Metabolism of selenium compounds catalyzed by the mammalian selenoprotein thioredoxin reductase.
The mammalian thioredoxin reductases (TrxR) are selenoproteins with a catalytic selenocysteine residue which in the oxidized enzyme forms a selenenylsulfide and in the reduced enzyme is present as a selenolthiol. Selenium compounds such as selenite, selenodiglutathione and selenocystine are substrates for the enzyme with low K(m)-values and the enzyme is implicated in reductive assimilation of selenium by generating selenide for selenoprotein synthesis. Redox cycling of reduced metabolites of these selenium compounds including selenide with oxygen via TrxR and reduced thioredoxin (Trx) will oxidize NADPH and produce reactive oxygen species inducing cell death at high concentrations explaining selenite toxicity. There is no free pool of selenocysteine since this would be toxic in an oxygen environment by redox cycling via thioredoxin systems. The importance of selenium compounds and TrxR in cancer and cardiovascular diseases both for prevention and treatment is discussed. A selenazol drug like ebselen is a direct substrate for mammalian TrxR and dithiol Trx and ebselen selenol is readily reoxidized by hydrogen peroxide and lipid hydroperoxides, acting as an anti-oxidant and anti-inflammatory drug.
Lu
Jun
J
Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE 171 77 Stockholm, Sweden.
Berndt
Carsten
C
Holmgren
Arne
A
D000818:Animals; D002319:Cardiovascular System / Q000378:metabolism; D002384:Catalysis; D006801:Humans; D008322:Mammals / Q000378:metabolism*; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism; D012643:Selenium / Q000378:metabolism; D018036:Selenium Compounds / Q000378:metabolism*; D051140:Selenoproteins / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism* / Q000502:physiology
D018036:Selenium Compounds; D051140:Selenoproteins; D013880:Thioredoxin-Disulfide Reductase; D012643:Selenium