Mammalian d-aspartyl endopeptidase: a scavenger for noxious racemized proteins in aging

The accumulation of d-isomers of aspartic acid ( d-Asp) in proteins during aging has been implicated in the pathogenesis of Alzheimer’s disease, cataracts, and arteriosclerosis. Here, we identified a specific lactacystin–sensitive endopeptidase that cleaves the d-Asp-containing protein and named it...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2004-02, Vol.314 (3), p.730-736
Main Authors: Kinouchi, Tadatoshi, Ishiura, Shoichi, Mabuchi, Yoko, Urakami-Manaka, Yasuko, Nishio, Hideki, Nishiuchi, Yuji, Tsunemi, Masahiko, Takada, Katsumi, Watanabe, Masatomo, Ikeda, Masashi, Matsui, Hisao, Tomioka, Shigeo, Kawahara, Hiroyuki, Hamamoto, Toshiro, Suzuki, Koichi, Kagawa, Yasuo
Format: Article
Language:English
Subjects:
Aging
Aging - metabolism
Animals
Aspartic Acid - chemistry
Aspartic Acid - metabolism
Aspartic Acid Endopeptidases - antagonists & inhibitors
Aspartic Acid Endopeptidases - isolation & purification
Aspartic Acid Endopeptidases - metabolism
Caenorhabditis elegans
Caenorhabditis elegans - enzymology
Caenorhabditis elegans - genetics
Cysteine Endopeptidases - genetics
Cysteine Endopeptidases - metabolism
d-amino acid
d-aspartic acid
Endopeptidases - metabolism
Escherichia coli
Escherichia coli - enzymology
Escherichia coli - genetics
Female
Isomerism
Male
Mice
Mice, Inbred Strains
Mitochondria
Mitochondria, Liver - enzymology
Oligopeptides - chemistry
Oligopeptides - metabolism
Peptidase
Protease
Protease inhibitor
Protease Inhibitors - pharmacology
Proteinase
Rabbits
Racemization
Saccharomyces cerevisiae
Saccharomyces cerevisiae - enzymology
Saccharomyces cerevisiae - genetics
Substrate Specificity
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Summary:The accumulation of d-isomers of aspartic acid ( d-Asp) in proteins during aging has been implicated in the pathogenesis of Alzheimer’s disease, 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 of mouse and rabbit, but DAEP activity was not detected in Escherichia coli, Saccharomyces cerevisiae, and Caenorhabditis elegans. A specific inhibitor for DAEP was newly synthesized, and inhibited DAEP activity (IC 50, 3 μM), a factor of 10 greater than lactacystin on DAEP. On the other hand, the inhibitor did not inhibit either the 20S or 26S proteasome.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2003.12.147