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 indicated by their relative abundance. Their function is the reduction of peroxides, specifically hydrogen peroxide, alkyl hydroperoxides, and peroxynitrite.

Classification

Prxs were historically divided into three classes: typical 2-Cys Prxs, atypical 2-Cys Prxs, and 1-Cys Prxs. 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.
Family members are now recognized to fall into six classes or subgroups by sequence/structure similarity, designated as AhpC/Prx1, Prx5, Prx6, PrxQ/BCP, 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 .

Peroxiredoxin-like

Mammals also have so-called "peroxiredoxin-like" genes. In humans there are three with the symbols PRXL2A, PRXL2B, PRXL2C. These are actually selenium-free orthologs of selenoprotein U, where the selenocysteine found in the version in fishes and birds is replaced with cysteine. The replacement happens to result in a CxxC pattern similar to peroxiredoxin.

Catalytic cycle

The active sites of the peroxiredoxins feature a redox-active cysteine residue, which undergoes oxidization 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, whereas 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. These enzymes are inactivated by over-oxidation of the active thiol to the sulfinic acid. This damage 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:.
  • 1-Cys enzymes: PRDX6
  • 2-Cys enzymes: PRDX1, PRDX2, PRDX3, PRDX4, and PRDX5

    Enzyme regulation

Peroxiredoxins can be regulated by phosphorylation, redox status such as sulfonation, acetylation, nitration, truncation and oligomerization states.

Function

Peroxiredoxin is reduced by thioredoxin after reducing hydrogen peroxide in the following reactions:
  • Prx + H2O2 → Prx + 2H2O
  • Prx + Trx → Prx + Trx
in chemical terms, these reactions can be represented:
  • RSH + H2O2 → RSOH + 2H2O
  • RSOH + R'SH → RSSR'
  • RSSR' + 2 R"SH → RSH + R'SH + R"SSR"
The oxidized form of Prx is inactive in its reductase activity, but can function as a molecular chaperone, 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.