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Antioxidants & Redox Signaling Oct 2015All cells must maintain a balance between oxidants and reductants, while allowing for fluctuations in redox states triggered by signaling, altered metabolic flow, or... (Review)
Review
SIGNIFICANCE
All cells must maintain a balance between oxidants and reductants, while allowing for fluctuations in redox states triggered by signaling, altered metabolic flow, or extracellular stimuli. Furthermore, they must be able to rapidly sense and react to various challenges that would disrupt the redox homeostasis.
RECENT ADVANCES
Many studies have identified Keap1 as a key sensor for oxidative or electrophilic stress, with modification of Keap1 by oxidation or electrophiles triggering Nrf2-mediated transcriptional induction of enzymes supporting reductive and detoxification pathways. However, additional mechanisms for Nrf2 regulation are likely to exist upstream of, or in parallel with, Keap1.
CRITICAL ISSUES
Here, we propose that the mammalian selenoprotein thioredoxin reductase 1 (TrxR1) is a potent regulator of Nrf2. A high chemical reactivity of TrxR1 and its vital role for the thioredoxin (Trx) system distinguishes TrxR1 as a prime target for electrophilic challenges. Chemical modification of the selenocysteine (Sec) in TrxR1 by electrophiles leads to rapid inhibition of thioredoxin disulfide reductase activity, often combined with induction of NADPH oxidase activity of the derivatized enzyme, thereby affecting many downstream redox pathways. The notion of TrxR1 as a regulator of Nrf2 is supported by many publications on effects in human cells of selenium deficiency, oxidative stress or electrophile exposure, as well as the phenotypes of genetic mouse models.
FUTURE DIRECTIONS
Investigation of the role of TrxR1 as a regulator of Nrf2 activation will facilitate further studies of redox control in diverse cells and tissues of mammals, and possibly also in animals of other classes.
Topics: Animals; Humans; Intracellular Signaling Peptides and Proteins; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Oxidation-Reduction; Selenocysteine; Signal Transduction; Thioredoxin Reductase 1
PubMed: 26058897
DOI: 10.1089/ars.2015.6378 -
Journal of Trace Elements in Medicine... Sep 2023To protect from toxicity at supra-essential doses of selenium, it is important to determine dose levels at which adverse effects occur. (Review)
Review
BACKGROUND
To protect from toxicity at supra-essential doses of selenium, it is important to determine dose levels at which adverse effects occur.
METHODS
We identified relevant literature on the repeated dosage of selenium and extracted dose descriptors on reported endpoints, except on genotoxicity/carcinogenicity.
RESULTS
Selenium forms with toxicological data were organic ones: selenomethionine, selenocystine/selenocysteine; and inorganic ones, including selenite (SeO), selenate (SeO), selenium sulphide (SeS), selenide (Se) and selenium nanoparticles. Clinical signs of selenium toxicity in humans include a garlicky-smelling breath, hair loss, and nail changes. One human study showed increased mortality following daily ingestion of 300 µg Se per day for 5 years, equal to a lowest-observed-adverse-effect level (LOAEL) of ∼4.3 µg/kg bw/days. The corresponding no-observed-adverse-effect level (NOAEL) was ∼2.9 µg Se/kg bw/day. One study reported an increased risk of type 2 diabetes after ∼2.9 µg Se/kg bw/day, but other studies with similar doses found no increases in mortality or incidence of type 2 diabetes. NOAELs on affected body weight in animal studies were 0.24-1.2 mg Se/kg bw/day. Other endpoints of selenium toxicity in animals include hepatotoxicity with a NOAEL as low as 2 µg/kg bw/day in rats, as well as gastrointestinal, cardiovascular, and reproductive toxicities with NOAELs of 0.6 (gastrointestinal), 0.08, and 0.4 (cardiovascular) and ≥ 0.04 mg Se/kg bw/day (reproductive), respectively.
CONCLUSIONS
Dose descriptors describing selenium toxicity were as low as 2-3 µg Se/kg bw/day.
