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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred

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Volume 397, Issue 1


IsoQC (QPCTL) knock-out mice suggest differential substrate conversion by glutaminyl cyclase isoenzymes

Andreas Becker / Rico Eichentopf / Reinhard Sedlmeier / Alexander Waniek
  • Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstraße 19, 04103 Leipzig, Germany
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/ Holger Cynis / Birgit Koch / Anett Stephan / Christoph Bäuscher / Stephanie Kohlmann / Torsten Hoffmann / Astrid Kehlen / Sabine Berg
  • Institute of Diabetes “Gerhardt Katsch”, Greifswalder Str. 11e, D-17495 Karlsburg, Germany
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/ Ernst-Joachim Freyse
  • Institute of Diabetes “Gerhardt Katsch”, Greifswalder Str. 11e, D-17495 Karlsburg, Germany
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/ Alexander Osmand
  • Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, 1414 Cumberland Avenue, Knoxville, TN 37996, USA
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/ Anne-Christine Plank
  • Department of Experimental Therapy, University of Erlangen-Nürnberg, Franz-Penzoldt-Center, Palmsanlage 5, D-91054 Erlangen, Germany
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/ Steffen Roßner
  • Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstraße 19, 04103 Leipzig, Germany
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/ Stephan von Hörsten
  • Department of Experimental Therapy, University of Erlangen-Nürnberg, Franz-Penzoldt-Center, Palmsanlage 5, D-91054 Erlangen, Germany
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/ Sigrid Graubner / Hans-Ulrich Demuth
  • Ingenium GmbH, Fraunhoferstrasse 13, D-82152 Martinsried, Germany
  • Probiodrug AG, Weinbergweg 22, D-06120 Halle/Saale, Germany
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/ Stephan Schilling
Published Online: 2015-08-19 | DOI: https://doi.org/10.1515/hsz-2015-0192


Secretory peptides and proteins are frequently modified by pyroglutamic acid (pE, pGlu) at their N-terminus. This modification is catalyzed by the glutaminyl cyclases QC and isoQC. Here, we decipher the roles of the isoenzymes by characterization of IsoQC-/- mice. These mice show a significant reduction of glutaminyl cyclase activity in brain and peripheral tissue, suggesting ubiquitous expression of the isoQC enzyme. An assay of substrate conversion in vivo reveals impaired generation of the pGlu-modified C-C chemokine ligand 2 (CCL2, MCP-1) in isoQC-/- mice. The pGlu-formation was also impaired in primary neurons, which express significant levels of QC. Interestingly, however, the formation of the neuropeptide hormone thyrotropin-releasing hormone (TRH), assessed by immunohistochemistry and hormonal analysis of hypothalamic-pituitary-thyroid axis, was not affected in isoQC-/-, which contrasts to QC-/-. Thus, the results reveal differential functions of isoQC and QC in the formation of the pGlu-peptides CCL2 and TRH. Substrates requiring extensive prohormone processing in secretory granules, such as TRH, are primarily converted by QC. In contrast, protein substrates such as CCL2 appear to be primarily converted by isoQC. The results provide a new example, how subtle differences in subcellular localization of enzymes and substrate precursor maturation might influence pGlu-product formation.

This article offers supplementary material which is provided at the end of the article.

Keywords: 5-oxo-L-proline; posttranslational modification; pyroglutamate; TRH


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About the article

Corresponding author: Stephan Schilling, Probiodrug AG, Weinbergweg 22, D-06120 Halle/Saale, Germany, e-mail:

aAndreas Becker and Rico Eichentopf: These authors contributed equally to this work.

bPresent address: Fraunhofer Institute for Cell Therapy and Immunology

Received: 2015-06-10

Accepted: 2015-08-12

Published Online: 2015-08-19

Published in Print: 2016-01-01

Citation Information: Biological Chemistry, Volume 397, Issue 1, Pages 45–55, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2015-0192.

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