Inhibition of glutaminyl cyclase alters pyroglutamate formation in mammalian cells |
| |
Authors: | Cynis Holger Schilling Stephan Bodnár Mandy Hoffmann Torsten Heiser Ulrich Saido Takaomi C Demuth Hans-Ulrich |
| |
Institution: | Probiodrug AG, Weinbergweg 22, 06120 Halle/Saale, Germany. |
| |
Abstract: | Mammalian cell lines were examined concerning their Glutaminyl Cyclase (QC) activity using a HPLC method. The enzyme activity was suppressed by a QC specific inhibitor in all homogenates. Aim of the study was to prove whether inhibition of QC modifies the posttranslational maturation of N-glutamine and N-glutamate peptide substrates. Therefore, the impact of QC-inhibition on amino-terminal pyroglutamate (pGlu) formation of the modified amyloid peptides Abeta(N3E-42) and Abeta(N3Q-42) was investigated. These amyloid-beta peptides were expressed as fusion proteins with either the pre-pro sequence of TRH, to be released by a prohormone convertase, or as engineered amyloid precursor protein for subsequent liberation of Abeta(N3Q-42) after beta- and gamma-secretase cleavage during posttranslational processing. Inhibition of QC leads in both expression systems to significantly reduced pGlu-formation of differently processed Abeta-peptides. This reveals the importance of QC-activity during cellular maturation of pGlu-containing peptides. Thus, QC-inhibition should impact bioactivity, stability or even toxicity of pyroglutamyl peptides preventing glutamine and glutamate cyclization. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|