Topics: Humans; Rats; Animals; Selenium; Diabetes Mellitus, Type 2; Selenious Acid; Selenocysteine; Nanoparticles
PubMed: 37285631
DOI: 10.1016/j.jtemb.2023.127235 -
The Journal of Biological Chemistry Apr 2014Selenoproteins are a unique family of proteins, characterized by the co-translational incorporation of selenium as selenocysteine, which play key roles in antioxidant...
Selenoproteins are a unique family of proteins, characterized by the co-translational incorporation of selenium as selenocysteine, which play key roles in antioxidant defense. Among selenoproteins, selenoprotein P (Sepp1) is particularly distinctive due to the fact that it contains multiple selenocysteine residues and has been postulated to act in selenium transport. Within the brain, Sepp1 delivers selenium to neurons by binding to the ApoER2 receptor. Upon feeding a selenium-deficient diet, mice lacking ApoER2 or Sepp1 develop severe neurological dysfunction and exhibit widespread brainstem neurodegeneration, indicating an important role for ApoER2-mediated Sepp1 uptake in normal brain function. Selenocysteine lyase (Scly) is an enzyme that plays an important role in selenium homeostasis, in that it catalyzes the decomposition of selenocysteine and allows selenium to be recycled for additional selenoprotein synthesis. We previously reported that constitutive deletion of Scly results in neurological deficits only when mice are challenged with a low selenium diet. To gain insight into the relationship between Sepp1 and Scly in selenium metabolism, we created novel transgenic mice constitutively lacking both genes (Scly(-/-)Sepp1(-/-)) and characterized the neurobehavioral phenotype. We report that deletion of Scly in conjunction with Sepp1 further aggravates the phenotype of Sepp1(-/-) mice, as these mice needed supraphysiological selenium supplementation to survive, and surviving mice exhibited impaired motor coordination, audiogenic seizures, and brainstem neurodegeneration. These findings provide the first in vivo evidence that Scly and Sepp1 work cooperatively to maintain selenoprotein function in the mammalian brain.
Topics: Animals; Behavior, Animal; Brain; Lyases; Mice; Mice, Knockout; Nerve Tissue Proteins; Neurodegenerative Diseases; Seizures; Selenocysteine; Selenoprotein P
PubMed: 24519931
DOI: 10.1074/jbc.M113.540682 -
Biomolecules Jul 2022The human genome has 25 genes coding for selenocysteine (Sec)-containing proteins, whose synthesis is supported by specialized Sec machinery proteins. Here, we carried...
The human genome has 25 genes coding for selenocysteine (Sec)-containing proteins, whose synthesis is supported by specialized Sec machinery proteins. Here, we carried out an analysis of the co-essentiality network to identify functional partners of selenoproteins and Sec machinery. One outstanding cluster included all seven known Sec machinery proteins and two critical selenoproteins, GPX4 and TXNRD1. Additionally, these nine genes were further positively associated with PRDX6 and negatively with SCD, linking the latter two genes to the essential role of selenium. We analyzed the essentiality scores of gene knockouts in this cluster across one thousand cancer cell lines and found that Sec metabolism genes are strongly selective for a subset of primary tissues, suggesting that certain cancer cell lineages are particularly dependent on selenium. A separate outstanding cluster included selenophosphate synthetase SEPHS1, which was linked to a group of transcription factors, whereas the remaining selenoproteins were linked neither to these clusters nor among themselves. The data suggest that key components of Sec machinery have already been identified and that their primary role is to support the functions of GPX4 and TXNRD1, with further functional links to PRDX6 and SCD.
