BBA - General Subjects (v.1790, #11)
Editorial Board (i).
Special issue on selenoprotein expression and function by Christopher Horst Lillig; Elias Arnér (1387-1388).
The labour pains of biochemical selenology: The history of selenoprotein biosynthesis by Leopold Flohé (1389-1403).
The serendipitous discoveries leading to the present knowledge on selenium's role in biology are reviewed. Detected in 1818 as by-product of sulphuric acid production, selenium first attracted medical attention as an industrial hazard. In parallel selenium intoxication was recognized as cause of life stock diseases. Reports on teratogenic effects and carcinogenicity of selenium followed since the middle of the past century. In 1954 first hints towards specific biological functions of selenium were contributed from microbiology, and its essentiality for mammalian life was discovered in 1957. Independent and unrelated studies led to the identification of selenium as an integral constituent of one mammalian and two bacterial enzymes in the early 70ies followed by the identification of selenocysteine in these proteins. In the 80ies, independent sequencing of selenoproteins and cloned DNAs revealed that the selenocysteine of selenoproteins is encoded by the termination codon TGA (UGA). Recoding of TGA as selenocysteine codon by secondary mRNA structures was first elucidated by molecular genetics in bacteria and later in mammals. During the 90ies, finally, the basic principles of selenoprotein synthesis were worked out by molecular biology tools. The article closes with spotlight comments on proven and potential biomedical benefits of selenium and related research deficits.
Keywords: History of selenium biochemistry; Selenocysteine; Selenoprotein biosynthesis; Glutathione peroxidase; Deficiency syndrome; Serendipity;
The many levels of control on bacterial selenoprotein synthesis by Satoko Yoshizawa; August Böck (1404-1414).
Selenium shares many chemical facets with sulphur but differs from it in the redox potential, especially of the Se2−/S2− oxidation state. The higher chemical reactivity of the deprotonated selenol has been used by Biology in the synthesis of the amino acid selenocysteine and its DNA-encoded incorporation into specific positions of proteins to enhance their structural role or their activity. Since selenocysteine is a steric isomer of cysteine, numerous control mechanisms have been developed which prevent cross-intrusion of the elements during biosynthesis and insertion. As described in this review, these fidelity steps occur at the genetic, biochemical and physiological level.
Keywords: Selenium; tRNASec; Translation factor SelB; Fidelity of selenocysteine synthesis and incorporation;
The selenium to selenoprotein pathway in eukaryotes: More molecular partners than anticipated by Christine Allmang; Laurence Wurth; Alain Krol (1415-1423).
The amino acid selenocysteine (Sec) is the major biological form of the trace element selenium. Sec is co-translationally incorporated in selenoproteins. There are 25 selenoprotein genes in humans, and Sec was found in the active site of those that have been attributed a function. This review will discuss how selenocysteine is synthesized and incorporated into selenoproteins in eukaryotes. Sec biosynthesis from serine on the tRNASec requires four enzymes. Incorporation of Sec in response to an in-frame UGA codon, otherwise signaling termination of translation, is achieved by a complex recoding machinery to inform the ribosomes not to stop at this position on the mRNA. A number of the molecular partners acting in this machinery have been identified but their detailed mechanism of action has not been deciphered yet. Here we provide an overview of the literature in the field. Particularly striking is the higher than originally envisaged number of factors necessary to synthesize Sec and selenoproteins. Clearly, selenoprotein synthesis is an exciting and very active field of research.
Keywords: RNA–protein interaction; SBP2; SECIS; Selenocysteine; Selenocysteine synthase; Hsp90; Selenoprotein;
Eukaryotic selenoproteins and selenoproteomes by Alexey V. Lobanov; Dolph L. Hatfield; Vadim N. Gladyshev (1424-1428).
Selenium is an essential trace element for which both beneficial and toxic effects in human health have been described. It is now clear that the importance of having adequate amounts of this micronutrient in the diet is primarily due to the fact that selenium is required for biosynthesis of selenocysteine, the twenty first naturally occurring amino acid in protein. In this review, we provide an overview of eukaryotic selenoproteins and selenoproteomes, which are sets of selenoproteins in these organisms. In eukaryotes, selenoproteins show a mosaic occurrence, with some organisms, such as vertebrates and algae, having dozens of these proteins, while other organisms, such as higher plants and fungi, having lost all selenoproteins during evolution. We also discuss selenoprotein functions and evolutionary trends in the use of these proteins in eukaryotes. Functional analysis of selenoproteins is critical for better understanding of the role of selenium in human health and disease.
