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

Abstract 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.