title: Selenium and the thioredoxin and glutaredoxin systems.
abstract: Thioredoxin (Trx) is a small ubiquitous dithiol protein which together with the FAD-containing enzyme thioredoxin reductase (TR) and NADPH (the Trx system) is a hydrogen donor for ribonucleotide reductase essential for DNA synthesis and a general protein disulfide reductase involved in redox regulation. Selenite, selenodiglutathione (GS-Se-SG) and selenocystine are efficiently reduced by thioredoxins and also directly by NADPH and mammalian TR but not by the E. coli enzyme. Incubation of selenite or GS-Se-SG with the Trx system or with mammalian TR results in a rapid formation of selenide, which by redox cycling with oxygen may cause a large non-stoichiometric oxidation of NADPH. Selenocystine is efficiently reduced into two molecules of the selenol amino acid selenocysteine by mammalian TR with a K(m)-value (6 mumol.L-1) and a high turnover number (kappa cat 3200 min-1) almost identical to the natural substrate Trx-S2. TR also directly reduces lipid hydroperoxides and this peroxidase reaction is strongly stimulated by the presence of catalytic amounts of free selenocysteine. Glutaredoxin (Grx) which catalyzes GSH-dependent disulfide reduction also via a redox-active disulfide and Trx are both efficient electron donors to the human plasma glutathione peroxidase providing a mechanism by which human plasma glutathione peroxidase may reduce hydroperoxides in an environment almost free from glutathione. Selenate is reduced by Grx and Trx in the presence of GSH. The DNA-binding of the transcription factor AP-1 is strongly inhibited by GS-Se-SG and selenite. Furthermore, selenide formed by TR-mediated reduction of selenite and GS-Se-SG inhibits lipoxygenase and changes the electron spin resonance spectrum of the active site iron. Mammalian TR with two subunits of 57 kDa has recently been cloned and shown to be homologous to glutathione reductase. The rat enzyme contains a selenocysteine residue in a unique Cterminal position and a conserved SECIS sequence directing insertion of the selenocysteine. The discovery of selenocysteine in mammalian TR may explain the broad substrate specificity of the enzyme and the requirement of selenium for cell proliferation.
authors.affiliation: Medical Nobel Institute for Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Björnstedt
authors.forename: S
authors.initials: S
authors.lastname: Kumar
authors.forename: L
authors.initials: L
authors.lastname: Björkhem
authors.forename: G
authors.initials: G
authors.lastname: Spyrou
authors.forename: A
authors.initials: A
authors.lastname: Holmgren
mesh_terms: D000595:Amino Acid Sequence; D054477:Glutaredoxins; D006801:Humans; D066298:In Vitro Techniques; D010084:Oxidation-Reduction; D010088:Oxidoreductases; D011506:Proteins / Q000378:metabolism*; D018036:Selenium Compounds / Q000378:metabolism*; D013880:Thioredoxin-Disulfide Reductase / Q000737:chemistry / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism*
chemical_list: C516005:GLRX protein, human; C516007:Glrx protein, rat; D054477:Glutaredoxins; D011506:Proteins; D018036:Selenium Compounds; D013879:Thioredoxins; D010088:Oxidoreductases; D013880:Thioredoxin-Disulfide Reductase