Keywords: Selenocysteine; Selenoprotein; Selenoproteome; SECIS element;
Transcriptional regulation of mammalian selenoprotein expression by Zoia R. Stoytcheva; Marla J. Berry (1429-1440).
Selenoproteins contain the twenty-first amino acid, selenocysteine, and are involved in cellular defenses against oxidative damage, important metabolic and developmental pathways, and responses to environmental challenges. Elucidating the mechanisms regulating selenoprotein expression at the transcriptional level is a key to understanding how these mechanisms are called into play to respond to the changing environment.This review summarizes published studies on transcriptional regulation of selenoprotein genes, focused primarily on genes whose encoded protein functions are at least partially understood. This is followed by in silico analysis of predicted regulatory elements in selenoprotein genes, including those in the aforementioned category as well as the genes whose functions are not known.Our findings reveal regulatory pathways common to many selenoprotein genes, including several involved in stress-responses. In addition, tissue-specific regulatory factors are implicated in regulating many selenoprotein genes.These studies provide new insights into how selenoprotein genes respond to environmental and other challenges, and the roles these proteins play in allowing cells to adapt to these changes.General significance: Elucidating the regulatory mechanisms affecting selenoprotein expression is essential for understanding their roles in human diseases, and for developing diagnostic and potential therapeutic approaches to address dysregulation of members of this gene family.
Keywords: Selenoprotein; Selenium; Transcription; Oxidative stress;
Selenoprotein P—Expression, functions, and roles in mammals by Raymond F. Burk; Kristina E. Hill (1441-1447).
Selenoprotein P (Sepp1) is a secreted protein that is made up of 2 domains. The larger N-terminal domain contains 1 selenocysteine residue in a redox motif and the smaller C-terminal domain contains the other 9 selenocysteines. Sepp1 isoforms of varying lengths occur but quantitation of them has not been achieved. Hepatic synthesis of Sepp1 affects whole-body selenium content and the liver is the source of most plasma Sepp1. ApoER2, a member of the lipoprotein receptor family, binds Sepp1 and facilitates its uptake into the testis and retention of its selenium by the brain. Megalin, another lipoprotein receptor, facilitates uptake of filtered Sepp1 into proximal tubule cells of the kidney. Thus, Sepp1 serves in homeostasis and distribution of selenium. Mice with deletion of Sepp1 suffer greater morbidity and mortality from infection with Trypanosoma congolense than do wild-type mice. Mice that express only the N-terminal domain of Sepp1 have the same severity of illness as wild-type mice, indicating that the protective function of Sepp1 against the infection resides in the N-terminal (redox) domain. Thus, Sepp1 has several functions. In addition, plasma Sepp1 concentration falls in selenium deficiency and, therefore, it can be used as an index of selenium nutritional status.
Keywords: Selenium transport and homeostasis; Selenium for spermatogenesis; Selenium for the brain; Selenium scavenging from glomerular filtrate; Binding of Sepp1 to the lipoprotein receptor apoER2 and megalin; Sepp1 as a marker of selenium nutritional status;
Selenoprotein expression and function—Selenoprotein W by P.D. Whanger (1448-1452).
Selenoprotein W (SeW) is a small selenoprotein (85 to 88 amino acids) first identified in sheep suffering from selenium deficiency. The levels are highest in muscle, heart (except rodents) spleen and brain. The deduced amino acid sequence has been obtained for mice, rats, monkeys, humans, sheep, pigs, fish and chickens. The sequences of SeW are identical in rats and mice as well as monkeys and humans. In all eight species of animals cysteine is present at residue number 9 and selenocysteine at residue number 13. Residue number 37 is cysteine in six species of animal with fish and chickens as the exceptions. Of those examined, the rodent SeW is the only one containing four cysteines whereas the others contain only two cysteines. Glutathionylaltion has been shown for SeW from rats and monkeys but has not been confirmed for this selenoprotein from the other six animals. The biological function of SeW has not been definitely identified. Evidence has been obtained that it can serve as an antioxidant, responds to stress, involved in cell immunity, specific target for methylmercury, and has thioredoxin-like function.
Keywords: Mammalian selenoprotein W; Amino acid sequence; Glutathione; Possible metabolic function;
Hierarchical regulation of selenoprotein expression and sex-specific effects of selenium by Lutz Schomburg; Ulrich Schweizer (1453-1462).
