Peroxiredoxin 6: a bifunctional enzyme with glutathione peroxidase and phospholipase A₂ activities.
TL;DR: Peroxiredoxin 6 (Prdx6) is the prototype and the only mammalian 1-Cys member of the Prdx family and has important roles in both antioxidant defense and homeostasis based on its ability to generate lysophospholipid substrate for the remodeling pathway of phospholipids synthesis.
Abstract: Peroxiredoxin 6 (Prdx6) is the prototype and the only mammalian 1-Cys member of the Prdx family. Major differences from 2-Cys Prdxs include the use of glutathione (GSH) instead of thioredoxin as the physiological reductant, heterodimerization with πGSH S-transferase as part of the catalytic cycle, and the ability either to reduce the oxidized sn-2 fatty acyl group of phospholipids (peroxidase activity) or to hydrolyze the sn-2 ester (alkyl) bond of phospholipids (phospholipase A(2) [PLA(2)] activity). The bifunctional protein has separate active sites for peroxidase (C47, R132, H39) and PLA(2) (S32, D140, H26) activities. These activities are dependent on binding of the protein to phospholipids at acidic pH and to oxidized phospholipids at cytosolic pH. Prdx6 can be phosphorylated by MAP kinases at T177, which markedly increases its PLA(2) activity and broadens its pH-activity spectrum. Prdx6 is primarily cytosolic but also is targeted to acidic organelles (lysosomes, lamellar bodies) by a specific targeting sequence (amino acids 31-40). Oxidant stress and keratinocyte growth factor are potent regulators of Prdx6 gene expression. Prdx6 has important roles in both antioxidant defense based on its ability to reduce peroxidized membrane phospholipids and in phospholipid homeostasis based on its ability to generate lysophospholipid substrate for the remodeling pathway of phospholipid synthesis.
Citations
More filters
TL;DR: The role of GPx-1 in cancer and cardiovascular disease is discussed and potential future therapies to harness the beneficial effects of this ubiquitous antioxidant enzyme are speculates.
Abstract: Reactive oxygen species, such as superoxide and hydrogen peroxide, are generated in all cells by mitochondrial and enzymatic sources. Left unchecked, these reactive species can cause oxidative damage to DNA, proteins, and membrane lipids. Glutathione peroxidase-1 (GPx-1) is an intracellular antioxidant enzyme that enzymatically reduces hydrogen peroxide to water to limit its harmful effects. Certain reactive oxygen species, such as hydrogen peroxide, are also essential for growth factor-mediated signal transduction, mitochondrial function, and maintenance of normal thiol redox-balance. Thus, by limiting hydrogen peroxide accumulation, GPx-1 also modulates these processes. This review explores the molecular mechanisms involved in regulating the expression and function of GPx-1, with an emphasis on the role of GPx-1 in modulating cellular oxidant stress and redox-mediated responses. As a selenocysteine-containing enzyme, GPx-1 expression is subject to unique forms of regulation involving the trace ...
851 citations
Cites background from "Peroxiredoxin 6: a bifunctional enz..."
...Recent findings suggest that peroxiredoxin 6 may also reduce phospholipid targets in cells (123)....
[...]
TL;DR: This article looks back to the antioxidant/free radical field in 1994 and discusses how it has progressed in the past 18 years and suggests that increasing endogenous antioxidant levels (e.g., by supplying "pro-oxidants") may be a better approach to therapeutics and disease prevention than consuming large doses of "dietary antioxidants."
Abstract: This article looks back to the antioxidant/free radical field in 1994 and discusses how it has progressed in the past 18 years. In some areas, there has been little change: the role of oxygen radicals and other reactive oxygen species (ROS) in the origin or progression of most human diseases remains uncertain, with cancer and neurodegenerative disease being likely exceptions. Even in diseases in which ROS are involved there has been little progress in developing effective antioxidant treatments. Mega-doses of dietary antioxidants have also generally failed to prevent human disease, in part because they do not decrease oxidative damage in vivo (as revealed by robust biomarkers). However, some strategies that are known to delay disease onset may act, at least in part, by decreasing oxidative damage levels. Nevertheless, far more is known today about endogenous antioxidant defenses and how they are regulated, which has led to a deeper understanding of how some ROS can act as signaling molecules. Increasing endogenous antioxidant levels (e.g., by supplying “pro-oxidants”) may be a better approach to therapeutics and disease prevention than consuming large doses of “dietary antioxidants.”
721 citations
TL;DR: This review summarizes the almost 50 years of research on these proteins, focusing primarily on data from vertebrates and mammals, that is, their potential impact and functions in different cell types, tissues, and various pathological conditions.
