ForumsTissue-specific functions of individual glutathione peroxidases
Introduction
About 30 mammalian selenoproteins have been detected as bands in gels after pulse labeling of rats with 75Se [1]. About a dozen mammalian selenoproteins have been characterized in terms of sequence and function. Four of these are glutathione peroxidases (see below). Further, three 5′-deiodinases [2], [3], [4], selenoprotein P [5], [6], selenoprotein W [7], at least one thioredoxin reductase [8], and selenophosphate synthetase-2 [9] have been identified as selenoproteins. Most of the selenoproteins display an unusual tissue distribution suggesting functions distinct from common metabolic pathways. This holds not only true for three of the glutathione peroxidases: type I 5′deiodinase is expressed in the thyroid, liver, kidney, and pituitary gland; type II in the thyroid, placenta, pituitary gland, central nervous system, and in the brown fat tissue of rodents; type III in skin, placenta and central nervous system [10]. Selenoprotein P is found in plasma where it binds up to 70% of the plasma selenium in humans. It is also expressed in Leydig cells of testis and in cerebellum [6]. Selenoprotein W is a muscle protein [7]. Only for thioredoxin reductase and the selenophosphate synthetase-2 no preferential expression has been shown so far.
The classical or cytosolic glutathione peroxidase (cGPx) [11] was the first mammalian selenoprotein to be identified [12], [13]. The phospholipid hydroperoxide glutathione peroxidase (PHGPx) was first described in 1982 [14] and later verified as selenoprotein by sequencing [15], [16], as was plasma GPx (pGPx) [17] and the gastrointestinal form (GI-GPx) [18]. All glutathione peroxidases reduce hydrogen peroxide and alkyl hydroperoxides at the expense of glutathione. Their specificities for the hydroperoxide substrate, however, differ markedly. Whereas cGPx reduces only soluble hydroperoxides, such as H2O2, and some organic hydroperoxides, like hydroperoxy fatty acids, cumene hydroperoxide or t-butyl hydroperoxide [19], PHGPx [20] and to some extent pGPx [21] also reduce hydroperoxides of more complex lipids like phosphatidylcholine hydroperoxide. PHGPx, however, efficiently reduces hydroperoxo groups of thymine [22], lipoproteins [23], and cholesterol esters [24] and is unique in acting on hydroperoxides integrated in membranes [25]. The GI-GPx appears to have a specificity similar to that of cGPx [18], although it has not yet been systematically analyzed in this respect. All glutathione peroxidases utilize glutathione as thiol substrate which does not imply that GSH has to be considered the physiologic substrate of all glutathione peroxidases under all circumstances. For instance, pGPx has been shown also to use thioredoxin as reductant [26]. Although cGPx, pGPx, and GI-GPx are homotetramers, the PHGPx is a monomer with a molecular size smaller than the subunits of the other glutathione peroxidases [16]. The small size and its hydrophobic surface has been implicated in its ability to react with complex lipids in membranes.
Nature’s need for so many glutathione peroxidases is not clear. Did the evolutionary pressure to cope with aerobic life result in redundant selenoperoxidases on top of backup systems like thioredoxin-fueled peroxiredoxins [27] to make sure that not a single one of the deleterious hydroperoxides can reach its targets? Not very likely so. Over the last years the image of hydroperoxides has changed from mere toxic compounds into molecules involved in cellular signaling, e.g., in TNF [28] or IL-1 [29] mediated activation of NF-κB. Hydroperoxides have further been shown to trigger programmed cell death [30], [31] and to play a role in the proliferation [32] and differentiation [33] of cells. They also contribute to maturation of red blood cells [34], [35]. Thus, it may not be advantageous to remove hydroperoxides wherever they appear. It may rather turn out that the maintenance of a certain peroxide tone is necessary for an adequate function of cells. The regulation of the delicate regional redox balance might therefore be one of the more important functions of peroxidases and of glutathione peroxidases in particular.
Interestingly, the individual glutathione peroxidases are not equally distributed. They display surprising preferences for certain organs and tissues. The aim of this article is to compile the knowledge on glutathione peroxidases with particular emphasis on tissue-specific expression and related functions. For general enzymology, catalytic mechanism, structural comparison and regulation of expression of glutathione peroxidases the reader is referred to recent reviews [36], [37], [38].
