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Chemistry (Weinheim An Der Bergstrasse,... Sep 2023Selenium, originally described as a toxin, turns out to be a crucial trace element for life that appears as selenocysteine and its dimer, selenocystine. From the point... (Review)
Review
Selenium, originally described as a toxin, turns out to be a crucial trace element for life that appears as selenocysteine and its dimer, selenocystine. From the point of view of drug developments, selenium-containing drugs are isosteres of sulfur and oxygen with the advantage that the presence of the selenium atom confers antioxidant properties and high lipophilicity, which would increase cell membrane permeation leading to better oral bioavailability. In this article, we have focused on the relevant features of the selenium atom, above all, the corresponding synthetic approaches to access a variety of organoselenium molecules along with the proposed reaction mechanisms. The preparation and biological properties of selenosugars, including selenoglycosides, selenonucleosides, selenopeptides, and other selenium-containing compounds will be treated. We have attempted to condense the most important aspects and interesting examples of the chemistry of selenium into a single article.
PubMed: 37378970
DOI: 10.1002/chem.202300030 -
Biomolecules Sep 2022The synthesis of selenoproteins requires the co-translational recoding of an in-frame UGASec codon. Interactions between the Selenocysteine Insertion Sequence (SECIS)...
The synthesis of selenoproteins requires the co-translational recoding of an in-frame UGASec codon. Interactions between the Selenocysteine Insertion Sequence (SECIS) and the SECIS binding protein 2 (SBP2) in the 3'untranslated region (3'UTR) of selenoprotein mRNAs enable the recruitment of the selenocysteine insertion machinery. Several selenoprotein mRNAs undergo unusual cap hypermethylation and are not recognized by the translation initiation factor 4E (eIF4E) but nevertheless translated. The human eukaryotic translation initiation factor 3 (eIF3), composed of 13 subunits (a-m), can selectively recruit several cellular mRNAs and plays roles in specialized translation initiation. Here, we analyzed the ability of eIF3 to interact with selenoprotein mRNAs. By combining ribonucleoprotein immunoprecipitation (RNP IP) in vivo and in vitro with cross-linking experiments, we found interactions between eIF3 and a subgroup of selenoprotein mRNAs. We showed that eIF3 preferentially interacts with hypermethylated capped selenoprotein mRNAs rather than mG-capped mRNAs. We identified direct contacts between GPx1 mRNA and eIF3 c, d, and e subunits and showed the existence of common interaction patterns for all hypermethylated capped selenoprotein mRNAs. Differential interactions of eIF3 with selenoprotein mRNAs may trigger specific translation pathways independent of eIF4E. eIF3 could represent a new player in the translation regulation and hierarchy of selenoprotein expression.
Topics: 3' Untranslated Regions; Codon; DNA Transposable Elements; Eukaryotic Initiation Factor-3; Eukaryotic Initiation Factor-4E; Humans; Protein Biosynthesis; RNA, Messenger; RNA-Binding Proteins; Ribonucleoproteins; Selenocysteine; Selenoproteins
PubMed: 36139107
DOI: 10.3390/biom12091268 -
Nucleic Acids Research Oct 2023Translational readthrough of UGA stop codons by selenocysteine-specific tRNA (tRNASec) enables the synthesis of selenoproteins. Seryl-tRNA synthetase (SerRS) charges...
Translational readthrough of UGA stop codons by selenocysteine-specific tRNA (tRNASec) enables the synthesis of selenoproteins. Seryl-tRNA synthetase (SerRS) charges tRNASec with serine, which is modified into selenocysteine and delivered to the ribosome by a designated elongation factor (eEFSec in eukaryotes). Here we found that components of the human selenocysteine incorporation machinery (SerRS, tRNASec, and eEFSec) also increased translational readthrough of non-selenocysteine genes, including VEGFA, to create C-terminally extended isoforms. SerRS recognizes target mRNAs through a stem-loop structure that resembles the variable loop of its cognate tRNAs. This function of SerRS depends on both its enzymatic activity and a vertebrate-specific domain. Through eCLIP-seq, we identified additional SerRS-interacting mRNAs as potential readthrough genes. Moreover, SerRS overexpression was sufficient to reverse premature termination caused by a pathogenic nonsense mutation. Our findings expand the repertoire of selenoprotein biosynthesis machinery and suggest an avenue for therapeutic targeting of nonsense mutations using endogenous factors.
