Glutaminyl cyclases unfold glutamyl cyclase activity under mild acid conditions

• Published in: FEBS letters Vol. 563; no. 1; pp. 191 - 196
• Main Authors: Schilling, Stephan, Hoffmann, Torsten, Manhart, Susanne, Hoffmann, Matthias, Demuth, Hans-Ulrich
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 09.04.2004
• Subjects: AD, Alzheimer's disease; Alzheimer's disease; Aminoacyltransferases - genetics; Aminoacyltransferases - metabolism; Aminopeptidases - metabolism; Amyloid precursor protein; APP, amyloid precursor protein; Aβ(3–11)a, amyloid-β peptide 3–11 amide; Carica - enzymology; Carica - metabolism; DPIV, dipeptidyl peptidase IV; EC, glutamyl cyclase; Escherichia coli - enzymology; Escherichia coli - metabolism; Glutamic Acid - metabolism; Glutamine cyclotransferase; Glutaminyl cyclase; Glutamyl cyclase; Glycine - metabolism; GnRH, gonadotropin-releasing hormone; Humans; Hydrogen-Ion Concentration; Mass Spectrometry; Molecular Structure; pGlu, pyroglutamic acid; Pichia - enzymology; Pichia - metabolism; Protein Denaturation; Protein Processing, Post-Translational; QC, glutaminyl cyclase; Recombinant Proteins - metabolism; Substrate Specificity; TRH, thyrotropin-releasing hormone; βNA, 2-naphthylamine; Glutamyl cyclase; QC, glutaminyl cyclase; Alzheimer’s disease; AD, Alzheimer’s disease; βNA, 2-naphthylamine; GnRH, gonadotropin-releasing hormone; Amyloid precursor protein; Glutamine cyclotransferase; DPIV, dipeptidyl peptidase IV; Glutaminyl cyclase; TRH, thyrotropin-releasing hormone; Aβ(3–11)a, amyloid-β peptide 3–11 amide; pGlu, pyroglutamic acid; EC, glutamyl cyclase; APP, amyloid precursor protein
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/S0014-5793(04)00300-X

N-terminal pyroglutamate (pGlu) formation from glutaminyl precursors is a posttranslational event in the processing of bioactive neuropeptides such as thyrotropin-releasing hormone and neurotensin during their maturation in the secretory pathway. The reaction is facilitated by glutaminyl cyclase (QC), an enzyme highly abundant in mammalian brain. Here, we describe for the first time that human and papaya QC also catalyze N-terminal glutamate cyclization. Surprisingly, the enzymatic Glu 1 conversion is favored at pH 6.0 while Gln 1 conversion occurs with an optimum at pH 8.0. This unexpected finding might be of importance for deciphering the events leading to deposition of highly toxic pyroglutamyl peptides in amyloidotic diseases.