Redox regulation of cellular function by thioredoxin and glutaredoxin systems

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• Prof. Arne Holmgren, Medical Nobel Institute of Biochemistry, Karolinska Institute, Stockholm, Sweden
• Wednesday 18 October 2006, 15:00-16:00
• Lecture Theatre, Level 7, www.mrc-dunn.cam.ac.uk.

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Thioredoxin and glutaredoxin systems: enzyme mechanisms and role in thiol redox control of cellular functions, defense against oxidative stress, control of apoptosis and cell proliferation. Thioredoxin (Trx) and glutaredoxin (Grx) systems catalyze thiol-disulfide exchange reactions and are required for electron transport from NADPH to enzymes like ribonucleotide reductase essential for DNA synthesis and peroxiredoxins invoved in signaling by hydrogen peroxide.Trx and Grx systems maintain a reducing intracellular redox potential and serve in redox regulation with ROS by reversible disulfide formation or Cys sulfur oxidation. Trx1 and Grx1 in the cytosol and Trx2 and Grx2a in the mitochondria operate by redox-active CXYC active sites. Trx is reduced to the dithiol form by NADPH and thioredoxin reductase (TrxR), which in mammalian cells are large selenoenzymes with a selenocysteine in the active site, whereas Grx1 and Grx2 are reduced by glutathione (GSH) or Grx2a also by TrxR. Both Trx and Grx in mammalian cells are in turn subject to redox regulation; Trx1 via oxidation of three structural Cys residues or nitrosylation and Grx2a by iron-sulfur cluster formation. The latter involves formation of an inactive dimer of Grx2 involving a two iron-two sulfur cluster which is formed by the N-terminal active site thiols of two Grx2 monomers and two molecules of GSH that are bound noncovalently and are in equilibrium with free GSH in solution. When GSH becomes limiting or under oxidative conditions the cluster dissociates yielding enzymatically active Grx2. Our aims are to understand the detailed mechanisms and role of Trx and Grx systems in signaling including the secretion/uptake of the proteins and their role in protection against oxidative stress.We work on drugs like ebselen, which is a substrate of Trx and TrxR from mammalian cells to protect from oxidative stress and inflammation. We hope to develop novel antibiotics based on the difference in mechanism of TrxR in bacteria ( low Mr TrxR) and mammlian cells ( high Mr selenoprotein). We focus our interest on reductive pathways in pathogenic bacteria like Staphylocus aureus, Helicobacter pylori or Mycobacterium tuberculosis, where TrxR is essential in contrast to E. coli.

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