Topics: Humans; Codon, Nonsense; Codon, Terminator; Protein Biosynthesis; RNA, Messenger; Selenocysteine; Selenoproteins; Serine-tRNA Ligase
PubMed: 37739431
DOI: 10.1093/nar/gkad773 -
Metallomics : Integrated Biometal... May 2021Selenium is an essential trace element whose compounds are widely metabolized by organisms from all three domains of life. Moreover, phylogenetic evidence indicates that... (Review)
Review
Selenium is an essential trace element whose compounds are widely metabolized by organisms from all three domains of life. Moreover, phylogenetic evidence indicates that selenium species, along with iron, molybdenum, tungsten, and nickel, were metabolized by the last universal common ancestor of all cellular lineages, primarily for the synthesis of the 21st amino acid selenocysteine. Thus, selenium metabolism is both environmentally ubiquitous and a physiological adaptation of primordial life. Selenium metabolic reactions comprise reductive transformations both for assimilation into macromolecules and dissimilatory reduction of selenium oxyanions and elemental selenium during anaerobic respiration. This review offers a comprehensive overview of the physiology and evolution of both assimilatory and dissimilatory selenium metabolism in bacteria and archaea, highlighting mechanisms of selenium respiration. This includes a thorough discussion of our current knowledge of the physiology of selenocysteine synthesis and incorporation into proteins in bacteria obtained from structural biology. Additionally, this is the first comprehensive discussion in a review of the incorporation of selenium into the tRNA nucleoside 5-methylaminomethyl-2-selenouridine and as an inorganic cofactor in certain molybdenum hydroxylase enzymes. Throughout, conserved mechanisms and derived features of selenium metabolism in both domains are emphasized and discussed within the context of the global selenium biogeochemical cycle.
Topics: Archaea; Bacteria; Evolution, Molecular; Mixed Function Oxygenases; Molybdenum; RNA, Transfer; Selenium; Selenocysteine
PubMed: 33930157
DOI: 10.1093/mtomcs/mfab024 -
Biological Trace Element Research Nov 2019The trace element selenium is an essential micronutrient that plays an important role in maintaining homeostasis of several tissues including the immune system of... (Review)
Review
The trace element selenium is an essential micronutrient that plays an important role in maintaining homeostasis of several tissues including the immune system of mammals. The vast majority of the biological functions of selenium are mediated via selenoproteins, proteins which incorporate the selenium-containing amino acid selenocysteine. Several bacterial infections of humans and animals are associated with decreased levels of selenium in the blood and an adjunct therapy with selenium often leads to favorable outcomes. Many pathogenic bacteria are also capable of synthesizing selenocysteine suggesting that selenoproteins may have a role in bacterial physiology. Interestingly, the composition of host microbiota is also regulated by dietary selenium levels. Therefore, bacterial pathogens, microbiome, and host immune cells may be competing for a limited supply of selenium. Elucidating how selenium, in particular selenoproteins, may regulate pathogen virulence, microbiome diversity, and host immune response during a bacterial infection is critical for clinical management of infectious diseases.
