Glutamate carboxypeptidase II does not process amyloid-beta peptide

0424007 - ÚOCHB 2014 RIV US eng J - Journal Article
Sedlák, František - Šácha, Pavel - Blechová, Miroslava - Březinová, Anna - Šafařík, Martin - Šebestík, Jaroslav - Konvalinka, Jan
Glutamate carboxypeptidase II does not process amyloid-beta peptide.
FASEB Journal. Roč. 27, č. 7 (2013), s. 2626-2632. ISSN 0892-6638. E-ISSN 1530-6860
R&D Projects: GA ČR GAP304/12/0847
Institutional support: RVO:61388963
Keywords : PSMA * Alzheimer's disease * disaggregation * exopeptidase * substrate specificity * depsipeptide
Subject RIV: CE - Biochemistry
Impact factor: 5.480, year: 2013

The accumulation of amyloid- (A) peptide is thought to be a major causative mechanism of Alzheimer's disease. A accumulation could be caused by dysregulated processing of amyloid precursor protein, yielding excessive amounts of A, and/or by inefficient proteolytic degradation of the peptide itself. Several proteases have been described as A degradation enzymes, most notably metalloendopeptidases, aspartic endopeptidases, and some exopeptidases. Recently a report suggested that another metallopeptidase, glutamate carboxypeptidase II (GCPII), can also cleave A. GCPII is a zinc exopeptidase that cleaves glutamate from N-acetyl-l-aspartyl-l-glutamate in the central nervous system and from pteroylpoly--glutamate in the jejunum. GCPII has been proposed as a promising therapeutic target for disorders caused by glutamate neurotoxicity. However, an A-degrading activity of GCPII would compromise potential pharmaceutical use of GCPII inhibitors, because the enzyme inhibition might lead to increased A levels and consequently to Alzheimer's disease. Therefore, we analyzed the reported A-degrading activity of GCPII using highly purified recombinant enzyme and synthetic A. We did not detect any A 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.Sedlak, F., Sacha, P., Blechova, M., Bezinova, A., Safaik, M., Sebestik, J., Konvalinka, J. Glutamate carboxypeptidase II does not process amyloid- peptide.
Permanent Link: http://hdl.handle.net/11104/0230161