The expression of selenoproteins is controlled on each one of the textbook steps of protein biosynthesis, i.e., during gene transcription, RNA processing, translation and posttranslational events as well as via control of the stability of the involved intermediates and final products. Selenoproteins are unique in their dependence on the trace element Se which they incorporate as the 21st proteinogenic amino acid, selenocysteine. Higher mammals have developed unique pathways to enable a fine-tuned expression of all their different selenoproteins according to developmental stage, actual needs, and current availability of the trace element. Tightly controlled and dynamic expression patterns of selenoproteins are present in different tissues. Interestingly, these patterns display some differences in male and female individuals, and can be grossly modified during disease, e.g. in cancer, inflammation or neurodegeneration. Likewise, important health issues related to the selenium status show unexpected sexual dimorphisms. Some detailed molecular insights have recently been gained on how the hierarchical Se distribution among the different tissues is achieved, how the selenoprotein biosynthesis machinery discriminates among the individual selenoprotein transcripts and how impaired selenoprotein biosynthesis machinery becomes phenotypically evident in humans. This review tries to summarize these fascinating findings and highlights some interesting and surprising sex-specific differences.
Keywords: Gender; Trace element; Diabetes; Sepsis; Fertility; Translation;
On the unique function of selenocysteine — Insights from the evolution of selenoproteins by Sergi Castellano (1463-1470).
The process of natural selection leaves signatures in our genome that can be used to identify functionally important amino acid changes in proteins. In natural populations, amino acids that are better adapted to local conditions might increase in frequency, whereas moderately to severely deleterious protein mutations tend to be eliminated and do not contribute to protein differences between species. Amino acid mutations with no fitness consequences are, however, lost or fixed without regard to natural selection. Looking for evidence of natural selection is, therefore, an attractive strategy for characterizing the contribution of a residue to protein function. Because the majority of identified selenoproteins have now been found in Cys-form, the extent of exchangeability between Sec and Cys residues can be measured in proteins over long periods of time. The statistical analysis of the pattern of Sec/Cys exchanges in diversity (within species) and divergence (between species) data, provides robust inferences of the strength and mode of natural selection acting on these protein sites. Such inferences inform us not only of the long-term exchangeability between Sec and Cys residues, but also of the nature of the selective factors shaping Sec usage in proteins.
Keywords: Selenium; Selenocysteine; Cysteine; Selenoprotein; Amino acid exchangeability; Natural selection;
Functions and evolution of selenoprotein methionine sulfoxide reductases by Byung Cheon Lee; Alexander Dikiy; Hwa-Young Kim; Vadim N. Gladyshev (1471-1477).
Methionine sulfoxide reductases (Msrs) are thiol-dependent enzymes which catalyze conversion of methionine sulfoxide to methionine. Three Msr families, MsrA, MsrB, and fRMsr, are known. MsrA and MsrB are responsible for the reduction of methionine-S-sulfoxide and methionine-R-sulfoxide residues in proteins, respectively, whereas fRMsr reduces free methionine-R-sulfoxide. Besides acting on proteins, MsrA can additionally reduce free methionine-S-sulfoxide. Some MsrAs and MsrBs evolved to utilize catalytic selenocysteine. This includes MsrB1, which is a major MsrB in cytosol and nucleus in mammalian cells. Specialized machinery is used for insertion of selenocysteine into MsrB1 and other selenoproteins at in-frame UGA codons. Selenocysteine offers catalytic advantage to the protein repair function of Msrs, but also makes these proteins dependent on the supply of selenium and requires adjustments in their strategies for regeneration of active enzymes. Msrs have roles in protecting cellular proteins from oxidative stress and through this function they may regulate lifespan in several model organisms.
Keywords: Methionine sulfoxide; MsrA; fRMsr; MsrB1; MsrB2; MsrB3; Selenoprotein; Selenocysteine; Aging; Antioxidants; ROS;
Protection against reactive oxygen species by selenoproteins by Holger Steinbrenner; Helmut Sies (1478-1485).
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.
Keywords: ROS; Oxidative stress; Selenium; Selenoprotein P; Glutathione peroxidase; Thioredoxin reductase;
Catalytic mechanisms and specificities of glutathione peroxidases: Variations of a basic scheme by Stefano Toppo; Leopold Flohé; Fulvio Ursini; Stefano Vanin; Matilde Maiorino (1486-1500).