Topics: Animals; Bacteria; Bacterial Infections; Bacterial Proteins; Humans; Microbiota; Selenoproteins
PubMed: 31489516
DOI: 10.1007/s12011-019-01877-2 -
Food & Nutrition Research 2023Selenium is an essential trace element in humans, critical to the normal physiology in all animal species. The main form of selenium in food is selenomethionine,... (Review)
Review
Selenium is an essential trace element in humans, critical to the normal physiology in all animal species. The main form of selenium in food is selenomethionine, selenocysteine and a variety of organic compounds, while inorganic salts mainly occur in food supplements. In animals and humans, selenium occurs as selenocysteine in selenoproteins encoded by 25 genes (specific selenium pool). Several selenoproteins are part of the antioxidant enzyme system and serve as oxido-reductases and in thyroid hormone regulation. SelenoproteinP (SELENOP) transports selenium to peripheral tissues, is the main plasma selenoprotein, and has been used as biomarker of selenium status and intake. SELENOP in plasma represents a saturable pool of selenium and is maximised at a selenium concentration in plasma of about 110 µg/L or an intake of selenomethionine at about 1.2 µg/kg body weight in adults. In Finland, with an estimated selenium intake of 88 µg/day in men and 68 µg/day in women, the average selenium concentration in plasma is about 110 µg/L. Imported wheat from selenium rich areas is an important dietary source in Norway. Dietary intakes in the Nordic and Baltic area vary from 39 to 88 µg/day in men and 22 to 68 µg/day in women, the highest levels were from Finland. Most intervention trials on the effect of selenium supplementation on health outcomes have been carried out in 'selenium-replete'-populations and show no beneficial effect, which from a nutritional point of view would rather not be expected. Some intervention studies conducted in populations low in selenium have showed a beneficial effect. Observational studies suggest an inverse relationship between selenium status and risk of cardiovascular diseases (CVDs), cancer and all-cause mortality, and some other outcomes at low levels of intake (<55 µg/day) or in plasma or serum (<100 µg/L). However, a lack of quantitative data and inconsistencies between studies precludes these studies to be used to derive dietary reference values. At high intakes above 330 to 450 µg/day selenium may cause toxic effects affecting liver, peripheral nerves, skin, nails, and hair. An upper tolerable level (UL) of 255 µg selenium/day in adults was established by EFSA.
PubMed: 38187789
DOI: 10.29219/fnr.v67.10320 -
Current Opinion in Chemical Biology Aug 2023Selenium is connected to three small molecule antioxidant compounds, ascorbate, α-tocopherol, and ergothioneine. Ascorbate and α-tocopherol are true vitamins, while... (Review)
Review
Selenium is connected to three small molecule antioxidant compounds, ascorbate, α-tocopherol, and ergothioneine. Ascorbate and α-tocopherol are true vitamins, while ergothioneine is a "vitamin-like" compound. Here we review how selenium is connected to all three. Selenium and vitamin E work together as a team to prevent lipid peroxidation. Vitamin E quenches lipid hydroperoxyl radicals and the resulting lipid hydroperoxide is then converted to the lipid alcohol by selenocysteine-containing glutathione peroxidase. Ascorbate reduces the resulting α-tocopheroxyl radical in this reaction back to α-tocopherol with concomitant production of the ascorbyl radical. The ascorbyl radical can be reduced back to ascorbate by selenocysteine-containing thioredoxin reductase. Ergothioneine and ascorbate are both water soluble, small molecule reductants that can reduce free radicals and redox-active metals. Thioredoxin reductase can reduce oxidized forms of ergothioneine. While the biological significance of this is not yet realized, this discovery underscores the centrality of selenium to all three antioxidants.
