Jump to ContentJump to Main Navigation
Show Summary Details
In This Section

Thomas, Douglas D.

Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Turk, Boris / Wittinghofer, Alfred

12 Issues per year


IMPACT FACTOR 2016: 3.273

CiteScore 2016: 3.01

SCImago Journal Rank (SJR) 2015: 1.607
Source Normalized Impact per Paper (SNIP) 2015: 0.751

Online
ISSN
1437-4315
See all formats and pricing
In This Section
Volume 386, Issue 12 (Dec 2005)

Issues

Trypsin inhibition by macrocyclic and open-chain variants of the squash inhibitor MCoTI-II

Olga Avrutina
  • Institute for Organic and Biomolecular Chemistry, Georg-August-University, D-37077 Göttingen, Germany
/ Hans-Ulrich Schmoldt
  • Department of Molecular Genetics, Institute for Microbiology and Genetics, Georg-August-University, D-37077 Göttingen, Germany
/ Dusica Gabrijelcic-Geiger
  • Department Clinical Chemistry and Clinical Biochemistry, Ludwig-Maximilians-University, D-80336 Munich, Germany
/ Dung Le Nguyen
  • Centre de Pharmacologie et Biotechnologie pour la Santé, CNRS UMR 5160, 15 avenue Charles Flahault, F-34093 Montpellier Cedex 5, France
/ Christian P. Sommerhoff
  • Department Clinical Chemistry and Clinical Biochemistry, Ludwig-Maximilians-University, D-80336 Munich, Germany
/ Ulf Diederichsen
  • Institute for Organic and Biomolecular Chemistry, Georg-August-University, D-37077 Göttingen, Germany
/ Harald Kolmar
  • Department of Molecular Genetics, Institute for Microbiology and Genetics, Georg-August-University, D-37077 Göttingen, Germany
Published Online: 2005-12-09 | DOI: https://doi.org/10.1515/BC.2005.148

Abstract

MCoTI-I and MCoTI-II from the seeds of Momordica cochinchinensis are inhibitors of trypsin-like proteases and the only known members of the large family of squash inhibitors that are cyclic and contain an additional loop connecting the amino- and the carboxy-terminus. To investigate the contribution of macrocycle formation to biological activity, we synthesized a set of open-chain variants of MCoTI-II that lack the cyclization loop and contain various natural and non-natural amino acid substitutions in the reactive-site loop. Upon replacement of P1 lysine residue #10 within the open-chain variant of MCoTI-II by the non-natural isosteric nucleo amino acid AlaG [β-(guanin-9-yl)-L-alanine], a conformationally restricted arginine mimetic, residual inhibitory activity was detected, albeit reduced by four orders of magnitude. While the cyclic inhibitors MCoTI-I and MCoTI-II were found to be very potent trypsin inhibitors, with picomolar inhibition constants, the open-chain variants displayed an approximately 10-fold lower affinity. These data suggest that the formation of a circular backbone in the MCoTI squash inhibitors results in enhanced affinity and therefore is a determinant of biological activity.

Keywords: cyclic squash inhibitors; cystine-knot microproteins; nucleic amino acids; trypsin inhibition

References

About the article

Corresponding author


Received: June 13, 2005

Accepted: September 14, 2005

Published Online: 2005-12-09

Published in Print: 2005-12-01



Citation Information: Biological Chemistry, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/BC.2005.148. Export Citation

