Oxidation of 2-Cys-peroxiredoxins by arachidonic acid peroxide metabolites of lipoxygenases and cyclooxygenase-2.
Human peroxiredoxins serve dual roles as anti-oxidants and regulators of H(2)O(2)-mediated cell signaling. The functional versatility of peroxiredoxins depends on progressive oxidation of key cysteine residues. The sulfinic or sulfonic forms of peroxiredoxin lose their peroxidase activity, which allows cells to accumulate H(2)O(2) for signaling or pathogenesis in inflammation, cancer, and other disorders. We report that arachidonic acid lipid hydroperoxide metabolites of 5-, 12-, 15-lipoxygenase-1, and cyclooxygenase-2 oxidize the 2-Cys-peroxiredoxins 1, 2, and 3 to their sulfinic and sulfonic forms. When added exogenously to cells, 5-, 12- and 15-hydroperoxy-eicosatetraenoic acids also over-oxidized peroxiredoxins. Our results suggest that lipoxygenases and cyclooxygenases may affect 2-Cys peroxiredoxin signaling, analogous to NADPH oxidases in the "floodgate" model (Wood, Z. A., Poole, L. B, and Karplus P. A. (2003) Science 300, 600-653). Peroxiredoxin-dependent mechanisms may modulate the receptor-dependent actions of autocoids derived from cellular lipoxygenase and cyclooxygenase catalysis.
Cordray
Pauline
P
Department of Pharmacology and Toxicology, and Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USA.
Doyle
Kelly
K
Edes
Kornelia
K
Moos
Philip J
PJ
Fitzpatrick
Frank A
FA
D016718:Arachidonic Acid / Q000378:metabolism*; D002384:Catalysis; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008084:Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D010084:Oxidation-Reduction; D010545:Peroxides / Q000378:metabolism*; D054464:Peroxiredoxins / Q000378:metabolism*; D011485:Protein Binding
D016859:Lipoxygenase Inhibitors; D010545:Peroxides; D016718:Arachidonic Acid; D054464:Peroxiredoxins; D008084:Lipoxygenase; D051546:Cyclooxygenase 2; D003545:Cysteine