Mitochondrial Peroxiredoxin 3 Is Rapidly Oxidized and Hyperoxidized by Fatty Acid Hydroperoxides
Human peroxiredoxin 3 (<i>Hs</i>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 hydrop...
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| Main Authors: | , , , , , , |
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| Format: | Book |
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MDPI AG,
2023-02-01T00:00:00Z.
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| Summary: | Human peroxiredoxin 3 (<i>Hs</i>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 (<sub>L</sub>FA-OOHs) which can be released to become free fatty acid hydroperoxides (<sub>f</sub>FA-OOHs). Herein, we report that <i>Hs</i>Prx3 is oxidized and hyperoxidized by <sub>f</sub>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<sup>7</sup> M<sup>−1</sup>s<sup>−1</sup>) and hyperoxidation (~2 × 10<sup>7</sup> M<sup>−1</sup>s<sup>−1</sup>). The endoperoxide-hydroperoxide PGG<sub>2</sub>, an intermediate in prostanoid synthesis, oxidized <i>Hs</i>Prx3 with a similar rate constant, but was less effective in causing hyperoxidation. Biophysical methodologies suggest that <i>Hs</i>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 <sub>f</sub>FA-OOHs in close proximity to the thiolate in the peroxidatic cysteine. Simulations performed using available and herein reported kinetic data indicate that <i>Hs</i>Prx3 should be considered a main target for mitochondrial <sub>f</sub>FA-OOHs. Finally, kinetic simulation analysis support that mitochondrial <sub>f</sub>FA-OOHs formation fluxes in the range of nM/s are expected to contribute to <i>Hs</i>Prx3 hyperoxidation, a modification that has been detected in vivo under physiological and pathological conditions. |
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| Item Description: | 10.3390/antiox12020408 2076-3921 |