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

[1]
Jun Zhang, Jintian Li, Zebo Huang, Bing Yang, Xiaojie Zhang, Dehua Li, David J. Craik, Alan J.M. Baker, Wensheng Shu, and Bin Liao
Journal of Plant Physiology, 2015, Volume 178, Page 17
[2]
Jun Zhang, Zhengshuang Hua, Zebo Huang, QiZhu Chen, Qingyun Long, David J. Craik, Alan J. M. Baker, Wensheng Shu, and Bin Liao
Planta, 2015, Volume 241, Number 4, Page 929
[3]
T. Mahatmanto, J. S. Mylne, A. G. Poth, J. E. Swedberg, Q. Kaas, H. Schaefer, and D. J. Craik
Molecular Biology and Evolution, 2015, Volume 32, Number 2, Page 392
[4]
Karen Stanger, Till Maurer, Harini Kaluarachchi, Mary Coons, Yvonne Franke, and Rami N. Hannoush
FEBS Letters, 2014, Volume 588, Number 23, Page 4487
[5]
Michael Reinwarth, Daichi Nasu, Harald Kolmar, and Olga Avrutina
Molecules, 2012, Volume 17, Number 12, Page 12533
[6]
Thomas Hofmeyer, Siyavuya Ishmael Bulani, Julius Grzeschik, Simon Krah, Bernhard Glotzbach, Christina Uth, Olga Avrutina, Michael Brecht, Hans Ulrich Göringer, Petrus van Zyl, and Harald Kolmar
Molecular Biotechnology, 2014, Volume 56, Number 1, Page 79
[7]
Bernhard Glotzbach, Stefan Schmelz, Michael Reinwarth, Andreas Christmann, Dirk W. Heinz, and Harald Kolmar
Acta Crystallographica Section D Biological Crystallography, 2013, Volume 69, Number 1, Page 114
[8]
Michael Reinwarth, Bernhard Glotzbach, Michael Tomaszowski, Sebastian Fabritz, Olga Avrutina, and Harald Kolmar
ChemBioChem, 2013, Volume 14, Number 1, Page 137
[9]
Frederic Zoller, Annette Markert, Philippe Barthe, Wenye Zhao, Wilko Weichert, Vasileios Askoxylakis, Annette Altmann, Walter Mier, and Uwe Haberkorn
Angewandte Chemie International Edition, 2012, Volume 51, Number 52, Page 13136
[10]
Lai Yue Chan, Wenjun He, Ninghua Tan, Guangzhi Zeng, David J. Craik, and Norelle L. Daly
Peptides, 2013, Volume 39, Page 29
[11]
Sebastian Fabritz, Sebastian Hörner, Doreen Könning, Martin Empting, Michael Reinwarth, Christian Dietz, Bernhard Glotzbach, Holm Frauendorf, Harald Kolmar, and Olga Avrutina
Organic & Biomolecular Chemistry, 2012, Volume 10, Number 31, Page 6287
[12]
J. A. Camarero
Proceedings of the National Academy of Sciences, 2011, Volume 108, Number 25, Page 10025
[14]
Frederic Zoller, Thimon Schwaebel, Annette Markert, Uwe Haberkorn, and Walter Mier
ChemMedChem, 2012, Volume 7, Number 2, Page 237
[15]
Christian P. Sommerhoff, Olga Avrutina, Hans-Ulrich Schmoldt, Dusica Gabrijelcic-Geiger, Ulf Diederichsen, and Harald Kolmar
Journal of Molecular Biology, 2010, Volume 395, Number 1, Page 167
[16]
Shadakshara S. Puttamadappa, Krishnappa Jagadish, Alexander Shekhtman, and Julio A. Camarero
Angewandte Chemie, 2011, Volume 123, Number 31, Page 7082
[17]
Martin Empting, Olga Avrutina, Reinhard Meusinger, Sebastian Fabritz, Michael Reinwarth, Markus Biesalski, Stephan Voigt, Gerd Buntkowsky, and Harald Kolmar
Angewandte Chemie, 2011, Volume 123, Number 22, Page 5313
[18]
Harald Kolmar
Expert Review of Molecular Diagnostics, 2010, Volume 10, Number 3, Page 361
[19]
Shadakshara S. Puttamadappa, Krishnappa Jagadish, Alexander Shekhtman, and Julio A. Camarero
Angewandte Chemie, 2010, Volume 122, Number 39, Page 7184
[20]
Regine García Boy, Walter Mier, Eva Maria Nothelfer, Annette Altmann, Michael Eisenhut, Harald Kolmar, Michael Tomaszowski, Susanne Krämer, and Uwe Haberkorn
Molecular Imaging and Biology, 2010, Volume 12, Number 4, Page 377
[21]
Jeffrey Austin, Wan Wang, Swamy Puttamadappa, Alexander Shekhtman, and Julio A. Camarero
ChemBioChem, 2009, Volume 10, Number 16, Page 2663
[22]
M. Werle, H. Kolmar, R. Albrecht, and A. Bernkop-Schnürch
Amino Acids, 2008, Volume 35, Number 1, Page 195
[23]
Panumart Thongyoo, Núria Roqué-Rosell, Robin J. Leatherbarrow, and Edward W. Tate
Organic & Biomolecular Chemistry, 2008, Volume 6, Number 8, Page 1462
[24]
Olga Avrutina, Hans-Ulrich Schmoldt, Dusica Gabrijelcic-Geiger, Alexander Wentzel, Holm Frauendorf, Christian P. Sommerhoff, Ulf Diederichsen, and Harald Kolmar
ChemBioChem, 2008, Volume 9, Number 1, Page 33
[25]
Julio A. Camarero, Richard H. Kimura, Youn-Hi Woo, Alexander Shekhtman, and Jason Cantor
ChemBioChem, 2007, Volume 8, Number 12, Page 1363
[26]
Panumart Thongyoo, Agnes M. Jaulent, Edward W. Tate, and Robin J. Leatherbarrow
ChemBioChem, 2007, Volume 8, Number 10, Page 1107
[27]
Panumart Thongyoo, Edward W. Tate, and Robin J. Leatherbarrow
Chemical Communications, 2006, Number 27, Page 2848

Comments (0)

Please log in or register to comment.
Log in