Kinetics and molecular mechanisms of GPx-type enzymes are reviewed with emphasis on structural features relevant to efficiency and specificity. In Sec-GPxs the reaction takes place at a single redox centre with selenocysteine as redox-active residue (peroxidatic Sec, UP). In contrast, most of the non-vertebrate GPx have the UP replaced by a cysteine (peroxidatic Cys, CP) and work with a second redox centre that contains a resolving cysteine (CR). While the former type of enzymes is more or less specific for GSH, the latter are reduced by “redoxins”. The common denominator of the GPx family is the first redox centre comprising the (seleno)cysteine, tryptophan, asparagine and glutamine. In this architectural context the rate of hydroperoxide reduction by UP or CP, respectively, is enhanced by several orders of magnitude compared to that of free selenolate or thiolate. Mammalian GPx-1 dominates H2O2 metabolism, whereas the domain of GPx-4 is the reduction of lipid hydroperoxides with important consequences such as counteracting 12/15-lipoxygenase-induced apoptosis and regulation of inflammatory responses. Beyond, the degenerate GSH specificity of GPx-4 allows selenylation and oxidation to disulfides of protein thiols. Heterodimer formation of yeast GPx with a transcription factor is discussed as paradigm of a redox sensing that might also be valid in vertebrates.
Keywords: Enzyme kinetics; Glutathione peroxidases; Hydroperoxide; Molecular phylogenesis; Redox signaling; Selenium;
Using chemical approaches to study selenoproteins—Focus on thioredoxin reductases by Robert J. Hondal (1501-1512).
The study of selenocysteine-containing proteins is difficult due to the problems associated with the heterologous production of these proteins. These problems are due to the intricate recoding mechanism used by cells to translate the UGA codon as a sense codon for selenocysteine. The process is further complicated by the fact that eukaryotes and prokaryotes have different UGA recoding machineries.This review focuses on chemical approaches to produce selenoproteins and study the mechanism of selenoenzymes. The use of intein-mediated peptide ligation is discussed with respect to the production of the mammalian selenoenzymes thioredoxin reductase and selenoprotein R, also known as methionine sulfoxide reductase B1. New methods for removing protecting groups from selenocysteine post-synthesis and methods for selenosulfide/diselenide formation are also reviewed.Chemical approaches have also been used to study the enzymatic mechanism of thioredoxin reductase. The approach divides the enzyme into two modules, a large protein module lacking selenocysteine and a small, synthetic selenocysteine-containing peptide. Study of this semisynthetic enzyme has revealed three distinct enzymatic pathways that depend on the properties of the substrate. The enzyme utilizes a macromolecular mechanism for protein substrates, a second mechanism for small molecule substrates and a third pathway for selenium-containing substrates such as selenocystine.
Keywords: Selenocysteine; Peptide ligation; Semisynthesis; Seleno effect; Thioredoxin reductase; Vicinal disulfide;
Metabolism of selenium compounds catalyzed by the mammalian selenoprotein thioredoxin reductase by Jun Lu; Carsten Berndt; Arne Holmgren (1513-1519).
The mammalian thioredoxin reductases (TrxR) are selenoproteins with a catalytic selenocysteine residue which in the oxidized enzyme forms a selenenylsulfide and in the reduced enzyme is present as a selenolthiol. Selenium compounds such as selenite, selenodiglutathione and selenocystine are substrates for the enzyme with low K m-values and the enzyme is implicated in reductive assimilation of selenium by generating selenide for selenoprotein synthesis. Redox cycling of reduced metabolites of these selenium compounds including selenide with oxygen via TrxR and reduced thioredoxin (Trx) will oxidize NADPH and produce reactive oxygen species inducing cell death at high concentrations explaining selenite toxicity. There is no free pool of selenocysteine since this would be toxic in an oxygen environment by redox cycling via thioredoxin systems. The importance of selenium compounds and TrxR in cancer and cardiovascular diseases both for prevention and treatment is discussed. A selenazol drug like ebselen is a direct substrate for mammalian TrxR and dithiol Trx and ebselen selenol is readily reoxidized by hydrogen peroxide and lipid hydroperoxides, acting as an anti-oxidant and anti-inflammatory drug.
Keywords: Selenoprotein; Thioredoxin reductase; Selenite; Selenocysteine; Ebselen; Redox cycling;
Selenoproteins in Archaea and Gram-positive bacteria by Tilmann Stock; Michael Rother (1520-1532).
