Thioredoxin-basierte regulatorische Netzwerke in Mensch und Malariaparasit

• Antragstellerin: Professorin Dr. Katja Becker, seit 12/2014
• Fachliche Zuordnung: Biochemie
• Förderung: Förderung von 2007 bis 2016
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 52506740

Human thioredoxin reductase (hTrxR) is a homodimeric flavoprotein crucially involved in the regulation of cellular redox reactions, growth and differentiation. The enzyme contains a selenocysteine residue at its C-terminal active site which is essential for catalysis and contributes to the regulation of apoptosis. This redox center is located on a flexible loop, it is solvent exposed and highly reactive towards electrophilic inhibitors. Thus TrxR represents an interesting target for antitumor drug development and an excellent probe for studying redox-regulatory cellular networks. Over the last years we studied hTrxR structurally and mechanistically in comparison with other disulfide reductases. We identified hTrxR inhibitors including organic gold compounds, terpyridineplatinum complexes and cisplatin nitrofuran complexes which are active in the (low) nanomolar range. Their cytostatic activity was verified on different highly malignant cell lines as well as in a glioblastoma animal model. We recently crystallized the hTrxR Sec(Cys mutant and solved the structure of the enzyme at a resolution of 2.8 Å including different conformations of the C-terminal redox site. Within the frame of the proposed project we aim at focussing on (i) the functional and structural characterization of hTrxR(-ligand) complexes and (ii) on the cell-biological consequences of hTrxR inhibition and mutation including modulation of redox networks, induction of apoptosis, and compensatory mechanisms in tumor cells.

• DFG-Verfahren: Sachbeihilfen
• Ehemalige Antragstellerin: Dr. Esther Jortzik, bis 11/2014