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Partial Characterisation of Dipeptidyl Peptidase 4 (DP 4

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Partial Characterisation of Dipeptidyl Peptidase 4 (DP 4 Partial Characterisation of Dipeptidyl Peptidase 4 (DP 4) for the Treatment of Type 2 Diabetes and its Identification as a novel Pharmaceutical Target for Stress-related Indications Beiträge zur Charakterisierung der Dipeptidylpeptidase 4 (DP 4) für die Behandlung von Typ-2-Diabetes und deren Identifizierung als ein neuartiges pharmazeutisches Ziel für stressvermittelte Indikationen Der Naturwissenschaftlichen Fakultät der Friedrich-Alexander-Universität Erlangen-Nürnberg zur Erlangung des Doktorgrades Dr. rer. nat. vorgelegt von M. Sc. (Biochemie) Leona Wagner aus Rheinfelden (Baden) Als Dissertation genehmigt von der Naturwissenschaftlichen Fakultät der Friedrich-Alexander-Universität Erlangen-Nürnberg Tag der mündlichen Prüfung: 23.10.2012 Vorsitzender der Promotionskommission: Prof. Dr. Rainer Fink Erstberichterstatter: Prof. Dr. med. Stephan von Hörsten Zweitberichterstatter: Prof. Dr. Johann Helmut Brandstätter Publications, Presentations and Posters Part of the present study have been published or submitted in the following journals or presented on the following conferences: Publications: 1. Hinke, S.A., McIntosh, C.H., Hoffmann, T., Kuhn-Wache, K., Wagner, L., Bar, J., Manhart, S., Wermann, M., Pederson, R.A., and Demuth, H.U. (2002) On combination therapy of diabetes with metformin and dipeptidyl peptidase IV inhibitors. Diabetes Care 25, 1490- 1491. 2. Bär, J., Weber, A., Hoffmann, T., Stork, J., Wermann, M., Wagner, L., Aust, S., Gerhartz, B., and Demuth, H.U. (2003) Characterisation of human dipeptidyl peptidase IV expressed in Pichia pastoris. A structural and mechanistic comparison between the recombinant human and the purified porcine enzyme. Biol. Chem. 384, 1553-1563. 3. Engel, M., Hoffmann, T., Wagner, L., Wermann, M., Heiser, U., Kiefersauer, R., Huber, R., Bode, W., Demuth, H.U., and Brandstetter, H. (2003). The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism. Proc. Natl. Acad. Sci. U. S. A. 100, 5063-5068. 4. Wagner, L., Hoffmann, T., Rahfeld, J.U., and Demuth, H.U. (2006) Distribution of dipeptidyl peptidase IV-like activity enzymes in canine and porcine tissue sections by RT-PCR. Adv. Exp. Med. Biol. 575, 109-116. 5. Frerker, N*., Wagner, L*., Wolf, R., Heiser, U., Hoffmann, T., Rahfeld, J.U., Schade, J., Karl, T., Naim, H.Y., Alfalah, M., Demuth, H.U., and von Hörsten, S. (2007) Neuropeptide Y (NPY) cleaving enzymes: structural and functional homologues of dipeptidyl peptidase 4. Peptides 28, 257-268. 6. Forssmann, U., Stoetzer, C., Stephan, M., Kruschinski, C., Skripuletz, T., Schade, J., Schmiedl, A., Pabst, R., Wagner, L., Hoffmann, T., Kehlen, A., Escher, S.E., Forssmann, W.G., Elsner, J., and von Hörsten, S. (2008) Inhibition of CD26/dipeptidyl peptidase IV enhances CCL11/eotaxin-mediated recruitment of eosinophils in vivo. J Immunol. 181, 1120-1127. 7. Schade, J., Stephan, M., Schmiedl, A., Wagner, L., Niestroj, A.J., Demuth, H.U., Frerker, N., Klemann, C., Raber, K.A., Pabst, R., and von Hörsten, S. (2008) Regulation of expression and function of dipeptidyl peptidase 4 (DP4), DP8/9, and DP10 in allergic responses of the lung in rats. J. Histochem. Cytochem. 