Selenium is an essential trace element for many organisms by serving important catalytic roles in the form of the 21st co-translationally inserted amino acid selenocysteine. It is mostly found in redox-active proteins in members of all three domains of life and analysis of the ever-increasing number of genome sequences has facilitated identification of the encoded selenoproteins. Available data from biochemical, sequence, and structure analyses indicate that Gram-positive bacteria synthesize and incorporate selenocysteine via the same pathway as enterobacteria. However, recent in vivo studies indicate that selenocysteine-decoding is much less stringent in Gram-positive bacteria than in Escherichia coli. For years, knowledge about the pathway of selenocysteine synthesis in Archaea and Eukarya was only fragmentary, but genetic and biochemical studies guided by analysis of genome sequences of Sec-encoding archaea has not only led to the characterization of the pathways but has also shown that they are principally identical. This review summarizes current knowledge about the metabolic pathways of Archaea and Gram-positive bacteria where selenium is involved, about the known selenoproteins, and about the respective pathways employed in selenoprotein synthesis.
Keywords: Selenium; Selenocysteine; Selenoprotein; Clostridium; Moorella; Eubacterium; Methanococcus maripaludis;
Selenoproteins and human health: Insights from epidemiological data by Margaret P. Rayman (1533-1540).
Knowledge of the plasma selenium levels associated with optimised concentration or activity of specific selenoproteins can provide considerable insights from epidemiological data on the possible involvement of those selenoproteins in health, most notably with respect to cancer. For cohort studies, if selenoproteins such as glutathione peroxidase and selenoprotein P are relevant to cancer, one might only expect to see an effect on risk when the concentrations in the cohort range from below, to above, the level needed to optimise the activity or concentration of these enzymes. Similarly, trials would only show a beneficial effect of supplementation if selenium status were raised from below, to above, the optimal concentration for the selenoproteins likely to be implicated in cancer risk, as occurred in the NPC trial but not in SELECT. The most powerful evidence for the involvement of selenoproteins in human health comes from epidemiological studies that have related single nucleotide polymorphisms in selenoproteins to disease risk. The totality of the evidence currently implicates GPx1, GPx4, SEPS1, Sep15, SEPP1 and TXNRD1 in conditions such as cardiovascular disease, pre-eclampsia and cancer. Future studies therefore need to determine not only selenium status, but genotype, both in selenoproteins and related pathways, when investigating the relationship of selenium with disease risk.
Keywords: Selenoprotein; Selenium; Epidemiology; Single nucleotide polymorphism; Health; Cancer;
Selenoproteins that function in cancer prevention and promotion by Dolph L. Hatfield; Min-Hyuk Yoo; Bradley A. Carlson; Vadim N. Gladyshev (1541-1545).
Of the many health benefits attributed to selenium, the one that has received the most attention is its role in cancer prevention. Selenium-containing proteins (selenoproteins) have been shown in recent years to have roles in cancer prevention. However, selenoproteins have diverse functions and their view as antioxidants is oversimplified. Some selenoproteins appear to have a split personality in having roles both in preventing and promoting cancer. The contrasting roles of one selenoprotein, thioredoxin reductase 1, in cancer are discussed in detail, but as also noted, at least one other selenoprotein may also have such a dual function. In addition, we discuss examples of inhibition of cancer development by selenoprotein deficiency in mouse models. These studies highlight the complex nature of selenium in relation to cancer.
Keywords: Selenoprotein; 15 kDa selenoprotein; Tumorigenesis; Thioredoxin reductase 1;
Molecular mechanisms by which selenoproteins affect cancer risk and progression by Pin Zhuo; Alan M. Diamond (1546-1554).
Selenoproteins comprise a unique class of proteins that contain selenium in the form of selenocysteine. Several selenoproteins have been implicated in the risk or development of cancers in humans by genetic data. These include Selenoprotein P, 3 members of the glutathione peroxidase family of anti-oxidant enzymes and Sep15. At-risk alleles in the germline indicate a likely role in determining susceptibility to cancer, while loss of heterozygosity or chromosomal epigenetic silencing indicate that the reduction in the levels of the corresponding proteins contribute to malignant progression. Lower levels of these proteins are likely to be detrimental due to the resulting cellular stress and perturbations in important regulatory signaling pathways. The genetic data indicating the involvement of these selenoproteins in cancer etiology are discussed, as are the possible mechanisms by which these genes might promote carcinogenesis.
