The accumulation of amyloid-β (Aβ) peptide is thought to be a major causative mechanism of Alzheimer's disease. Aβ accumulation could be caused by dysregulated processing of amyloid precursor protein, yielding excessive amounts of Aβ, and/or by inefficient proteolytic degradation of the peptide itself. Several proteases have been described as Aβ degradation enzymes, most notably metalloendopeptidases, aspartic endopeptidases, and some exopeptidases. Recently a report suggested that another metallopeptidase, glutamate carboxypeptidase II (GCPII), can also cleave Aβ. GCPII is a zinc exopeptidase that cleaves glutamate from N-acetyl-L-aspartyl-L-glutamate in the central nervous system and from pteroylpoly-γ-glutamate in the jejunum. GCPII has been proposed as a promising therapeutic target for disorders caused by glutamate neurotoxicity. However, an Aβ-degrading activity of GCPII would compromise potential pharmaceutical use of GCPII inhibitors, because the enzyme inhibition might lead to increased Aβ levels and consequently to Alzheimer's disease. Therefore, we analyzed the reported Aβ-degrading activity of GCPII using highly purified recombinant enzyme and synthetic Aβ. We did not detect any Aβ degradation activity of GCPII or its homologue even under prolonged incubation at a high enzyme to substrate ratio. These results are in good agreement with the current detailed structural understanding of the substrate specificity and enzyme-ligand interactions of GCPII.

• MeSH
• amyloidní beta-protein chemie   metabolismus   MeSH
• antigeny povrchové genetika   metabolismus   MeSH
• biokatalýza účinky léků   MeSH
• dipeptidy metabolismus   MeSH
• glutamátkarboxypeptidasa II antagonisté a inhibitory   genetika   metabolismus   MeSH
• hmotnostní spektrometrie MeSH
• hydrolýza MeSH
• katalytická doména MeSH
• lidé MeSH
• molekulární struktura MeSH
• neprilysin genetika   metabolismus   MeSH
• organofosforové sloučeniny farmakologie   MeSH
• peptidové fragmenty chemie   metabolismus   MeSH
• proteolýza MeSH
• rekombinantní proteiny metabolismus   MeSH
• substrátová specifita MeSH
• tritium MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH