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Current Opinion in Chemical Biology Oct 2014Once considered highly toxic, the element selenium is now recognized as a micronutrient essential for human health. It is inserted co-translationally into many proteins... (Review)
Review
Once considered highly toxic, the element selenium is now recognized as a micronutrient essential for human health. It is inserted co-translationally into many proteins as the non-canonical amino acid selenocysteine, providing the resulting selenoprotein molecules with a range of valuable redox properties; selenocysteine is also increasingly exploited as a structural and mechanistic probe in synthetic peptides and proteins. Here we review topical investigations into the preparation and characterization of natural and artificial selenoproteins. Such molecules are uniquely suited as tools for protein chemistry and as a test bed for studying novel catalytic activities.
Topics: Animals; Humans; Oxidation-Reduction; Protein Biosynthesis; Protein Folding; Recombinant Proteins; Selenocysteine; Selenoproteins
PubMed: 25261915
DOI: 10.1016/j.cbpa.2014.09.010 -
Amino Acids Sep 2018Selenium (Se) is an essential trace element for several organisms and is mostly present in proteins as L-selenocysteine (Sec or U). Sec is synthesized on its... (Review)
Review
Selenium (Se) is an essential trace element for several organisms and is mostly present in proteins as L-selenocysteine (Sec or U). Sec is synthesized on its L-seryl-tRNA to produce Sec-tRNA molecules by a dedicated selenocysteine synthesis machinery and incorporated into selenoproteins at specified in-frame UGA codons. UGA-Sec insertion is signaled by an mRNA stem-loop structure called the SElenoCysteine Insertion Sequence (SECIS). tRNA transcription regulation and folding have been described showing its importance to Sec biosynthesis. Here, we discuss structural aspects of Sec-tRNA and its role in Sec biosynthesis as well as Sec incorporation into selenoproteins. Defects in the Sec biosynthesis or incorporation pathway have been correlated with pathological conditions.
Topics: Animals; Codon, Terminator; Humans; Protein Biosynthesis; RNA, Messenger; RNA, Transfer, Cys; Selenocysteine
PubMed: 29948343
DOI: 10.1007/s00726-018-2595-6 -
IUBMB Life Feb 2016Selenium (Se) is an essential micronutrient that exerts multiple and complex effects on human health. Se is essential for human well-being largely due to its potent... (Review)
Review
Selenium (Se) is an essential micronutrient that exerts multiple and complex effects on human health. Se is essential for human well-being largely due to its potent antioxidant, anti-inflammatory, and antiviral properties. The physiological functions of Se are carried out by selenoproteins, in which Se is specifically incorporated as the amino acid, selenocysteine. Importantly, both beneficial and toxic effects of Se have been reported suggesting that the mode of action of Se is strictly chemical form and concentration dependent. Additionally, there is a relatively narrow window between Se deficiency and toxicity and growing evidence suggests that Se health effects depend greatly on the baseline level of this micronutrient. Thus, Se supplementation is not an easy task and requires an individualized approach. It is essential that we continue to explore and better characterize Se containing compounds and mechanisms of action, which could be crucial for disease prevention and treatment.
Topics: Antioxidants; Humans; Micronutrients; Selenium; Selenium Compounds; Selenocysteine; Selenoproteins
PubMed: 26714931
DOI: 10.1002/iub.1466 -
Free Radical Biology & Medicine Oct 2022The habitual intake of selenium (Se) varies strongly around the world, and many people are at risk of inadequate supply and health risks from Se deficiency. Within the... (Review)
Review
The habitual intake of selenium (Se) varies strongly around the world, and many people are at risk of inadequate supply and health risks from Se deficiency. Within the human organism, efficient transport mechanisms ensure that organs with a high demand and relevance for reproduction and survival are preferentially supplied. To this end, selenoprotein P (SELENOP) is synthesized in the liver and mediates Se transport to essential tissues such as the endocrine glands and the brain, where the "SELENOP cycle" maintains a privileged Se status. Mouse models indicate that SELENOP is not essential for life, as supplemental Se supply was capable of preventing the development of severe symptoms. However, knockout mice died under limiting supply, arguing for an essential role of SELENOP in Se deficiency. Many clinical studies support this notion, pointing to close links between health risks and low SELENOP levels. Accordingly, circulating SELENOP concentrations serve as a functional biomarker of Se supply, at least until a saturated status is achieved and SELENOP levels reach a plateau. Upon toxic intake, a further increase in SELENOP is observed, i.e., SELENOP provides information about possible selenosis. The SELENOP transcripts predict an insertion of ten selenocysteine residues. However, the decoding is imperfect, and not all these positions are ultimately occupied by selenocysteine. In addition to the selenocysteine residues near the C-terminus, one selenocysteine resides central within an enzyme-like environment. SELENOP proved capable of catalyzing peroxide degradation in vitro and protecting e.g. LDL particles from oxidation. An enzymatic activity in the intact organism is unclear, but an increasing number of clinical studies provides evidence for a direct involvement of SELENOP-dependent Se transport as an important and modifiable risk factor of disease. This interaction is particularly strong for cardiovascular and critical disease including COVID-19, cancer at various sites and autoimmune thyroiditis. This review briefly highlights the links between the growing knowledge of Se in health and disease over the last 50 years and the specific advances that have been made in our understanding of the physiological and clinical contribution of SELENOP to the current picture.