Section snippets
Ranking order of glutathione peroxidases
Biosynthesis of selenoproteins, of course, depends on the availability of selenium. Selenium is incorporated as selenocysteine into the growing polypeptide chain. Unexpectedly, selenium is evenly used for the biosynthesis of the selenoproteins only at optimum selenium supply. At limiting concentrations, however, selenium is preferentially channeled into some of the selenoproteins, whereas others are less well supplied. In consequence, some selenoproteins respond fast to selenium deficiency with
Distribution
pGPx was first detected in blood plasma and found to be different from cGPx [17]. It was subsequently purified and cloned from human [52] and mouse [53] placenta, from where it is released into the maternal circulation [54]. Because the plasma GSH concentration of about 30μM is not able to maintain a GPx turnover at reasonable rates and for longer than a few catalytic cycles [55], the role of an extracellular GPx was not easily understood. This was probably the reason why pGPx was not studied
Conclusion and outlook
Four decades after the discovery of cGPx and 25 years after its characterization as a selenoprotein, the field of glutathione-mediated and selenium-catalyzed peroxide metabolism remains fascinating. Only one aspect of the field so far could be established as originally proposed: the role of cGPx as an emergency device to counteract oxidative stress. However, the bewildering multiplicity of glutathione peroxidases that is further complicated by structurally related or unrelated nonselenium
Acknowledgements
The work was supported by the Deutsche Forschungsgemeinschaft, DFG (INK 26/A1-1,TP3) and the European Community (Biomed II program, PL 963202). Thanks go to “Mr. glutathione peroxidase,” Leopold Flohé, for critically reading the manuscript and stimulating discussions.
References (165)
- et al.
Identification of type I iodothyronine 5′-deiodinase as a selenoenzyme
Biochem. Biophys. Res. Commun.
(1990) - et al.
Cloning of a cDNA for the type II iodothyroine deiodinase
J. Biol. Chem.
(1995) - et al.
Cloning and expression of a cDNA for a mammalian type III iodothyronine deiodinase
J. Biol. Chem.
(1995) - et al.
Selenoprotein P. A selenium-rich extracellular glycoprotein
J. Nutr.
(1994) - et al.
Glutathione peroxidasea selenoenzyme
FEBS Lett.
(1973) - et al.
Purification from pig liver of a protein which protects liposomes and biomembranes from peroxidative degradation and exhibits glutathione peroxidase activity on phosphatidylcholine hydroperoxides
Biochim. Biophys. Acta
(1982) - et al.
Phospholipid-hydroperoxide glutathione peroxidase. Genomic DNA, cDNA, and deduced amino acid sequence
J. Biol. Chem.
(1994) - et al.
Purification and characterization of human plasma glutathione peroxidasea selenoglycoprotein distinct from the known cellular enzyme
Arch. Biochem. Biophys.
(1987) - et al.
Expression, characterization, and tissue distribution of a new cellular selenium-dependent glutathione peroxidase, GSH-Px-GI
J. Biol. Chem.
(1993) - et al.
Rat liver cytosolic glutathione peroxidasereactivity with linoleic acid hydroperoxide and cumene hydroperoxide
Arch. Biochem. Biophys.
(1979)
The selenoenzyme phospholipid hydroperoxide glutathione peroxidase
Biochim. Biophys. Acta
Glutathione peroxidase isolated from plasma reduces phospholipid hydroperoxides
Arch. Biochem. Biophys.
Reduction of thymine hydroperoxide by phospholipid hydroperoxide glutathione peroxidase and glutathione transferases
FEBS Lett.
Reduction of HDL- and LDL-associated cholesterylester and phospholipid hydroperoxides by phospholipid hydroperoxide glutathione peroxidase and ebselen (PZ51)
Arch. Biochem. Biophys.
Protective action of phospholipid hydroperoxide glutathione peroxidase against membrane-damaging lipid peroxidation
J. Biol. Chem.
The role of selenium peroxidases in the protection against oxidative damage of membranes
Chem. Phys. Lipids
The thioredoxin and glutaredoxin systems are efficient electron donors to human plasma glutathione peroxidase
J. Biol. Chem.
Lipid hydroperoxides induce apoptosis in T cells displaying a HIV-associated glutathione peroxidase deficiency
J. Biol. Chem.
Different prooxidant levels stimulate growth, trigger apoptosis, or produce necrosis of insulin-secreting RINm5F cells. The role of intracellular polyamines
J. Biol. Chem.
Occurrence of lipoxygenase products in membranes of rabbit reticulocytes
J. Biol. Chem.
Phospholipid hydroperoxide glutathione peroxidase activity in various mouse organs during selenium deficiency and repletion
Biochim. Biophys. Acta
Dietary selenium stabilizes glutathione peroxidase mRNA in rat liver
J. Nutr.
Selective control of cytosolic glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase mRNA stability by selenium supply
FEBS Lett.