Abstract: Thioredoxins (Trxs), glutaredoxins (Grxs), and peroxiredoxins (Prxs) have been characterized as electron donors, guards of the intracellular redox state, and “antioxidants”. Today, these redox catalysts are increasingly recognized for their specific role in redox signaling. The number of publications published on the functions of these proteins continues to increase exponentially. The field is experiencing an exciting transformation, from looking at a general redox homeostasis and the pathological oxidative stress model to realizing redox changes as a part of localized, rapid, specific, and reversible redox-regulated signaling events. This review summarizes the almost 50 years of research on these proteins, focusing primarily on data from vertebrates and mammals. The role of Trx fold proteins in redox signaling is discussed by looking at reaction mechanisms, reversible oxidative post-translational modifications of proteins, and characterized interaction partners. On the basis of this analysis, th...
572 citations
TL;DR: Peroxiredoxins contain an active site cysteine that is sensitive to oxidation by H2O2, and Regulation of Prx via phosphorylation in response to extracellular signals allows the local accumulation of H2 O2 and thereby enables its messenger function.
471 citations
TL;DR: This review examines the regulation of cellular ROS, their modes of production and removal, and the redox-sensitive targets that are modified by their flux and the role of mitochondria in modulating these pathways.
Abstract: Redox-dependent processes influence most cellular functions, such as differentiation, proliferation, and apoptosis. Mitochondria are at the center of these processes, as mitochondria both generate reactive oxygen species (ROS) that drive redox-sensitive events and respond to ROS-mediated changes in the cellular redox state. In this review, we examine the regulation of cellular ROS, their modes of production and removal, and the redox-sensitive targets that are modified by their flux. In particular, we focus on the actions of redox-sensitive targets that alter mitochondrial function and the role of these redox modifications on metabolism, mitochondrial biogenesis, receptor-mediated signaling, and apoptotic pathways. We also consider the role of mitochondria in modulating these pathways, and discuss how redox-dependent events may contribute to pathobiology by altering mitochondrial function. Antioxid. Redox Signal. 16, 1323–1367.
443 citations
References
More filters
TL;DR: Future investigations are expected to reveal that a balance between positive and negative factors regulates ARE-mediated gene expression and induction, and a complete mechanism of signal transduction from antioxidants and xenobiotics to the transcription factors, such as Nrf2, that bind to ARE.
1,163 citations
TL;DR: Comparing the efficiency of three different antioxidant enzymes: Cu/Zn-superoxide dismutase, catalase, and selenium-glutathione peroxidase shows that all three antioxidant enzymes give protection for the cells, and emphasizes the fact that each enzyme has a specific as well as an irreplaceable function.
1,156 citations
TL;DR: The rat and yeast TSA proteins show significant sequence homology to the 21-kDa component (AhpC) of Salmonella typhimurium alkyl hydroperoxide reductase, and it is found that AhpC exhibits TSA activity.
Abstract: A cDNA corresponding to a thiol-specific antioxidant enzyme (TSA) was isolated from a rat brain cDNA library with the use of antibodies to bovine TSA. The cDNA clone encoded an open reading frame capable of encoding a 198-residue polypeptide. The rat and yeast TSA proteins show significant sequence homology to the 21-kDa component (AhpC) of Salmonella typhimurium alkyl hydroperoxide reductase, and we have found that AhpC exhibits TSA activity. AhpC and TSA define a family of > 25 different proteins present in organisms from all kingdoms. The similarity among the family members extends over the entire sequence and ranges between 23% and 98% identity. A majority of the members of the AhpC/TSA family contain two conserved cysteines. At least eight of the genes encoding AhpC/TSA-like polypeptides are found in proximity to genes encoding other oxidoreductase activities, and the expression of several of the homologs has been correlated with pathogenicity. We suggest that the AhpC/TSA family represents a widely distributed class of antioxidant enzymes. We also report that a second family of proteins, defined by the 57-kDa component (AhpF) of alkyl hydroperoxide reductase and by thioredoxin reductase, has expanded to include six additional members.
728 citations
658 citations
TL;DR: In this series of projects regarding the accumulation of sequence information of unidentified human genes, the sequences of 40 full-length cDNA clones of human cell line KG-1 are newly deduced, and the coding sequences of the corresponding genes are predicted.
Abstract: In this series of projects regarding the accumulation of sequence information of unidentified human genes, we newly deduced the sequences of 40 full-length cDNA clones of human cell line KG-1, and predicted the coding sequences of the corresponding genes, named KIAA0121 to 0160. The results of a computer search of public databases indicated that the sequences of 13 genes were unrelated to any reported genes, while the remaining 27 genes carried sequences which showed some similarities to known genes. Obvious unique sequences noted were as follows. A stretch of triplet repeats was contained in each of three genes: These were GAG(Glu) in KIAA0122 and KIAA0147, and TCC(Ser) in KIAA0150. A stretch of 10 amino acid-residues was repeated 21 times in KIAA0139, and a homologous sequence of 76-78 nucleotides was found repeated 6 times in the untranslated region of KIAA0125. Northern hybridization analysis demonstrated that 13 genes were expressed in a cell- or tissue-specific manner. Although a vast number of expressed sequence tags (ESTs) have been registered for comprehensive analysis of cDNA clones, our sequence data indicated that their distribution is very unbalanced: e.g. while no EST hit 7 genes, 85 ESTs fell in a single gene.
561 citations