Topics: Animals; Biomarkers; COVID-19; Carrier Proteins; Humans; Mice; Peroxides; Selenium; Selenocysteine; Selenoprotein P
PubMed: 36067902
DOI: 10.1016/j.freeradbiomed.2022.08.022 -
Free Radical Biology & Medicine Oct 2022Methionine (Met) can be oxidized to methionine sulfoxide (MetO), which exist as R- and S-diastereomers. Present in all three domains of life, methionine sulfoxide... (Review)
Review
Methionine (Met) can be oxidized to methionine sulfoxide (MetO), which exist as R- and S-diastereomers. Present in all three domains of life, methionine sulfoxide reductases (MSR) are the enzymes that reduce MetO back to Met. Most characterized among them are MSRA and MSRB, which are strictly stereospecific for the S- and R-diastereomers of MetO, respectively. While the majority of MSRs use a catalytic Cys to reduce their substrates, some employ selenocysteine. This is the case of mammalian MSRB1, which was initially discovered as selenoprotein SELR or SELX and later was found to exhibit an MSRB activity. Genomic analyses demonstrated its occurrence in most animal lineages, and biochemical and structural analyses uncovered its catalytic mechanism. The use of transgenic mice and mammalian cell culture revealed its physiological importance in the protection against oxidative stress, maintenance of neuronal cells, cognition, cancer cell proliferation, and the immune response. Coincident with the discovery of Met oxidizing MICAL enzymes, recent findings of MSRB1 regulating the innate immunity response through reversible stereospecific Met-R-oxidation of cytoskeletal actin opened up new avenues for biological importance of MSRB1 and its role in disease. In this review, we discuss the current state of research on MSRB1, compare it with other animal Msrs, and offer a perspective on further understanding of biological functions of this selenoprotein.
Topics: Actins; Animals; Humans; Mammals; Methionine; Methionine Sulfoxide Reductases; Mice; Mice, Transgenic; Selenocysteine; Selenoproteins
PubMed: 36084791
DOI: 10.1016/j.freeradbiomed.2022.08.043 -
Molecules (Basel, Switzerland) Feb 2021The trace element selenium (Se) is a crucial element for many living organisms, including soil microorganisms, plants and animals, including humans. Generally, in Nature... (Review)
Review
The trace element selenium (Se) is a crucial element for many living organisms, including soil microorganisms, plants and animals, including humans. Generally, in Nature Se is taken up in the living cells of microorganisms, plants, animals and humans in several inorganic forms such as selenate, selenite, elemental Se and selenide. These forms are converted to organic forms by biological process, mostly as the two selenoamino acids selenocysteine (SeCys) and selenomethionine (SeMet). The biological systems of plants, animals and humans can fix these amino acids into Se-containing proteins by a modest replacement of methionine with SeMet. While the form SeCys is usually present in the active site of enzymes, which is essential for catalytic activity. Within human cells, organic forms of Se are significant for the accurate functioning of the immune and reproductive systems, the thyroid and the brain, and to enzyme activity within cells. Humans ingest Se through plant and animal foods rich in the element. The concentration of Se in foodstuffs depends on the presence of available forms of Se in soils and its uptake and accumulation by plants and herbivorous animals. Therefore, improving the availability of Se to plants is, therefore, a potential pathway to overcoming human Se deficiencies. Among these prospective pathways, the Se-biofortification of plants has already been established as a pioneering approach for producing Se-enriched agricultural products. To achieve this desirable aim of Se-biofortification, molecular breeding and genetic engineering in combination with novel agronomic and edaphic management approaches should be combined. This current review summarizes the roles, responses, prospects and mechanisms of Se in human nutrition. It also elaborates how biofortification is a plausible approach to resolving Se-deficiency in humans and other animals.
Topics: Animals; Antioxidants; Biofortification; Humans; Plants; Selenic Acid; Selenium; Selenocysteine; Selenomethionine; Selenoproteins; Soil
PubMed: 33562416
DOI: 10.3390/molecules26040881 -
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 -
Current Pharmaceutical Design 2019Selenium is an essential non-metal trace element, and the imbalance in the bioavailability of selenium is associated with many diseases ranking from acute respiratory... (Review)
Review
Selenium is an essential non-metal trace element, and the imbalance in the bioavailability of selenium is associated with many diseases ranking from acute respiratory distress syndrome, myocardial infarction and renal failure (Se overloading) to diseases associated with chronic inflammation like inflammatory bowel diseases, rheumatoid arthritis, and atherosclerosis (Se unload). The only source of selenium is the diet (animal and cereal sources) and its intestinal absorption is limiting for selenocysteine and selenomethionine synthesis and incorporation in selenoproteins. In this review, after establishing the link between selenium and inflammatory diseases, we envisaged the potential of selenium nanoparticles and organic selenocompounds to compensate the deficit of selenium intake from the diet. With high selenium loading, nanoparticles offer a low dosage to restore selenium bioavailability whereas organic selenocompounds can play a role in the modulation of their antioxidant or antiinflammatory activities.
Topics: Anti-Inflammatory Agents; Antioxidants; Biological Availability; Diet; Humans; Inflammation; Nanoparticles; Selenium; Selenocysteine; Selenomethionine; Selenoproteins; Trace Elements
PubMed: 31267853
DOI: 10.2174/1381612825666190701153903 -
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