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Antioxidants (Basel, Switzerland) Oct 2023Selenocysteine (Sec), the 21st amino acid, is structurally similar to cysteine but with a sulfur to selenium replacement. This single change retains many of the chemical... (Review)
Review
Selenocysteine (Sec), the 21st amino acid, is structurally similar to cysteine but with a sulfur to selenium replacement. This single change retains many of the chemical properties of cysteine but often with enhanced catalytic and redox activity. Incorporation of Sec into proteins is unique, requiring additional translation factors and multiple steps to insert Sec at stop (UGA) codons. These Sec-containing proteins (selenoproteins) are found in all three domains of life where they often are involved in cellular homeostasis (e.g., reducing reactive oxygen species). The essential role of selenoproteins in humans requires us to maintain appropriate levels of selenium, the precursor for Sec, in our diet. Too much selenium is also problematic due to its toxic effects. Deciphering the role of Sec in selenoproteins is challenging for many reasons, one of which is due to their complicated biosynthesis pathway. However, clever strategies are surfacing to overcome this and facilitate production of selenoproteins. Here, we focus on one of the 25 human selenoproteins, selenoprotein M (SELENOM), which has wide-spread expression throughout our tissues. Its thioredoxin motif suggests oxidoreductase function; however, its mechanism and functional role(s) are still being uncovered. Furthermore, the connection of both high and low expression levels of SELENOM to separate diseases emphasizes the medical application for studying the role of Sec in this protein. In this review, we aim to decipher the role of SELENOM through detailing and connecting current evidence. With multiple proposed functions in diverse tissues, continued research is still necessary to fully unveil the role of SELENOM.
PubMed: 38001759
DOI: 10.3390/antiox12111906 -
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 -
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 -
Biomeditsinskaia Khimiia Dec 2023The review considers modern data on the mechanisms of activation and redox regulation of the NLRP3 inflammasome and gasdermins, as well as the role of selenium in these... (Review)
Review
The review considers modern data on the mechanisms of activation and redox regulation of the NLRP3 inflammasome and gasdermins, as well as the role of selenium in these processes. Activation of the inflammasome and pyroptosis represent an evolutionarily conserved mechanism of the defense against pathogens, described for various types of cells and tissues (macrophages and monocytes, microglial cells and astrocytes, podocytes and parenchymal cells of the kidneys, periodontal tissues, osteoclasts and osteoblasts, as well as cells of the digestive and urogenital systems, etc.). Depending on the characteristics of redox regulation, the participants of NLRP3 inflammation and pyroptosis can be subdivided into 2 groups. Members of the first group block the mitochondrial electron transport chain, promote the formation of reactive oxygen species and the development of oxidative stress. This group includes granzymes, the mitochondrial antiviral signaling protein MAVS, and others. The second group includes thioredoxin interacting protein (TXNIP), erythroid-derived nuclear factor-2 (NRF2), Kelch-like ECH-associated protein 1 (Keap1), ninjurin (Ninj1), scramblase (TMEM16), inflammasome regulatory protein kinase NLRP3 (NEK7), caspase-1, gasdermins GSDM B, D and others. They have redox-sensitive domains and/or cysteine residues subjected to redox regulation, glutathionylation/deglutathionylation or other types of regulation. Suppression of oxidative stress and redox regulation of participants in NLRP3 inflammation and pyroptosis depends on the activity of the antioxidant enzymes glutathione peroxidase (GPX) and thioredoxin reductase (TRXR), containing a selenocysteine residue Sec in the active site. The expression of GPX and TRXR is regulated by NRF2 and depends on the concentration of selenium in the blood. Selenium deficiency causes ineffective translation of the Sec UGA codon, translation termination, and, consequently, synthesis of inactive selenoproteins, which can cause various types of programmed cell death: apoptosis of nerve cells and sperm, necroptosis of erythrocyte precursors, pyroptosis of infected myeloid cells, ferroptosis of T- and B-lymphocytes, kidney and pancreatic cells. In addition, suboptimal selenium concentrations in the blood (0.86 μM or 68 μg/l or less) have a significant impact on expression of more than two hundred and fifty genes as compared to the optimal selenium concentration (1.43 μM or 113 μg/l). Based on the above, we propose to consider blood selenium concentrations as an important parameter of redox homeostasis in the cell. Suboptimal blood selenium concentrations (or selenium deficiency states) should be used for assessment of the risk of developing inflammatory processes.
