Peroxiredoxin as an Antioxidant and a Signaling Modulator

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(Last Updated On: October 21, 2017)
peroredoxin as an antioxidant

Peroxiredoxin can act as an antioxidant to balance the cellular peroxide level. Image: Perkins et al. 2015

peroredoxin as a modulator of the signaling

Peroxiredoxin can act as an antioxidant to balance the cellular peroxide level. Image: Perkins et al. 2015

Peroxiredoxin is a type of cysteine-dependent peroxidase enzymes that play an important role in the regulation of peroxide level in the cell. They are usually present in a higher amount to clear the peroxides rapidly. Though these enzymes vary in susceptibility and regulation by hyper oxidative inactivation and post-translational modification, a cysteine residue in the active site is always conserved which involves in the reaction catalysis.


It was initially over-shaded by well-known antioxidant enzymes catalase and glutathione peroxidase. However, a new study in kinetics measurement reveals that about 90% of the cellular peroxides are reduced by the peroxiredoxins.

It has also been shown that peroxiredoxin can be inactivated by its own substrate hydrogen peroxide enabling the peroxide-mediated cell signaling in the eukaryotes. However, the inactivation is irreversible and can be reactivated back to the active form by an enzyme called as sulfiredoxin.

Peroxiredoxin is a tumor suppressor protein and its expression level has been found to be high in various cancer tissues. The high level of the cellular peroxiredoxin provides resistance of the tumor cells towards the chemo and radiotherapies.

Peroxiredoxins are cysteine-based enzymes and do not require any cofactor. The thiolate group of the cysteine residue in the active site (Cys-SH) is oxidized to sulfenic acid (Cys-SOH) by hydroperoxides and later forms inter-disulfide bridge before being reduced back to the thiolate group by reductants. Because of its redox potential it is not only useful in balancing the cellular peroxide levels, but it can also be useful in redox sensing and signaling pathways to recover the oxidatively damaged proteins.

There are six subtypes of peroxiredoxins that vary in their subunits and interfaces as well as the location of the cysteine residue in the active site. During the catalysis, the thiolate sulfur of the cysteine residue in the active site attacks the HO-O- bond breaking the peroxide bond to form a sulfenic acid (Cys-SOH). That was also supported by the site-directed mutagenesis and hybrid quantum mechanical analysis.

Besides acting as an antioxidant to balance the cellular peroxide level, peroxiredoxin also acts as a signaling molecule in different cellular processes like platelet-derived growth factor signaling. In peroxiredoxin signaling process, H2O2 plays a critical role as a second messenger. H2O2 plays as a second messenger in some other processes too, like angiogenesis, a Toll-like receptor, cytokine receptors, etc. For all these purposes, H2O2 are produced by the NADPH oxidase catalyzed reactions.

NADPH oxidase catalyzes the formation of H2O2 promotes the phosphorylation of the tyrosine kinase domain of the growth factor receptors by inhibiting protein tyrosine phosphatases. Thus, Cys residue of the active site in the protein tyrosine phosphatases is the second target of the H2O2. The inactivation of protein tyrosine phosphatases by the H2O2 act as a brake for the kinase-mediated phosphorylation cascade. However, H2O2 production is highly localized within the cell otherwise it would oxidize many proteins and lipids.

In non-stress related signaling like a circadian synthesis of the corticosteroids in the mitochondria of the adrenal cortex, H2O2 is produced locally by the cytochrome P450 and leads to the activation of P38 and negative feedback inhibition of the steroidogenesis. Another example of the non-stress related signaling mediated by H2O2 involves in the regulation of Src Kinase driven phosphorylation of the Tyr-194 in the peroxiredoxin by the growth factors.

In stress-related signaling like in case of the yeast, when yeast is exposed to very high level of the peroxides, hyper oxidative inactivation of the Tpx1 acts as a priority event conserving the cellular antioxidants to repair the damaged proteins and hyperoxidized peroxiredoxins produced during the peroxide stress or heat shock in budding yeast acts as a chaperone to help restore the proper folding and function of other proteins.

Therefore, peroxidase-dependent and independent secondary functions of the peroxiredoxins play important roles in the growth and survival.

Reference: Trends in Biochemical Sciences

Article doi: 10.1016/j.tibs.2015.05.001

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