Review
Protection against reactive oxygen species by selenoproteins

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Abstract

Reactive oxygen species (ROS) are derived from cellular oxygen metabolism and from exogenous sources. An excess of ROS results in oxidative stress and may eventually cause cell death. ROS levels within cells and in extracellular body fluids are controlled by concerted action of enzymatic and non-enzymatic antioxidants. The essential trace element selenium exerts its antioxidant function mainly in the form of selenocysteine residues as an integral constituent of ROS-detoxifying selenoenzymes such as glutathione peroxidases (GPx), thioredoxin reductases (TrxR) and possibly selenoprotein P (SeP). In particular, the dual role of selenoprotein P as selenium transporter and antioxidant enzyme is highlighted herein. A cytoprotective effect of selenium supplementation has been demonstrated for various cell types including neurons and astrocytes as well as endothelial cells. Maintenance of full GPx and TrxR activity by adequate dietary selenium supply has been proposed to be useful for the prevention of several cardiovascular and neurological disorders. On the other hand, selenium supplementation at supranutritional levels has been utilised for cancer prevention: antioxidant selenoenzymes as well as prooxidant effects of selenocompounds on tumor cells are thought to be involved in the anti-carcinogenic action of selenium.

Introduction

Reactive oxygen species (ROS) include free radicals such as the superoxide anion, hydroxyl and lipid radicals as well as oxidizing non-radical species such as hydrogen peroxide, peroxynitrite and singlet oxygen. ROS are continuously produced in the respiratory chain of mitochondria by one-electron reduction of molecular oxygen. NAD(P)H oxidases, xanthine oxidase, myeloperoxidase, cyclooxygenase and lipoxygenase are major enzymatic sources of ROS in mammalian cells, whereas UV irradiation represents an example for an environmental ROS-inducing factor. At higher concentrations, ROS can damage cellular macromolecules including DNA, proteins and lipids. Thus, cells possess antioxidative systems for detoxification of ROS and repair of deleterious oxidative modifications on cellular structures. Oxidative stress, resulting from an imbalance of oxidants and antioxidants in favor of the oxidants [1], may lead to subsequent cell death and is thought to be involved in the pathogenesis of diverse illnesses ranging from cardiovascular and neurological diseases to some forms of cancer [2]. On the other hand, low levels of ROS modulate signal transduction pathways, as it has been revealed for insulin-induced superoxide and hydrogen peroxide [3]. A number of hormones, growth factors and cytokines have been shown to elicit ROS production upon binding to their respective receptors. Based on the novel role of ROS as part of intracellular signaling cascades, the definition of oxidative stress has been refined recently as a “disruption of redox signaling and control” [4].

Among the dietary supplements, ingested by many individuals to improve their state of health, the essential micronutrient selenium has received attention for its antioxidant properties. Usually, humans take up selenium with their diet, predominantly from cereals, fish and meat. Selenium-enriched yeast and garlic are two natural products containing selenium mostly as highly bioavailable selenomethionine or gamma-glutamyl-Se-methylselenocysteine [5]. In addition, inorganic selenium compounds such as sodium selenite are available.

Most of the antioxidant capacity of selenium appears to rely on ROS-degrading selenoenzymes, containing selenocysteine in their catalytic center. In contrast to other metal ions, which are associated with their respective apoproteins as cofactors, selenium is co-translationally incorporated into selenoproteins as selenocysteine [6], the selenium analogue of cysteine. The selenoproteome of all species investigated so far is rather small. Based on computational sequence analyses, genes for 25 human selenoproteins have been identified [7]. Nevertheless, synthesis of selenoproteins is essential for mammals, as proven by occurrence of early embryonic lethality in mice lacking the selenocysteine-tRNASec gene [8]. The efficient catalysis of redox reactions by selenoenzymes is mainly based on two biochemical properties of selenocysteine: as the selenol group in selenocysteine (pKa  5.2) is more acidic than the thiol group in cysteine (pKa  8.5), it is deprotonated at physiological pH values and is more reactive in nucleophilic reactions [9]. In addition, selenocysteine is more readily oxidized than cysteine [10]. Apart from its function in the catalytic center of selenoenzymes, selenocysteine has the potential to repair oxidative damage by reducing tyrosyl radicals in proteins [11]. Intracellular concentrations of free selenocysteine are low, and it may exert this radical scavenger activity as constituent of selenoproteins.

Selenomethionine, the selenium analogue of methionine, can also act as ROS scavenger. Free selenomethionine is rapidly oxidized by peroxynitrite to methionine selenoxide [12], which can be reduced back to selenomethionine in a non-enzymatic reaction maintained by glutathione [13]. Recently, this reaction has been reported to occur in the same manner with selenomethionine residues in proteins [14], where selenomethionine can be incorporated non-specifically instead of methionine. Therefore, selenomethionine residues in proteins may provide a first line of defense against peroxynitrite and other oxidants.

Section snippets

ROS-detoxifying selenoenzymes

Enzymatic and non-enzymatic antioxidants are in charge for defense against ROS-mediated cytotoxicity. Among the most important intracellular antioxidant enzymes in humans are the superoxide dismutases (SOD), catalase and glutathione peroxidases (GPx). In 1973, cytosolic glutathione peroxidase (GPx-1) was the first mammalian enzyme realized to be a selenoprotein [15], [16]. Currently, five human selenocysteine-containing GPx isoenzymes are known, exhibiting tissue-specific expression and

Cardiovascular protection by selenium

Oxidative damage to the vascular endothelium is thought to be involved in initiation and progression of cardiovascular diseases such as hypertension, heart failure and atherosclerosis [61]. In situations of inflammation and infection, large amounts of ROS are produced in the vasculature, in particular by the enzyme family of NAD(P)H oxidases, generating superoxide. NAD(P)H oxidases are present in leukocytes as well as in endothelial and vascular smooth muscle cells, and they are activated by

Neuroprotection by selenium

The brain is more susceptible to oxidative stress than most other organs due to its high oxygen consumption. Other hallmarks of the brain are a high iron content in some areas such as the substantia nigra and the presence of large amounts of unsaturated fatty acids serving as substrates for lipid peroxidation [84], [85]. In particular, high quantities of hydrogen peroxide and organic hydroperoxides are continuously generated in the brain. A rapid clearance of hydrogen peroxide has been reported

Involvement of selenoproteins in cancer prevention by selenium

There is strong evidence to suggest a beneficial impact of selenium for prevention and therapy of several forms of cancer. A study with participants from 27 countries, which has already been undertaken in the 1970s, found an inverse correlation between dietary selenium intake and cancer mortality [107]. Many intervention trials with selenocompounds have been carried out since then, and the currently available data point to a tumor-protective capacity of selenium in humans, particularly

Final remarks

Dietary mineral and/or vitamin supplements are regularly taken by many individuals in Europe and in particular in the USA. Among the trace elements essential for human health, selenium stands out due to its narrow “therapeutic window” and due to its unique biochemistry relying on selenocysteine-containing selenoproteins. Beginning with the discovery of GPx-1 as the first mammalian selenoprotein in 1973 [15], [16], considerable progress has been made in recent decades elucidating structure,

Acknowledgements

This work was supported by Deutsche Forschungsgemeinschaft (DFG), Bonn, Germany (Sonderforschungsbereich 575/B4 and STE 1782/2-1). We are grateful to DFG for financial support of our research on selenoprotein P in the DFG priority program 1087 “Selenoproteine” from 2000 to 2007 (Si 255/11). H. Sies is a Fellow of the National Foundation for Cancer Research (NFCR), Bethesda, MD.

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