eng
NlmUniqueID: 9200312
Isolation and characterization of mammalian D-aspartyl endopeptidase. Keywords Mesh Terms:
KEYWORDS: Succinate Dehydrogenase
MESH TERMS: isolation & purification
Chemical & Substance for Abstract: Isolation and characterization of mammalian D-aspartyl endopeptidase. Information
Substance Name: Proteasome Endopeptidase Complex
Registry Number: EC 3.4.25.1
Grant and Affiliation Information for Isolation and characterization of mammalian D-aspartyl endopeptidase.
AFFILIATION: Department of Radiation Life Science and Radiation Medical Science, Research Reactor Institute, Kyoto University, Osaka, Japan. kinouchi@HL.rri.kyoto-u.ac.jp
Country: Austria
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MEDLINETA: Amino Acids
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