Human thioredoxin Reductases: Selenoproteins as Potential Drug Targets

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The selenoenzyme thioredoxin reductase (TrxR) and its product, reduced thioredoxin, represent cornerstones of the cellular thiol metabolism. They contribute to deoxyribonucleotide production, to the redox control of various metabolic pathways as well as to cell proliferation and differentiation. Human TrxR is so potently inhibited by different cytostatic and antirheumatic agents that the enzyme currently represents one of the most promising target molecules for the de novo development and improvement of drugs. In the proposed project we plan to crystallize cytosolic hTrxR and to elucidate its three-dimensional structure. Furthermore, the catalytic mechanism of the enzyme and the function of the redox-active selenocysteine shall be characterized. By systematic inhibitor screening (e.g. gold compounds, platinum complexes, and peroxynitrite) and the crystallization of hTrxR-inhibitor complexes new inhibition strategies will be developed. Mitochondrial and cytosolic hTrxR represent two of only four human selenoenzymes known so far. Studying structure and mechanism of hTrxRs but also genetic knockout experiments in animal models would essentially contribute to our understanding of the function of selenium in man.