56, 147-155. 8. Frerker, N., Raber, K., Bode, F., Skripuletz, T., Nave, H., Klemann, C., Pabst, R., Stephan, M., Schade, J., Brabant, G., Wedekind, D., Jacobs, R., Jorns, A., Forssmann, U., Straub, R.H., Johannes, S., Hoffmann, T., Wagner, L., Demuth, H.U., and von Hörsten, S. (2009) Phenotyping of congenic dipeptidyl peptidase 4 (DP4) deficient Dark Agouti (DA) rats suggests involvement of DP4 in neuro-, endocrine, and immune functions. Clin. Chem. Lab Med. 47, 275-287. 9. Wagner, L., Wermann, M., Rosche, F., Rahfeld, J.-U., Hoffmann, T., and Demuth, H.-U. (2011) Isolation of dipeptidyl peptidase IV isoforms from porcine kidney by preparative isoelectric focusing. Biol. Chem. 392, 665-677. 10. Alcázar, M.A., Boehler, E., Klaffenbach, D., Hartner, A., Allabauer, I., Wagner, L., von Hörsten, S., Plank, C., and Doetsch, J. (2011) Persistent changes within the intrinsic kidney- associated NPY system and tubular function by litter size reduction. Nephrol.Dial.Transplant. 26, 2453-2465. Publications, Presentations and Posters 11. Wagner, L., Wolf, R., Zeitschel, U., Rossner, S., Pedersen, A., Leavitt, B., Haydn, M., Kästner, F., Rothermundt, M., Gärtner, U.-T, Weber, A., Schlenzig, D., Frerker, N., Schade, J., Manhart, S., Rahfeld, J.U., Hoffmann, T., Demuth, H.-U., and von Hörsten, S. (2012a) Metabolism of neuropeptide Y (NPY) from head to toe identified novel NPY-cleaving enzymes and revealed potential drug interactions. (in preparation). 12. Ruiz-Carrillo, D*.Wagner, L*., Jaenckel, N., Börgel, A., Parthier, C., Böhme M., Rosche, F., von Hörsten, S. Demuth H.-U., Rahfeld J.-U., and Stubbs, M. T. (2012) Structural characterization of the recombinant human dipeptidyl peptidase 2. (in preparation). 13. Wagner, L., Kästner, F., Wolf, R., Stiller, H., Heiser, U., Gärtner, U.-T., Manhart, S., Klemm, K., Hoffmann, T., Rahfeld, J., Demuth, H.-U., von Hörsten, S., and Rothermundt, M. (2012b) Identifying neuropeptide Y (NPY) as the main stress-related substrate of dipeptidyl peptidase 4 in blood. (in preparation). 14. Wagner, L., Hult, S., Wolf, R., Börgel, A., Schlenzig, D., Manhart, S., Rahfeld, J.-U., Leavitt, B., Haydn, M., Demuth, H.-U., Petersén, A., von Hörsten, S. (2012c) Verification of CSF NPY levels in Huntington patients revealed differential degradation of NPY1-30 metabolite. (in preparation). 15. Wagner, L., Kästner, F., Wolf, R., Stiller, H., Gans, K., Ruiz-Carrillo, D., Niestroj, A.J., Manhart, S., Hoffmann, T., Rahfeld, J.-U., Demuth, H.-U., von Hörsten, S., and Rothermundt, M. (2012d) Galanin (GAL) is a substrate of prolyl endopeptidase (PEP) in the human blood. (in preparation). Oral Presentations: Wagner,L., Gündel,D., Zeitschel,U., Rossner,S.,Frerker,N., Schade,J.Stiller,J., Niestroj, A.J., Thümmler,A., Wolf,R., Gärtner, U.-T., Manhart,S., Kehlen,A., Rahfeld, J.-U., Hoffmann,T., von Hörsten,S., and Demuth, H.-U. “Tissue-distribution of dipeptidyl peptidase 4-like enzymes in distinct brain areas and neuronal tissues” 3rd International Conference on Dipeptidyl Peptidases and Related Proteins. 