Topics: Cell Line; Genome, Human; Humans; Peroxiredoxin VI; Phospholipid Hydroperoxide Glutathione Peroxidase; Selenium; Selenocysteine; Selenoproteins; Stearoyl-CoA Desaturase; Thioredoxin Reductase 1
PubMed: 36008942
DOI: 10.3390/biom12081049 -
Free Radical Biology & Medicine Sep 2022Human thioredoxin reductase (TrxR) is a selenoprotein with a central role in cellular redox homeostasis, utilizing a highly reactive and solvent-exposed selenocysteine... (Review)
Review
Human thioredoxin reductase (TrxR) is a selenoprotein with a central role in cellular redox homeostasis, utilizing a highly reactive and solvent-exposed selenocysteine (Sec) residue in its active site. Pharmacological modulation of TrxR can be obtained with several classes of small compounds showing different mechanisms of action, but most often dependent upon interactions with its Sec residue. The clinical implications of TrxR modulation as mediated by small compounds have been studied in diverse diseases, from rheumatoid arthritis and ischemia to cancer and parasitic infections. The possible involvement of TrxR in these diseases was in some cases serendipitously discovered, by finding that existing clinically used drugs are also TrxR inhibitors. Inhibiting isoforms of human TrxR is, however, not the only strategy for human disease treatment, as some pathogenic parasites also depend upon Sec-containing TrxR variants, including S. mansoni, B. malayi or O. volvulus. Inhibiting parasite TrxR has been shown to selectively kill parasites and can thus become a promising treatment strategy, especially in the context of quickly emerging resistance towards other drugs. Here we have summarized the basis for the targeting of selenoprotein TrxR variants with small molecules for therapeutic purposes in different human disease contexts. We discuss how Sec engagement appears to be an indispensable part of treatment efficacy and how some therapeutically promising compounds have been evaluated in preclinical or clinical studies. Several research questions remain before a wider application of selenoprotein TrxR inhibition as a first-line treatment strategy might be developed. These include further mechanistic studies of downstream effects that may mediate treatment efficacy, identification of isoform-specific enzyme inhibition patterns for some given therapeutic compounds, and the further elucidation of cell-specific effects in disease contexts such as in the tumor microenvironment or in host-parasite interactions, and which of these effects may be dependent upon the specific targeting of Sec in distinct TrxR isoforms.
Topics: Humans; Neoplasms; Selenocysteine; Selenoproteins; Thioredoxin-Disulfide Reductase; Tumor Microenvironment
PubMed: 35987423
DOI: 10.1016/j.freeradbiomed.2022.07.020 -
The Journal of Biological Chemistry Jul 2011Biological trace elements are needed in small quantities but are used by all living organisms. A growing list of trace element-dependent proteins and trace element... (Comparative Study)
Comparative Study Review
Biological trace elements are needed in small quantities but are used by all living organisms. A growing list of trace element-dependent proteins and trace element utilization pathways highlights the importance of these elements for life. In this minireview, we focus on recent advances in comparative genomics of trace elements and explore the evolutionary dynamics of the dependence of user proteins on these elements. Many zinc protein families evolved representatives that lack this metal, whereas selenocysteine in proteins is dynamically exchanged with cysteine. Several other elements, such as molybdenum and nickel, have a limited number of user protein families, but they are strictly dependent on these metals. Comparative genomics of trace elements provides a foundation for investigating the fundamental properties, functions, and evolutionary dynamics of trace element dependence in biology.
Topics: Animals; Evolution, Molecular; Genomics; Humans; Metalloproteins; Metals; Selenocysteine; Trace Elements
PubMed: 21566146
DOI: 10.1074/jbc.R110.172833 -
International Journal of Molecular... Oct 2021The selenoprotein family includes 25 members, many of which are antioxidant or redox regulating enzymes. A unique member of this family is Selenoprotein I (SELENOI),... (Review)
Review
The selenoprotein family includes 25 members, many of which are antioxidant or redox regulating enzymes. A unique member of this family is Selenoprotein I (SELENOI), which does not catalyze redox reactions, but instead is an ethanolamine phosphotransferase (Ept). In fact, the characteristic selenocysteine residue that defines selenoproteins lies far outside of the catalytic domain of SELENOI. Furthermore, data using recombinant SELENOI lacking the selenocysteine residue have suggested that the selenocysteine amino acid is not directly involved in the Ept reaction. SELENOI is involved in two different pathways for the synthesis of phosphatidylethanolamine (PE) and plasmenyl PE, which are constituents of cellular membranes. Ethanolamine phospholipid synthesis has emerged as an important process for metabolic reprogramming that occurs in pluripotent stem cells and proliferating tumor cells, and this review discusses roles for upregulation of SELENOI during T cell activation, proliferation, and differentiation. SELENOI deficiency lowers but does not completely diminish de novo synthesis of PE and plasmenyl PE during T cell activation. Interestingly, metabolic reprogramming in activated SELENOI deficient T cells is impaired and this reduces proliferative capacity while favoring tolerogenic to pathogenic phenotypes that arise from differentiation. The implications of these findings are discussed related to vaccine responses, autoimmunity, and cell-based therapeutic approaches.
