Mitochondrial Peroxiredoxin 3 Is Rapidly Oxidized and Hyperoxidized by Fatty Acid Hydroperoxides.

Antioxidants (Basel, Switzerland)(2023)

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Abstract
Human peroxiredoxin 3 (Prx3) is a thiol-based peroxidase responsible for the reduction of most hydrogen peroxide and peroxynitrite formed in mitochondria. Mitochondrial disfunction can lead to membrane lipoperoxidation, resulting in the formation of lipid-bound fatty acid hydroperoxides (FA-OOHs) which can be released to become free fatty acid hydroperoxides (FA-OOHs). Herein, we report that Prx3 is oxidized and hyperoxidized by FA-OOHs including those derived from arachidonic acid and eicosapentaenoic acid peroxidation at position 15 with remarkably high rate constants of oxidation (>3.5 × 10 Ms) and hyperoxidation (~2 × 10 Ms). The endoperoxide-hydroperoxide PGG, an intermediate in prostanoid synthesis, oxidized Prx3 with a similar rate constant, but was less effective in causing hyperoxidation. Biophysical methodologies suggest that Prx3 can bind hydrophobic structures. Indeed, molecular dynamic simulations allowed the identification of a hydrophobic patch near the enzyme active site that can allocate the hydroperoxide group of FA-OOHs in close proximity to the thiolate in the peroxidatic cysteine. Simulations performed using available and herein reported kinetic data indicate that Prx3 should be considered a main target for mitochondrial FA-OOHs. Finally, kinetic simulation analysis support that mitochondrial FA-OOHs formation fluxes in the range of nM/s are expected to contribute to Prx3 hyperoxidation, a modification that has been detected in vivo under physiological and pathological conditions.
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Key words
antioxidant systems,fatty acid hydroperoxide,kinetics,lipid peroxidation,mitochondria,peroxiredoxin
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