Peroxiredoxin


Peroxiredoxins are a ubiquitous family of antioxidant enzymes that also control cytokine-induced peroxide levels and thereby mediate signal transduction in mammalian cells. The family members in humans are PRDX1, PRDX2, PRDX3, PRDX4, PRDX5, and PRDX6. The physiological importance of peroxiredoxins is illustrated by their relative abundance.

Classification

Prxs were historically divided into three classes:
The designation of "1-Cys" and "2-Cys" Prxs was introduced in 1994 as it was noticed that, among the 22 Prx sequences known at the time, only one Cys residue was absolutely conserved; this is the residue now recognized as the peroxidatic cysteine, CP. The second, semi-conserved cysteine noted at the time is the resolving cysteine, CR, which forms an intersubunit disulfide bond with CP in the widespread and abundant Prxs sometimes referred to as the "typical 2-Cys Prxs". Ultimately it was realized that the CR can reside in multiple positions in various Prx family members, leading to the addition of the "atypical 2-Cys Prx" category.
With the large amount of information currently available regarding Prx structures and sequences, family members are now recognized to fall into six classes or subgroups, designated as Prx1, Prx5, Prx6, PrxQ, Tpx and AhpE groups. It is now recognized that the existence and location of CR across all 6 groups is heterogeneous. Thus, even though the "1-Cys Prx" designation was originally associated with the Prx6 group based on the lack of a CR in human PrxVI, and many Prx6 group members appear not to have a CR, there are "1-Cys" members in all of the subgroups. Moreover, the CR can be located in 5 locations in the structure, yielding either an intersubunit or intrasubunit disulfide bond in the oxidized protein. To assist with identification of new members and the subgroup to which they belong, a searchable database including Prx sequences identified from GenBank was generated by bioinformatics analysis and is publicly .

Catalytic cycle

These enzymes share the same basic catalytic mechanism, in which a redox-active cysteine in the active site is oxidized to a sulfenic acid by the peroxide substrate. The recycling of the sulfenic acid back to a thiol is what distinguishes the three enzyme classes. 2-Cys peroxiredoxins are reduced by thiols such as thioredoxins, thioredoxin-like proteins, or possibly glutathione, while the 1-Cys enzymes may be reduced by ascorbic acid or glutathione in the presence of GST-π. Using high resolution crystal structures, a detailed catalytic cycle has been derived for Prxs, including a model for the redox-regulated oligomeric state proposed to control enzyme activity. Inactivation of these enzymes by over-oxidation of the active thiol to sulfinic acid can be reversed by sulfiredoxin.
Peroxiredoxins are frequently referred to as alkyl hydroperoxide reductase in bacteria. Other names include thiol specific antioxidant and thioredoxin peroxidase.
Mammals express six peroxiredoxins:
Peroxiredoxins can be regulated by phosphorylation, redox status such as sulfonation, acetylation, nitration, truncation and oligomerization states.

Function

Peroxiredoxin uses thioredoxin to recharge after reducing hydrogen peroxide in the following reactions:
The oxidized form of Prx is inactive in its reductase activity, but can function as a molecular chaperon, requiring the donation of electrons from reduced Trx to restore its catalytic activity.
The physiological importance of peroxiredoxins is illustrated by their relative abundance as well as studies in knockout mice. Mice lacking peroxiredoxin 1 or 2 develop severe haemolytic anemia, and are predisposed to certain haematopoietic cancers. Peroxiredoxin 1 knockout mice have a 15% reduction in lifespan. Peroxiredoxin 6 knockout mice are viable and do not display obvious gross pathology, but are more sensitive to certain exogenous sources of oxidative stress, such as hyperoxia. Peroxiredoxin 3 knockout mice are viable and do not display obvious gross pathology. Peroxiredoxins are proposed to play a role in cell signaling by regulating H2O2 levels.
Plant 2-Cys peroxiredoxins are post-translationally targeted to chloroplasts, where they protect the photosynthetic membrane against photooxidative damage. Nuclear gene expression depends on chloroplast-to-nucleus signalling and responds to photosynthetic signals, such as the acceptor availability at photosystem II and ABA.

Circadian clock

Peroxiredoxins have been implicated in the 24-hour internal circadian clock of many organisms.