23 - 25 April 2008, Antwerp, Belgium. Wagner, L., Wolf R., Zeitschel U., Rossner S., Petersen A., Leavitt, B., Haydn M., Kästner M., Rothermundt M., Gärtner U., Weber A., Schlenzig S., Frerker N., Schade J., Manhart S., Rahfeld J-U., von Hörsten S., Demuth H.-U. Metabolomic investigations of neuropeptide Y (NPY) identified seven novel NPY-cleaving enzymes and revealed potential drug interactions. 27th Winter School. 24 - 28 February 2010, Tiers, Italy. Wagner, L., Wolf R., Zeitschel U., Rossner S., Gündel D., Stiller H, Petersen A, Leavitt B., Haydn M. , Kästner F., Rothermundt M., Gärtner U., Weber A., Schlenzig D., Frerker N, Schade J., Manhart S, Rahfeld J-U, Demuth H-U., von Hörsten, S. “Dipeptidyl Peptidase 4 (DP 4) and Neuropeptide Y (NPY): A novel pharmaceutical target against stress?” International Meeting on Proline-Specific cleavage and Oxoprolyl Formation. 26 - 29 May 2010, Halle, Germany. Wagner, L., Wolf R., Zeitschel U., Rossner S., Gündel D., Stiller H, Petersen A, Leavitt B., Haydn M. , Kästner F., Rothermundt M., Gärtner U., Weber A., Schlenzig D., Frerker N, Schade J., Manhart S, Rahfeld J-U, Demuth H-U., von Hörsten S. “Dipeptidyl Peptidase 4 (DP 4) and Neuropeptide Y (NPY): A novel pharmaceutical target against stress?” Neuropeptides 2010 (The 7th Joint Meeting of the European Neuropeptide Club and the American Summer Neuropeptide Conference) 21 - 24 June 2010, Pécs, Hungary. Publications, Presentations and Posters Posters: Wagner, L., Wermann, M., Hoffmann, T., and Demuth, H.-U. “Purification of porcine dipeptidyl peptidase IV from the kidney and isolation of its isoforms by preparative isoelectric focusing.” International Protease Symposium (IPS), 1 - 5 November 2001, Freising, Germany. Wagner, L., Hoffmann, T., Gerhartz, B., and Demuth, H.-U. “Distribution of dipeptidyl peptidase IV activity-like enzymes in canine and porcine tissue sections by nested RT-PCR” Dipeptidyl-Aminopeptidases: Basic Science and Clinical Applications. 26 - 29 September 2002, Berlin, Germany. Friedrich,D., Wermann, M., Wagner,L., Kühn-Wache, K., Hoffmann,T., and Demuth,H.-U. “Isolation and Characterization of Attractin-2” Dipeptidyl-Aminopeptidases: Basic Science and Clinical Applications. 26 - 29 September 2002, Berlin, Germany. Engel, M., Hoffmann, T., Wagner, L., Wermann, M., Heiser, U., Kiefersauer, R., Huber, R., Bode, W., Demuth, H.U., and Brandstetter, H. “1.8 Å Crystal structure of native porcine Dipeptidyl peptidase IV (CD26).” ScreenTech World Summit Protease Inhibitors. 23 - 27 March 2003 San Diego, USA. Wagner L., Rahfeld, J.-U., Niestroj,A.J., Heiser,U., and Demuth,H.-U. “Distribution of dipeptidyl peptidase IV activity-like enzymes in canine and porcine tissue sections by nested RT- PCR” 2nd International Conference of Dipeptidyl Aminopeptidases: Basic Science and Clinical Applications. 13 - 15 April 2005, Magdeburg, Germany. Wagner, L., Hoffmann,T., Rahfeld,J.-U., Niestroj,A.J., Heiser,U., and Demuth, H.-U. “Characterisation of Dipeptidyl peptidase IV-like activity enzymes in porcine pancreas and isolated islets of Langerhans” 7th Young Scientists Meeting of DGZ. 22 - 24 September 2005, Jena, Germany. Wagner,L., Frerker,N., Gündel,G., Wolf,R., Kehlen,A., Thümmler,A., Niestroj,A.J., Heiser,U., Rahfeld,J.-U., Hoffmann,T., von Hörsten,S., and Demuth, H.-U. “Characterization
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