title: Glutaminyl cyclases unfold glutamyl cyclase activity under mild acid conditions.
abstract: 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.
authors.affiliation: Probiodrug AG, Biocenter, Weinbergweg 22, 06120 Halle/Saale, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Schilling
authors.forename: Torsten
authors.initials: T
authors.lastname: Hoffmann
authors.forename: Susanne
authors.initials: S
authors.lastname: Manhart
authors.forename: Matthias
authors.initials: M
authors.lastname: Hoffmann
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Demuth
mesh_terms: D019881:Aminoacyltransferases / Q000235:genetics / Q000378:metabolism*; D000626:Aminopeptidases / Q000378:metabolism; D029441:Carica / Q000201:enzymology / Q000378:metabolism; D004926:Escherichia coli / Q000201:enzymology / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D005998:Glycine / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D013058:Mass Spectrometry; D015394:Molecular Structure; D010843:Pichia / Q000201:enzymology / Q000378:metabolism; D011489:Protein Denaturation; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D011994:Recombinant Proteins; D018698:Glutamic Acid; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase; D000626:Aminopeptidases; D005998:Glycine