Inhibitors of Glutaminyl Cyclases against Alzheimer`s Disease
P. Kolenko1,3, B. Koch2, S. Schilling2, J.-U. Rahfeld2, H.-U. Demuth2, M.T. Stubbs3
1Institute of Macromolecular Chemistry AS CR, v.v.i., Heyrovského nám. 2/1888, 162 06 – Prague 6, Czech Republic
2Probiodrug AG, Weinbergweg 22,
06 120 Halle (Saale), Germany
3Institut für Biochemie und Biotechnologie, Martin-Luther Universität, Kurt-Mothes-Straße 3, 06 120 Halle (Saale), Germany
petr.kolenko@gmail.com
N-terminal formation of pyroglutamate (pGlu) is catalyzed by glutaminyl cyclases (QCs) [1,2]. This form of post-translational modification is observed on numerous bioactive peptides. Formation of pGlu-amyloid has been also linked with Alzheimer`s disease [3-5]. Inhibitors of human QCs are currently the subject of intense development and testing [6,7].
We have currently solved crystal structures of two isoforms of QCs from Drosophila melanogaster [7]. Comparative study of structures of human, murine, and insect QCs from the PDB [8] allowed us reasonable evaluation of various binding modes of inhibitor PBD150. Structural observations are in concert with our inhibition studies.
This work was supported by ProNet-T3of the German Bundesministerium für Bildung und Forschung Initiative „Spitzenforschung und Innovation“, and by the Ministry of Education, Youth and Sports of the Czech Republic (grant No. CZ.1.07/2.3.00/30.0029).
1. S. Schilling, S. Manhart, T. Hoffmann, H.H. Ludwig, C. Wasternack, H.U. Demuth, Biol. Chem., 384, (2003), 1583-1592.
2. K.F. Huang, Y.L. Liu, W.J. Cheng, T.P. Ko, A.H.J. Wang, PNAS, 102, (2005), 13117-13122.
3. S. Schilling, U. Zeitschel, T. Hoffmann, U. Heiser, M. Francke, A. Kehlen, M. Holzer, B. Hutter-Paier, M. Prokesch, M. Windisch, W. Jagla, D. Schlenzig, C. Lindner, T. Rudolph, G. Reuter, H. Cynis, D. Montag, H.U. Demuth, S. Rossner, Nat. Med., 14, (2008), 1106-1111.
4. J.M. Nussbaum, S. Schilling, H. Cynis, A. Silva, E. Swanson, T. Wangsanut, K. Tayler, B. Wiltgen, A. Hatami, R. Rönicke, K. Reymann, B. Hutter-Paier, A. Alexandru, W. Jagla, S. Graubner, C.G. Glabe, H.U. Demuth, G.S. Gloom, Nature, 485, (2012), 651-655.
5. D. Ruiz Carrillo, B. Koch, C. Parthier, M. Wermann, T. Dambe, M. Buchholz, H.H. Ludwig, U. Heiser, J.U. Rahfeld, M.T. Stubbs, S. Schilling, H.U. Demuth, Biochemistry, 50, (2011), 6280-6288.
6. M. Buchholz, U. Heiser, S. Schilling, A.J. Niestroj, K. Zunkel, H.U. Demuth, J. Med. Chem., 49, (2006), 664-677.
7. B. Koch, P. Kolenko, M. Buchholz, D.R. Carrillo, C. Parthier, M. Wermann, J.U. Rahfeld, G. Reuter, S. Schilling, M.T. Stubbs, H.U. Demuth, Biochemistry, 51, (2012), 7383-7392.
8. H.M. Berman, J. Westbrook, Z. Feng, G. Gilliland, T.N. Bhat, H. Weissig, I.N. Shindyalov, P.E. Bourne, Nuc. Ac. Res., 28, (2000), 235-242.