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Oxidative stress is a major factor in various disease conditions. Classically, oxidative streess is defined as imbalance between prooxidants, mostly reactive oxygen species (ROS), and antioxidants. Over the past years a number of key observations have challenged this model. These include: (1) indivdual redox systems, e.g. NADPH/NADP or GSH/GSSG, are not in equilibrium within a given cellular compartment; (2) the different redox systems in different cellular compartments are activley maintained at different potentials by the cell. Thus, oxidative stress may be better defined as disruption of individual redox control and signaling events. The central effectors of redox signaling are protein thiol groups found in cysteinyl residues of various proteins. Glutaredoxins (Grxs) and thioredoxins (Trxs) are the major thiol-disulphide oxidoreductases of the cell and therefore the major effectors of redox signaling. The Grx system consists of Grx, glutathione (GSH), and the NADPH-dependent glutathione reductase. Grxs usually contain the active site motif CPYC and react via a monothiol or a dithiol mechanism. Two glutaredoxins have been identified in mammals so far. Cytosolic Grx1 is involved in general disulphide-dithiol exchanges, dehydroascorbate reduction, protein de-glutathionylation and several other processes. The more recently discovered mammalian Grx2 is present in different isoforms derived from alternative splicing events. Two thioredoxins are present in mammals, i.e. cytosolic Trx1 and mitochondrial Trx2, both of which are essential for embryonic development. Other thioredoxin family members include the peroxiredoxins (Prx), of which 6 are present in mammals. These proteins use electros provided by Trxs to reduce hydrogen peroxide. Our main interest is to identify redox control circuits of medical relevance and how these are altered in different disease conditions including Diabetes mellitus, neurodegenrative disorders, cardiovascular disease, and cancer. The following questions are the basis for our work:
Lillig, C.H. and Berndt, C. Thioredoxins and Glutaredoxins. Functions and Metal Ion Interactions. in "Metallothioneins and Related Chelators" , Vol. 5 of 'Metal Ions in Life Sciences'; A. Sigel, H. Sigel, R. K. and O. Sigel, Eds.; The Royal Society of Chemistry, Cambridge, UK, in press (2009) [publisher/RSC] Lillig, C.H., Berndt, C., and Holmgren, A. Glutaredoxin systems. Biochim. Biophys. Acta - Gen. Sub. 1340: 1304-1317 (2008) [pdf] [medline] [journal/BBA] Berndt, C., Lillig, C.H., and Holmgren, A.Thioredoxins and glutaredoxins as facilitators of protein folding. Biochim. Biophys. Acta - Mol. Cell Res. 1783: 641-650 (2008) [pdf] [medline] [journal/BBA] Hudemann, C., Berndt, C., and Lillig, C.H., Glutaredoxine und Eisen-Schwefel Zentren. Biospektrum 14: 32-35 (2008) [pdf in German] Berndt, C., Lillig, C.H., and Holmgren, A. Thiol-based mechanisms of the thioredoxin and glutaredoxin systems: implications for diseases in the cardiovascular system. Am. J. Physiol. Heart Circ. Physiol. 292: H1227-1236 (2007) [pdf] [medline] [journal/AJPHCP] Lillig, C.H., and Holmgren, A., Thioredoxin and related molecules - from biology to health and disease. Antioxid. Redox Signal. 9: 25-47 (2007) [pdf] [medline] [journal/ARS] Holmgren, A., Johansson, C., Berndt, C., Lönn, M.E., Hudemann, C., and Lillig, C.H., Thiol redox control via thioredoxin and glutaredoxin systems. Biochem. Soc. Trans. 33: 1375-1377 (2005) [pdf] [medline] [journal/BST] (Our full publication list can be found here) |
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We gratefully acknowledge the financial support provided by the following funding organizations: |
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 The German Research Foundation Sonderforschungsbereich 593 |
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 von Behring-Röntgen Foundation | ||
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 The Swedish Society for Medical Research, Stockholm, Sweden |
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 Karolinska Institutet, |
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