Serial Review: Peroxiredoxins Serial Review Editor: Henry J. FormanPeroxiredoxin 6, a 1-Cys peroxiredoxin, functions in antioxidant defense and lung phospholipid metabolism☆
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Physiological electron donor for peroxidase activity
Prdx6, like other peroxiredoxins, functions as a peroxidase. However, as stated above, this enzyme, unlike other members of the Prdx family, does not utilize thioredoxin as the physiological reductant [9], [26] and the physiological electron donor for peroxidatic activity of Prdx6 has been controversial. The non-selenium GSH peroxidase isolated from the bovine ciliary body demonstrated peroxide reduction in the presence of GSH [5], [27]. Native protein isolated from the rat olfactory epithelium
Enzymatic activities of Prdx6
Prdx6 is a bifunctional protein with both GSH peroxidase and PLA2 activities and has been called a “moonlighting” protein [37]. The protein is composed of 224 amino acids with a molecular mass of 25.1 kDa. The structure of the protein shows the thioredoxin fold with a loop–helix region at the active site characteristic of the peroxiredoxin family [38]. GSH peroxidase activity has been measured using the GSH/GSH reductase assay coupled to NADPH reduction [26]. Fig. 2 shows that t-butyl
Structure–function relationships of Prdx6
Human recombinant Prdx6 has been crystallized as a homodimer formed by hydrophobic head-to-tail interaction of monomers [32]. To accomplish crystallization, the conserved catalytic Cys47 was oxidized to cysteine sulfenic acid by the addition of H2O2 and the nonconserved surface Cys91 was mutated to Ser [32]. The major structural feature of Prdx6 is a thioredoxin “fold,” which comprises ∼80 amino acids. The thioredoxin fold contains four central β strands and two α helices, which are essential
Species and tissue localization of Prdx6
The cDNA for Prdx6 has been identified for human (GenBank Accession No. D14662), rat (AF014009), mouse (AF004670), cow (AF090194), and pig (AJ243849) [7], [8], [10], [24], [25], [26], [30]. Comparisons of the cDNAs and deduced protein compositions of Prdx6 from these species have shown greater than 95% nucleotide and amino acid similarity [8], [44]. This high degree of conservation suggests an important role for Prdx6 in the metabolism of mammalian cells. Homologous 1-Cys peroxiredoxin proteins
Antioxidant function of Prdx6
An increasing number of studies have provided evidence that Prdx6 can function in vivo as an antioxidant enzyme. Initial experiments were carried out with isolated cells and more recently with intact animals. Overexpression of Prdx6 as a fusion construct with green fluorescent protein in H441 cells, a lung epithelial cell line that does not express Prdx6, protected against peroxide (H2O2, t-butyl hydroperoxide) or OH-mediated oxidative stress; overexpressing cells showed less lipid peroxidation
PLA2 function of Prdx6
The PLA2 activity of Prdx6 has not been studied as widely as the peroxidase activity and essentially all information related to the functional significance of this activity has been obtained from studies of lung surfactant phospholipids. Lung surfactant is a physiologically important secretion of the lung alveolar epithelium that functions to stabilize lung alveoli during respiration. DPPC is the major phospholipid component of surfactant and along with other lipids and specific proteins is
Summary
Prdx6 has both GSH peroxidase and PLA2 activities that play important physiological roles in antioxidant defense and lung surfactant metabolism. Although Prdx6 is a peroxiredoxin based on homology of structure, properties of the enzyme clearly differentiate Prdx6 from other mammalian members of this superfamily (Table 2). Prdx6 is a 1-Cys enzyme that has a different mechanism for enzymatic catalysis compared to other peroxiredoxins, which are 2-Cys enzymes; the latter form a disulfide either
Acknowledgments
This work was supported by HL19737 and HL65543.
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This article is part of a series of reviews on “Peroxiredoxins”. The full list of papers may be found on the home page of the journal.