Superoxide production by dinitrophenyl-derivatized thioredoxin reductase--a model for the mechanism and correlation to immunostimulation by dinitrohalobenzenes.
Mammalian thioredoxin reductase catalyzes NADPH dependent reduction of a wide variety of substrates and plays a central role in redox regulation and antioxidant defence. Recently the enzyme was discovered to be a selenoprotein with a catalytically active penultimate selenocysteine residue. Dinitrohalobenzenes irreversibly inhibit the enzyme with a concomitant induction of an NADPH oxidase activity, producing superoxide. A model explaining the reactivity of dinitrohalobenzenes with thioredoxin reductase is presented, involving dinitrophenyl-derivatization of both the selenocysteine residue and its neighboring cysteine residue, reduction by NADPH of the enzyme-bound flavin in dinitrophenyl-alkylated enzyme (dnp-TrxR), followed by two consecutive one-electron transfers from the flavin to nitro groups of the dnp-moieties in dnp-TrxR, forming nitro anion radicals. The nitro radicals react with oxygen to form superoxide, again generating dnp-TrxR with an oxidized flavin, which may then follow another cycle of NADPH-dependent superoxide production. Dinitrohalobenzene compounds are well known for their immunostimulatory properties. Here it is proposed that the inflammatory components of this immunostimulation can be mediated by interaction with the thioredoxin system, via effects on cell function by superoxide production, oxidative stress and increased extracellular levels of thioredoxin.
Arnér
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ES
Medical Nobel Institute for Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska institute, Stockholm, Sweden. Elias.Arner@mbb.ki.se
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D001555:Benzene Derivatives / Q000494:pharmacology*; D004140:Dinitrophenols / Q000494:pharmacology*; D008322:Mammals; D008956:Models, Chemical; D019255:NADPH Oxidases / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism*; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D001555:Benzene Derivatives; D004140:Dinitrophenols; D009578:Nitrobenzenes; D013481:Superoxides; D019255:NADPH Oxidases; D013880:Thioredoxin-Disulfide Reductase