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Free Radic Biol Med. 2019 Jul 16;141:492-501. doi: 10.1016/j.freeradbiomed.2019.07.016. [Epub ahead of print]

Unraveling the effects of peroxiredoxin 2 nitration; role of C-terminal tyrosine 193.

Author information

1
Laboratorio I+D de Moléculas Bioactivas, CENUR Litoral Norte, Universidad de la República, Paysandú, Uruguay; Laboratorio de Fisicoquímica Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay; Centro de Investigaciones Biomédicas, Universidad de la República, Uruguay.
2
Laboratorio de Fisicoquímica Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay; Centro de Investigaciones Biomédicas, Universidad de la República, Uruguay.
3
Department of Biochemistry and Center for Redox Biology and Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
4
Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina; Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), Buenos Aires, Argentina.
5
Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR, USA.
6
Department of Biochemistry and Center for Redox Biology and Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA. Electronic address: lbp@csb.wfu.edu.
7
Laboratorio de Fisicoquímica Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay; Centro de Investigaciones Biomédicas, Universidad de la República, Uruguay. Electronic address: denicola@fcien.edu.uy.

Abstract

Peroxiredoxins (Prx) are enzymes that efficiently reduce hydroperoxides through active participation of cysteine residues (CP, CR). The first step in catalysis, the reduction of peroxide substrate, is fast, 107 - 108 M-1s-1 for human Prx2. In addition, the high intracellular concentration of Prx positions them not only as good antioxidants but also as central players in redox signaling pathways. These biological functions can be affected by post-translational modifications that could alter the peroxidase activity and/or interaction with other proteins. In particular, inactivation by hyperoxidation of CP, which occurs when a second molecule of peroxide reacts with the CP in the sulfenic acid form, modulates their participation in redox signaling pathways. The higher sensitivity to hyperoxidation of some Prx has been related to the presence of structural motifs that disfavor disulfide formation at the active site, making the CP sulfenic acid more available for hyperoxidation or interaction with a redox protein target. We previously reported that treatment of human Prx2 with peroxynitrite results in tyrosine nitration, a post-translational modification on non-catalytic residues, yielding a more active peroxidase with higher resistance to hyperoxidation. In this work, studies on various mutants of hPrx2 confirm that the presence of the tyrosyl side-chain of Y193, belonging to the C-terminal YF motif of eukaryotic Prx, is necessary to observe the increase in Prx2 resistance to hyperoxidation. Moreover, our results underline the critical role of this structural motif on the rate of disulfide formation that determines the differential participation of Prx in redox signaling pathways.

KEYWORDS:

Hydrogen peroxide; Hyperoxidation; Oxidative stress; Peroxiredoxin; Peroxynitrite; Post‐translational modification (PTM); Redox signaling; Tyrosine nitration

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