Topics: Cellular Reprogramming; Ethanolamine; Ethanolaminephosphotransferase; Humans; Lymphocyte Activation; Phosphatidylethanolamines; Phospholipids; Selenium; Selenocysteine; Selenoproteins; T-Lymphocytes; Up-Regulation
PubMed: 34681834
DOI: 10.3390/ijms222011174 -
Journal of Bacteriology Apr 2002Selenophosphate synthetase (SPS), the selD gene product from Escherichia coli, catalyzes the biosynthesis of monoselenophosphate, AMP, and orthophosphate in a 1:1:1...
Selenophosphate synthetase (SPS), the selD gene product from Escherichia coli, catalyzes the biosynthesis of monoselenophosphate, AMP, and orthophosphate in a 1:1:1 ratio from selenide and ATP. It was recently demonstrated that selenium delivered from selenocysteine by an E. coli NifS-like protein could replace free selenide in the in vitro SPS assay for selenophosphate formation (G. M. Lacourciere, H. Mihara, T. Kurihara, N. Esaki, and T. C. Stadtman, J. Biol. Chem. 275:23769-23773, 2000). During growth of E. coli in the presence of 0.1 microM (75)SeO(3)(2-) and increasing amounts of L-selenocysteine, a concomitant decrease in (75)Se incorporation into formate dehydrogenase H and nucleosides of bulk tRNA was observed. This is consistent with the mobilization of selenium from L-selenocysteine in vivo and its use in selenophosphate formation. The ability of E. coli to utilize selenocysteine as a selenium source for selenophosphate biosynthesis in vivo supports the participation of the NifS-like proteins in selenium metabolism.
Topics: Biological Transport; Escherichia coli; Formate Dehydrogenases; Hydrogenase; Multienzyme Complexes; Phosphates; RNA, Transfer; Selenium; Selenium Compounds; Selenocysteine
PubMed: 11889101
DOI: 10.1128/JB.184.7.1940-1946.2002 -
Molecular Cell Jan 2004Reprogrammed genetic decoding signals in mRNAs productively overwrite the normal decoding rules of translation. These "recoding" signals are associated with sites of... (Review)
Review
Reprogrammed genetic decoding signals in mRNAs productively overwrite the normal decoding rules of translation. These "recoding" signals are associated with sites of programmed ribosomal frameshifting, hopping, termination codon suppression, and the incorporation of the unusual amino acids selenocysteine and pyrrolysine. This review summarizes current knowledge of the structure and function of recoding signals in cellular genes, the biological importance of recoding in gene regulation, and ways to identify new recoded genes.
Topics: Animals; Base Sequence; Codon; Escherichia coli; Gene Expression; Humans; Lysine; Molecular Sequence Data; Protein Biosynthesis; RNA, Messenger; Saccharomyces cerevisiae; Selenocysteine
PubMed: 14759362
DOI: 10.1016/s1097-2765(04)00031-0 -
Current Protocols Feb 2021Selenoproteins contain the 21st amino acid, selenocysteine. Selenocysteine is the only amino acid that is synthesized on its cognate tRNA, and it is inserted at specific...
Selenoproteins contain the 21st amino acid, selenocysteine. Selenocysteine is the only amino acid that is synthesized on its cognate tRNA, and it is inserted at specific recoded UGA stop codons via a complex translation system. Although highly similar to cysteine, selenocysteine has unique properties, including a stronger nucleophilic ability and lower reduction potential. Efforts to site-specifically incorporate selenocysteine to create recombinant selenoproteins involve a recoded UAG stop codon and expression of the necessary selenocysteine translation machinery. This article presents a protocol for expressing and purifying selenoproteins in Escherichia coli. © 2021 Wiley Periodicals LLC. Basic Protocol: Recombinant selenoprotein production in E. coli using a rewired translation system.
Topics: Codon, Terminator; Escherichia coli; Recombinant Proteins; Selenocysteine; Selenoproteins
PubMed: 33566458
DOI: 10.1002/cpz1.54