Human thioredoxin reductase directly reduces lipid hydroperoxides by NADPH and selenocystine strongly stimulates the reaction via catalytically generated selenols.
Human placenta thioredoxin reductase (HP-TR) in the presence of NADPH-catalyzed reduction of (15S)-hydroperoxy-(5Z),(8Z),11(Z),13(E)-eicosatetraenoic acid ((15S)-HPETE) into the corresponding alcohol ((15S)-HETE). Incubation of 50 nM HP-TR and 0.5 mM NADPH with 300 microM 15-HPETE for 5 min resulted in formation of 16.5 microM 15-HETE. After 60 min, 74.7 microM 15-HPETE was reduced. The rate of the reduction of 15-HPETE by the HP-TR/NADPH peroxidase system was increased 8-fold by the presence of 2.5 microM selenocystine, a diselenide amino acid. In this case, 15-HPETE was catalytically reduced by the selenol amino acid, selenocysteine, generated from the diselenide by the HP-TR/NADPH system. To a smaller extent, selenodiglutathione or human thioredoxin also potentiated the reduction of 15-HPETE by HP-TR. Hydrogen peroxide and 15-HPETE were reduced at approximately the same rate by HP-TR, thioredoxin, and selenocystine. In contrast, t-butyl hydroperoxide was reduced at a 10-fold lower rate. Our data suggest two novel pathways for the reduction and detoxification of lipid hydroperoxides, hydrogen peroxide, and organic hydroperoxides, i.e. the human thioredoxin reductase-dependent pathway and a coupled reduction in the presence of selenols or selenide resulting from the reduction of selenocystine or selenodiglutathione.
Björnstedt
M
M
Medical Nobel Institute for Biochemistry, Karolinska Institutet, Stockholm, Sweden.
Hamberg
M
M
Kumar
S
S
Xue
J
J
Holmgren
A
A
D002384:Catalysis; D003553:Cystine / Q000031:analogs & derivatives* / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D015289:Leukotrienes / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D008054:Lipid Peroxides / Q000378:metabolism*; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D008954:Models, Biological; D009249:NADP / Q000378:metabolism*; D016566:Organoselenium Compounds / Q000378:metabolism* / Q000494:pharmacology; D010084:Oxidation-Reduction; D010545:Peroxides / Q000378:metabolism; D010920:Placenta / Q000201:enzymology; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D017279:Selenocysteine / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000494:pharmacology*; D013879:Thioredoxins / Q000494:pharmacology; D020122:tert-Butylhydroperoxide
D006893:Hydroxyeicosatetraenoic Acids; D015289:Leukotrienes; D008054:Lipid Peroxides; D016566:Organoselenium Compounds; D010545:Peroxides; D017279:Selenocysteine; C009226:selenocystine; C017710:selenodiglutathione; D003553:Cystine; D013879:Thioredoxins; D009249:NADP; C025086:15-hydroperoxy-5,8,11,13-eicosatetraenoic acid; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D020122:tert-Butylhydroperoxide; D006861:Hydrogen Peroxide; D013880:Thioredoxin-Disulfide Reductase; D005982:Glutathione Transferase; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D005978:Glutathione