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Professor Harald Tschesche
Faculty of Chemistry anbd Biochemistry
University Bielefeld
P.O. Box 100131, D-33501 Bielefeld - Germany
Email: harald.tschesche@uni-bielefeld.de
Tel: +49-521-106 2079
Fax: +49-521-106 6014

Our research interests are the human enzymes involved in the degradation of extracellular plasma and tissue proteins. Having started in former days with the pancreatic enzymes trypsin and chymotrypsin, then with plasmin, kallikreins and leucocyte elastase we isolated and described in structure and function, we turned to their natural antagonists, the secretory inhibitors (Kazal-type inhibitors), from which we isolated, described and sequenced several types. Having sequenced for the first time a tissue kallikrein we got involved in the structure and function of the Kunitz inhibitor aprotinin. The structure of which was varied at its active site by semisynthetic and genetic approaches to study the relationship between backbone variations, rigidity and inhibitory properties. This gave clear structural information for the requirements to exhibit inhibitory properties. Finally we could change the inhibitory properties from trypsin to chymotrypsin or elastase inhibition.
New interests involved the isolation and cloning of human (leucocyte) matrix metalloproteinases, MMP-8, -9, -12, -13, and -14, their mechanisms of activation and their roles in leukodiapedesis and in other physiological processes as well as their importance in cancer invasion and metastasis. Investigations on clinical tumor specimen revealed their significance for clinical outcome and survival. Amounts of the cloned catalytic domains of MMP-8, -12 (and MMP-14, i.e. MT1-MMP) were used to obtain crystals from which the X-ray 3D-structures of the enzymes were obtained. The structure of MMP-12 could be revealed at a resolution of 1.1 A°. The structure of the MMP-14 in complex with the tissue inhibitor of MMPs, TIMP-1, revealed the mode of binding of its natural antagonist.
Several complexes of the catalytic domain of MMP-8 and synthetic, low molecular weight inhibitors were crystallized and revealed the type of binding of the inhibitors. The structural information was further used to develope several new types of synthetic inhibitors discriminating between individual members of the family of MMPs. This work is still going on and contributes to the development of potential, therapeutic agents.
This wide and complex range of research interests from natural tissue sources, cloning, sequence and structural work of human enzymes to clinical investigations and synthetic, therapeutic applications required world wide cooperations and contacts that we have estimated.

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