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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

IMPACT FACTOR 2018: 3.014
5-year IMPACT FACTOR: 3.162

CiteScore 2018: 3.09

SCImago Journal Rank (SJR) 2018: 1.482
Source Normalized Impact per Paper (SNIP) 2018: 0.820

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Volume 392, Issue 3


Selective inhibition of dipeptidyl peptidase 4 by targeting a substrate-specific secondary binding site

Kerstin Kühn-Wache
  • Probiodrug AG, Weinbergweg 22, Biocenter, D-06120 Halle, Germany
  • These authors contributed equally to this work.
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Joachim W. Bär
  • Probiodrug AG, Weinbergweg 22, Biocenter, D-06120 Halle, Germany
  • These authors contributed equally to this work.
  • Present address: Boehringer Ingelheim Pharma GmbH&Co. KG, Birkendorfer Straße 65, D-88397 Biberach an der Riss, Germany.
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Torsten Hoffmann / Raik Wolf / Jens-Ulrich Rahfeld / Hans-Ulrich Demuth
Published Online: 2011-06-18 | DOI: https://doi.org/10.1515/bc.2011.028


Dipeptidyl peptidase 4/CD26 (DP4) is a multifunctional serine protease liberating dipeptide from the N-terminus of (oligo)peptides which can modulate the activity of these peptides. The enzyme is involved in physiological processes such as blood glucose homeostasis and immune response. DP4 substrate specificity is characterized in detail using synthetic dipeptide derivatives. The specificity constant k cat/K m strongly depends on the amino acid in P1-position for proline, alanine, glycine and serine with 5.0×105 m -1s-1, 1.8×104 m -1s-1, 3.6×102 m -1s-1, 1.1×102 m -1s-1, respectively. By contrast, kinetic investigation of larger peptide substrates yields a different pattern. The specific activity of DP4 for neuropeptide Y (NPY) cleavage comprising a proline in P1-position is the same range as the k cat/K m values of NPY derivatives containing alanine or serine in P1-position with 4×105 m -1s-1, 9.5×105 m -1s-1 and 2.1×105 m -1s-1, respectively. The proposed existence of an additional binding region outside the catalytic center is supported by measurements of peptide substrates with extended chain length. This ‘secondary’ binding site interaction depends on the amino acid sequence in P4′–P8′-position. Interactions with this binding site could be specifically blocked for substrates of the GRF/glucagon peptide family. By contrast, substrates not belonging to this peptide family and dipeptide derivative substrates that only bind to the catalytic center of DP4 were not inhibited. This more selective inhibition approach allows, for the first time, to distinguish between substrate families by substrate-discriminating inhibitors.

Keywords: dipeptidyl peptidase 4; neuropeptide Y; secondary binding site; substrates; substrate-specific inhibition

About the article

Corresponding author

Received: 2010-09-20

Accepted: 2010-12-21

Published Online: 2011-06-18

Published in Print: 2011-03-01

Citation Information: Biological Chemistry, Volume 392, Issue 3, Pages 223–231, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/bc.2011.028.

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