title: Phosphate ions and glutaminyl cyclases catalyze the cyclization of glutaminyl residues by facilitating synchronized proton transfers.
abstract: Phosphate ions and glutaminyl cyclase (QC) both catalyze the formation of pyroglutamate (pE, pGlu) from N-terminal glutamine residues of peptides and proteins. Here, we studied the mechanism of glutamine cyclization using kinetic secondary deuterium and solvent isotope effects. The data suggest that proton transfer(s) are rate determining for the spontaneous reaction, and that phosphate and QC are accelerating the reaction by promoting synchronized proton transfers in a concerted mechanism. Thus, non-enzymatic and enzymatic catalysis of pyroglutamate formation exploit a similar mode of transition-state stabilization.
authors.affiliation: Albrecht-von-Haller-Institute, University of Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Seifert
authors.affiliation: Probiodrug AG, Weinbergweg 22, 06120 Halle, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Demuth
authors.affiliation: Probiodrug AG, Weinbergweg 22, 06120 Halle, Germany.
authors.forename: Teresa
authors.initials: T
authors.lastname: Weichler
authors.affiliation: Probiodrug AG, Weinbergweg 22, 06120 Halle, Germany.
authors.forename: Hans-Henning
authors.initials: HH
authors.lastname: Ludwig
authors.affiliation: Albrecht-von-Haller-Institute, University of Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Tittmann
authors.affiliation: Probiodrug AG, Weinbergweg 22, 06120 Halle, Germany. Electronic address: Stephan.Schilling@izi.fraunhofer.de.
authors.forename: Stephan
authors.initials: S
authors.lastname: Schilling
mesh_terms: D019881:Aminoacyltransferases / Q000378:metabolism*; D000818:Animals; D003500:Cyclization; D004331:Drosophila melanogaster / Q000201:enzymology* / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism*; D011522:Protons; D011761:Pyrrolidonecarboxylic Acid / Q000378:metabolism*
chemical_list: D010710:Phosphates; D011522:Protons; D005973:Glutamine; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase; D011761:Pyrrolidonecarboxylic Acid
keywords: 5-Oxo-l-proline; Acyl transfer; Glutamine; Pyroglutamic acid