Keywords: Selenoprotein; Polymorphism; Cancer; Loss of heterozygosity; Anti-oxidant;
Glutathione peroxidases in different stages of carcinogenesis by Regina Brigelius-Flohé; Anna Kipp (1555-1568).
Cancer cells produce high amounts of reactive oxygen species (ROS) and evade apoptosis. Hydroperoxides support proliferation, invasion, migration and angiogenesis, but at higher levels induce apoptosis, thus being pro- and anti-carcinogenic. Accordingly, glutathione peroxidases (GPxs) regulating hydroperoxide levels might have dual roles too. GPx1, clearly an antioxidant enzyme, is down-regulated in many cancer cells. Its main role would be prevention of cancer initiation by ROS-mediated DNA damage. GPx2 is up-regulated in cancer cells. GPx1/GPx2 double knockout mice develop colitis and intestinal cancer. However, GPx2 knockdown cancer cells grow better in vitro and in vivo probably reflecting the physiological role of GPx2 in intestinal mucosa homeostasis. GPx2 counteracts COX-2 expression and PGE2 production, which explains its potential to inhibit migration and invasion of cultured cancer cells. Overexpression of GPx3 inhibits tumor growth and metastasis. GPx4 is decreased in cancer tissues. GPx4-overexpressing cancer cells have low COX-2 activity and tumors derived therefrom are smaller than from control cells and do not metastasize. Collectively, GPxs prevent cancer initiation by removing hydroperoxides. GPx4 inhibits but GPx2 supports growth of established tumors. Metastasis, but also apoptosis, is inhibited by all GPxs. GPx-mediated regulation of COX/LOX activities may be relevant to early stages of inflammation-mediated carcinogenesis.
Keywords: Glutathione peroxidase; Cancer development; Cyclooxygenase; Hydroperoxide; Metastasis; Apoptosis;
Selenoprotein function and muscle disease by Alain Lescure; Mathieu Rederstorff; Alain Krol; Pascale Guicheney; Valérie Allamand (1569-1574).
The crucial role of the trace element selenium in livestock and human health, in particular in striated muscle function, has been well established but the underlying molecular mechanisms remain poorly understood. Over the last decade, identification of the full repertoire of selenium-containing proteins has opened the way towards a better characterization of these processes. Two selenoproteins have mainly been investigated in muscle, namely SelW and SelN. Here we address their involvement in muscle development and maintenance, through the characterization of various cellular or animal models. In particular, mutations in the SEPN1 gene encoding selenoprotein N (SelN) cause a group of neuromuscular disorders now referred to as SEPN1-related myopathy. Recent findings on the functional consequences of these mutations suggest an important contribution of SelN to the regulation of oxidative stress and calcium homeostasis. Importantly, the conclusions of these experiments have opened new avenues of investigations that provide grounds for the development of therapeutic approaches.
Keywords: Selenium; Selenocysteine; SelN; Muscular disease; Oxidative stress;
Transgenic mouse models for the vital selenoenzymes cytosolic thioredoxin reductase, mitochondrial thioredoxin reductase and glutathione peroxidase 4 by Marcus Conrad (1575-1585).
Selenium, as an integral part of selenoproteins, is essential for mammals. Unequivocal evidence had been provided more than a decade ago when it was proven that mice incapable of producing any of the 24 selenoproteins failed to develop beyond the gastrulation stage (E6.5). Since then, more specific attempts have been made to unmask novel and essential functions of individual selenoproteins in mice. Genetic disruption of glutathione peroxidase 4 (GPx4; also referred to as phospholipid hydroperoxide glutathione peroxidase, PHGPx) in mice showed for the first time that a specific selenoenzyme is in fact required for early embryonic development. Later on, systemic ablation of cytosolic thioredoxin reductase (Txnrd1) or mitochondrial thioredoxin reductase (Txnrd2) yielded embryonic lethal phenotypes. Beside those three, no other selenoproteins have been found being indispensable for murine development so far. This review aims at summarizing mainly the in vivo findings on these important mammalian selenoenzymes, which have not only common attributes of being required for embryogenesis, but that they are also instrumental in the regulation of cellular redox metabolism.
Keywords: Apoptosis inducing factor (AIF); Cre/loxP; 12/15-lipoxygenase; Oxidative stress; PHGPx; Redox regulation;