Effect of selenium deficiency on cellular and extracellular glutathione peroxidasesimmunochemical detection on mRNA analysis in rat kidney and serum
Free Radic. Biol. Med.
Effect of selenium status on mRNA levels for glutathione peroxidase in rat liver
Biochem. Biophys. Res. Comm.
Glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase are differentially egulated in rats by dietary selenium
J. Nutr.
Tissue specificity of selenoprotein gene expression in rats
J. Nutr. Biochem.
Expression of plasma glutathione peroxidase in human liver in addition to kidney, heart, lung, and breast in humans and rodents
Blood
Partial sequence of human plasma glutathione peroxidase and immunologic identification of milk glutathione peroxidase as the plasma enzyme
J. Nutr.
Tissue-specific expression of glutathione peroxidase gene in guinea pigs
Biochim. Biophys. Acta
Oxidative stress as a mediator of apoptosis
Immunol. Today
HIV-induced cysteine deficiency and T-cell disfunction—a rationale for treatment with N-acetylcysteine
Immunol. Today
Selenium deficiency in HIV infection and the acquired immunodeficiency syndrome (AIDS)
Chem. Biol. Interact.
Antioxidant defenses influence HIV-1 replication and associated cytopathic effects
Free Radic. Biol. Med.
Lipid hydroperoxide induced apoptosislack of inhibition by bcl-2 over-expression
FEBS Lett.
Mice with a homozygous null mutation for the most abundant glutathione peroxidase, Gpx1, show increased susceptibility to the oxidative stress-inducing agents paraquat and hydrogen peroxide
J. Biol. Chem.
Cellular glutathione peroxidase is the mediator of body selenium to protect against paraquat lethality in transgenic mice
J. Nutr.
Variation in cellular glutathione peroxidase activity in lens epithelial cells, transgenics and knockouts does not significantly change the response to H2O2 stress
Exp. Eye Res.
Newly found selenium-containing proteins in the tissues of the rat
Biol. Trace Elem. Res.
Analysis of the mouse selenoprotein P gene
Biol. Chem.
Rat skeletal muscle selenoprotein WcDNA clone and mRNA modulation by dietary selenium
Proc. Natl. Acad. Sci. USA
A new selenoprotein from human lung adenocarcinoma cellspurification, properties, and thioredoxin reductase activity
Proc. Natl. Acad. Sci. USA
Identification of a novel selD homolog from eukaryotes, bacteria, and archea; is there an autoregulatory mechanism in selenocysteine metabolism?
Proc. Natl. Acad. Sci. USA
Local activation and inactivation of thyroid hormons
Mol. Cell. Endocrin.
SeleniumBiochemical role as a component of glutathione peroxidase
Science
Phospholipid hydroperoxide glutathione peroxidase is a selenoenzyme distinct from the classical glutathione peroxidase as evident from cDNA and amino acid sequencing
Free Radic. Comms.
A family of novel peroxidases, peroxiredoxins
Biofactors
Inibition of IκB-a phosphorylation and degradation and subsequent NF-κB activation by glutathione peroxidase overexpression
J. Cell Biol.
Interleukin-1-induced nuclear factor kappaB activation is inhibited by overexpression of phospholipid hydroperoxide glutathione peroxidase in a human endothelial cell line
Biochem. J.
Cited by (0)
- 1
Regina Brigelius-Flohé was trained in biochemistry at the University of Tübingen from 1968 to 1974. While there, she started to study the toxicity as well as the physiology of oxidative stress, a topic she has never completely left during her scientific life. After completing her doctorate, she worked with Dr. Sies in Münich and Düsseldorf measuring glutathione mixed disulfides, then she was hidden in the industry for 7 years where she learned molecular biology and how to produce tons of heterologous proteins with bacteria. Dr. Brigelius-Flohé is now a professor at the University of Potsdam and is head of the Department of Vitamins and Artherosclerosis at the German Institute of Human Nutrition. Her present work concentrates on vitamin E metabolism and the role of glutathione peroxidases and hydroperoxides in the redox regulation of cytokine signaling and processes relevant for atherogenesis.