Topics: Humans; Gasdermins; Glutathione Peroxidase; Inflammasomes; Inflammation; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidation-Reduction; Pyroptosis; Selenium; Semen; Thioredoxin-Disulfide Reductase
PubMed: 38153050
DOI: 10.18097/PBMC20236906333 -
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 -
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 -
Nature Metabolism Feb 2024The canonical biological function of selenium is in the production of selenocysteine residues of selenoproteins, and this forms the basis for its role as an essential...
The canonical biological function of selenium is in the production of selenocysteine residues of selenoproteins, and this forms the basis for its role as an essential antioxidant and cytoprotective micronutrient. Here we demonstrate that, via its metabolic intermediate hydrogen selenide, selenium reduces ubiquinone in the mitochondria through catalysis by sulfide quinone oxidoreductase. Through this mechanism, selenium rapidly protects against lipid peroxidation and ferroptosis in a timescale that precedes selenoprotein production, doing so even when selenoprotein production has been eliminated. Our findings identify a regulatory mechanism against ferroptosis that implicates sulfide quinone oxidoreductase and expands our understanding of selenium in biology.
Topics: Selenium; Ubiquinone; Ferroptosis; Selenoproteins; Sulfides; Oxidoreductases
PubMed: 38351124
DOI: 10.1038/s42255-024-00974-4 -
Angewandte Chemie (International Ed. in... Dec 2023Mild strategies for the selective modification of peptides and proteins are in demand for applications in therapeutic peptide and protein discovery, and in the study of...
Mild strategies for the selective modification of peptides and proteins are in demand for applications in therapeutic peptide and protein discovery, and in the study of fundamental biomolecular processes. Herein, we describe the development of an electrochemical selenoetherification (e-SE) platform for the efficient site-selective functionalization of polypeptides. This methodology utilizes the unique reactivity of the 21st amino acid, selenocysteine, to effect formation of valuable bioconjugates through stable selenoether linkages under mild electrochemical conditions. The power of e-SE is highlighted through late-stage C-terminal modification of the FDA-approved cancer drug leuprolide and assembly of a library of anti-HER2 affibody conjugates bearing complex cargoes. Following assembly by e-SE, the utility of functionalized affibodies for in vitro imaging and targeting of HER2 positive breast and lung cancer cell lines is also demonstrated.
Topics: Selenocysteine; Peptides; Proteins; Cell Line; Antineoplastic Agents
PubMed: 37818778
DOI: 10.1002/anie.202313037 -
The Journal of Clinical Investigation Jul 2023Some studies suggest that the trace element selenium protects against colorectal cancer (CRC). However, the contribution of selenoprotein P (SELENOP), a unique...
Some studies suggest that the trace element selenium protects against colorectal cancer (CRC). However, the contribution of selenoprotein P (SELENOP), a unique selenocysteine-containing protein, to sporadic colorectal carcinogenesis challenges this paradigm. SELENOP is predominately secreted by the liver but is also expressed in various cells of the small intestine and colon in mice and humans. In this issue of the JCI, Pilat et al. demonstrate that increased SELENOP expression promoted the progression of conventional adenomas to carcinoma. SELENOP functioned as a modulator of canonical WNT signaling activity through interactions with WNT3A and its coreceptor LDL receptor-related protein 5/6 (LRP5/6). Secreted SELENOP formed a concentration gradient along the gut crypt axis, which might amplify WNT signaling activity by binding to LRPL5/6. The mechanism for WNT control via SELENOP may affect colorectal tumorigenesis and provide therapeutic targets for CRC.
Topics: Humans; Mice; Animals; Selenoprotein P; Carcinogenesis; Liver; Cell Transformation, Neoplastic; Selenium; Colorectal Neoplasms; Low Density Lipoprotein Receptor-Related Protein-5; Wnt3A Protein
PubMed: 37395277
DOI: 10.1172/JCI171885 -
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