Topics: Ascorbic Acid; Selenium; Ergothioneine; alpha-Tocopherol; Selenocysteine; Thioredoxin-Disulfide Reductase; Vitamin E; Antioxidants; Vitamins; Oxidation-Reduction; Free Radicals; Lipid Peroxides
PubMed: 37236134
DOI: 10.1016/j.cbpa.2023.102328 -
International Journal of Molecular... Mar 2023Dietary selenium (Se) intake within the physiological range is critical to maintain various biological functions, including antioxidant defence, redox homeostasis,... (Review)
Review
Dietary selenium (Se) intake within the physiological range is critical to maintain various biological functions, including antioxidant defence, redox homeostasis, growth, reproduction, immunity, and thyroid hormone production. Chemical forms of dietary Se are diverse, including organic Se (selenomethionine, selenocysteine, and selenium-methyl-selenocysteine) and inorganic Se (selenate and selenite). Previous studies have largely investigated and compared the health impacts of dietary Se on agricultural stock and humans, where dietary Se has shown various benefits, including enhanced growth performance, immune functions, and nutritional quality of meats, with reduced oxidative stress and inflammation, and finally enhanced thyroid health and fertility in humans. The emergence of nanoparticles presents a novel and innovative technology. Notably, Se in the form of nanoparticles (SeNPs) has lower toxicity, higher bioavailability, lower excretion in animals, and is linked to more powerful and superior biological activities (at a comparable Se dose) than traditional chemical forms of dietary Se. As a result, the development of tailored SeNPs for their use in intensive agriculture and as candidate for therapeutic drugs for human pathologies is now being actively explored. This review highlights the biological impacts of SeNPs on growth and reproductive performances, their role in modulating heat and oxidative stress and inflammation and the varying modes of synthesis of SeNPs.
Topics: Animals; Humans; Selenium; Selenocysteine; Antioxidants; Nanoparticles; Inflammation
PubMed: 37047040
DOI: 10.3390/ijms24076068 -
ChemMedChem May 2024The chemical and biological interest in this element and the molecules bearing selenium has been exponentially growing over the years. Selenium, formerly designated as a...
The chemical and biological interest in this element and the molecules bearing selenium has been exponentially growing over the years. Selenium, formerly designated as a toxin, becomes a vital trace element for life that appears as selenocysteine and its dimeric form, selenocystine, in the active sites of selenoproteins, which catalyze a wide variety of reactions, including the detoxification of reactive oxygen species and modulation of redox activities. From the point of view of drug developments, organoselenium drugs are isosteres of sulfur-containing and oxygen-containing drugs with the advantage that the presence of the selenium atom confers antioxidant properties and high lipophilicity, which would increase cell membrane permeation leading to better oral bioavailability. This statement is the paramount relevance considering the big number of clinically employed compounds bearing sulfur or oxygen atoms if their structures including nucleosides and carbohydrates. Thus, in this article we have focused on the relevant features of the application of selenium in medicinal chemistry. With the increasing interest in selenium chemistry, we have attempted to highlight the most significant published data on this subject, mainly concentrating the analysis on the last years. In consequence, the recent advances of relevant pharmacological organoselenium compounds are discussed.
PubMed: 38778500
DOI: 10.1002/cmdc.202400063 -
Antioxidants (Basel, Switzerland) Sep 2019The enzyme selenocysteine β-lyase (SCLY) was first isolated in 1982 from pig livers, followed by its identification in bacteria. SCLY works as a homodimer, utilizing... (Review)
Review
The enzyme selenocysteine β-lyase (SCLY) was first isolated in 1982 from pig livers, followed by its identification in bacteria. SCLY works as a homodimer, utilizing pyridoxal 5'-phosphate as a cofactor, and catalyzing the specific decomposition of the amino acid selenocysteine into alanine and selenide. The enzyme is thought to deliver its selenide as a substrate for selenophosphate synthetases, which will ultimately be reutilized in selenoprotein synthesis. SCLY subcellular localization is unresolved, as it has been observed both in the cytosol and in the nucleus depending on the technical approach used. The highest SCLY expression and activity in mammals is found in the liver and kidneys. Disruption of the gene in mice led to obesity, hyperinsulinemia, glucose intolerance, and hepatic steatosis, with SCLY being suggested as a participant in the regulation of energy metabolism in a sex-dependent manner. With the physiological role of SCLY still not fully understood, this review attempts to discuss the available literature regarding SCLY in animals and provides avenues for possible future investigation.
PubMed: 31480609
DOI: 10.3390/antiox8090357