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 D-aspartyl endopeptidase (DAEP). DAEP has a multi-complex structure (MW: 600kDa) 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), 3microM), a factor of 10 greater than lactacystin on DAEP. On the other hand, the inhibitor did not inhibit either the 20S or 26S proteasome.
Kinouchi
Tadatoshi
T
Department of Biochemistry, Jichi Medical School, 329-0498, Tochigi, Japan. kinouchi@jichi.ac.jp
Ishiura
Shoichi
S
Mabuchi
Yoko
Y
Urakami-Manaka
Yasuko
Y
Nishio
Hideki
H
Nishiuchi
Yuji
Y
Tsunemi
Masahiko
M
Takada
Katsumi
K
Watanabe
Masatomo
M
Ikeda
Masashi
M
Matsui
Hisao
H
Tomioka
Shigeo
S
Kawahara
Hiroyuki
H
Hamamoto
Toshiro
T
Suzuki
Koichi
K
Kagawa
Yasuo
Y
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001224:Aspartic Acid / Q000737:chemistry / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D017173:Caenorhabditis elegans / Q000201:enzymology / Q000235:genetics; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D005260:Female; D007536:Isomerism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008930:Mitochondria, Liver / Q000201:enzymology; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D011817:Rabbits; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D013379:Substrate Specificity
D009842:Oligopeptides; D011480:Protease Inhibitors; D001224:Aspartic Acid; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D016282:Aspartic Acid Endopeptidases