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Advanced Materials (Deerfield Beach,... Apr 2024Osteoclast hyperactivation stands as a significant pathological factor contributing to the emergence of bone disorders driven by heightened oxidative stress levels. The...
Osteoclast hyperactivation stands as a significant pathological factor contributing to the emergence of bone disorders driven by heightened oxidative stress levels. The modulation of the redox balance to scavenge reactive oxygen species emerges as a viable approach to addressing this concern. Selenoproteins, characterized by selenocysteine (SeCys) as the active center, are crucial for selenium-based antioxidative stress therapy for inflammatory diseases. This study reveals that surface-active elemental selenium (Se) nanoparticles, particularly lentinan-Se (LNT-Se), exhibit enhanced cellular accumulation and accelerated metabolism to SeCys, the primary active Se form in biological systems. Consequently, LNT-Se demonstrates significant inhibition of osteoclastogenesis. Furthermore, in vivo studies underscore the superior therapeutic efficacy of LNT-Se over SeCys, potentially attributable to the enhanced stability and safety profile of LNT-Se. Specifically, LNT-Se effectively modulates the expression of the selenoprotein GPx1, thereby exerting regulatory control over osteoclastogenesis inhibition, and the prevention of osteolysis. In summary, these results suggest that the prompt activation of selenoproteins by Se nanoparticles serves to suppress osteoclastogenesis and pathological bone loss by upregulating GPx1. Moreover, the utilization of bioactive Se species presents a promising avenue for effectively managing bone disorders.
PubMed: 38621414
DOI: 10.1002/adma.202401620 -
Current Research in Structural Biology 2024The 21st amino acid, selenocysteine (Sec), is synthesized on its dedicated transfer RNA (tRNA). In bacteria, Sec is synthesized from Ser-tRNA by Selenocysteine Synthase...
The 21st amino acid, selenocysteine (Sec), is synthesized on its dedicated transfer RNA (tRNA). In bacteria, Sec is synthesized from Ser-tRNA by Selenocysteine Synthase (SelA), which is a pivotal enzyme in the biosynthesis of Sec. The structural characterization of bacterial SelA is of paramount importance to decipher its catalytic mechanism and its role in the regulation of the Sec-synthesis pathway. Here, we present a comprehensive single-particle cryo-electron microscopy (SPA cryoEM) structure of the bacterial SelA with an overall resolution of 2.69 Å. Using recombinant SelA, we purified and prepared samples for single-particle cryoEM. The structural insights from SelA, combined with previous and knowledge, underscore the indispensable role of decamerization in SelA's function. Moreover, our structural analysis corroborates previous results that show that SelA adopts a pentamer of dimers configuration, and the active site architecture, substrate binding pocket, and key K295 catalytic residue are identified and described in detail. The differences in protein architecture and substrate coordination between the bacterial enzyme and its counterparts offer compelling structural evidence supporting the independent molecular evolution of the bacterial and archaea/eukarya Ser-Sec biosynthesis present in the natural world.
PubMed: 38681238
DOI: 10.1016/j.crstbi.2024.100143 -
Inorganic Chemistry Oct 2023The biological activity of Pd(II) and Pt(II) complexes toward three different cancer cell lines as well as inhibition of selenoenzyme thioredoxin reductase (TrxR) was...
Taming the Biological Activity of Pd(II) and Pt(II) Complexes with Triazolato "Protective" Groups: H, Se Nuclear Magnetic Resonance and X-ray Crystallographic Model Studies with Selenocysteine to Elucidate Differential Thioredoxin Reductase Inhibition.
The biological activity of Pd(II) and Pt(II) complexes toward three different cancer cell lines as well as inhibition of selenoenzyme thioredoxin reductase (TrxR) was modulated in an unexpected way by the introduction of triazolate as a "protective group" to the inner metal coordination sphere using the iClick reaction of [M(N)(terpy)]PF [M = Pd(II) or Pt(II) and terpy = 2,2':6',2″-terpyridine] with an electron-poor alkyne. In a cell proliferation assay using A549, HT-29, and MDA-MB-231 human cancer cell lines, the palladium compound was significantly more potent than the isostructural platinum analogue and exhibited submicromolar activity on the most responsive cell line. This difference was also reflected in the inhibitory efficiency toward TrxR with IC values of 0.1 versus 5.4 μM for the Pd(II) and Pt(II) complexes, respectively. UV/Vis kinetic studies revealed that the Pt compound binds to selenocysteine faster than to cysteine [ = (22.9 ± 0.2)·10 vs (7.1 ± 0.2)·10 s]. Selective triazolato ligand exchange of the title compounds with cysteine (Hcys) and selenocysteine (Hsec)─but not histidine (His) and 9-ethylguanine (9EtG)─was confirmed by H, Se, and Pt NMR spectroscopy. Crystal structures of three of the four ligand exchange products were obtained, including [Pt(sec)(terpy)]PF as the first metal complex of selenocysteine to be structurally characterized.
PubMed: 37713601
DOI: 10.1021/acs.inorgchem.3c02701 -
Applied Microbiology and Biotechnology Dec 2023Cordycepin, a nucleoside analog, is the main antioxidative and antimicrobial substance in Cordyceps militaris. To improve the metabolism of cordycepin, carbon sources,...
Cordycepin, a nucleoside analog, is the main antioxidative and antimicrobial substance in Cordyceps militaris. To improve the metabolism of cordycepin, carbon sources, nitrogen sources, trace elements, and precursors were studied by single factor, Plackett-Burman, and central composite designs in C. militaris mycelial fermentation. Under the regulation of the multifactorial interactions of selenite, ferrous chloride, xylose, and glycine, cordycepin production was increased by 5.2-fold compared with the control. The gene expression of hexokinase, ATP phosphoribosyltransferase, adenylosuccinate synthetase, and cns1-3 in the glycolysis, pentose phosphate, and adenosine synthesis pathways were increased by 3.2-7.5 times due to multifactorial interactions, while the gene expression of histidine biosynthesis trifunctional protein and histidinol-phosphate aminotransferase in histidine synthesis pathway were decreased by 23.4%-56.2%. Increasing with cordycepin production, glucose uptake was accelerated, mycelia growth was inhibited, and the cell wall was damaged. Selenomethionine (SeMet), selenocysteine (SeCys), and selenium nanoparticles (SeNPs) were the major Se species in C. militaris mycelia. This study provides a new insight for promoting cordycepin production by regulating glycolysis, pentose phosphate, and histidine metabolism. KEY POINTS: • Cordycepin production in the CCD group was 5.2-fold than that of the control. • Glucose uptake of the CCD group was accelerated and cell wall was damaged. • The metabolic flux was concentrated to the cordycepin synthesis pathway.
Topics: Selenium; Cordyceps; Xylose; Iron; Glycine; Histidine; Deoxyadenosines; Glucose; Phosphates
PubMed: 37773218
DOI: 10.1007/s00253-023-12792-x -
Food and Chemical Toxicology : An... Nov 2023To evaluate and compare the safety of four selenium supplements, namely Se-enriched peptides (SeP), yeast selenium (SeY), L-Se-methylselenocysteine (L-SeMc) and sodium...
To evaluate and compare the safety of four selenium supplements, namely Se-enriched peptides (SeP), yeast selenium (SeY), L-Se-methylselenocysteine (L-SeMc) and sodium selenite (NaSeO), the subchronic toxicity study was designed by 90-day gavage administration in Sprague-Dawley rats. The doses of SeP, SeY, L-SeMc and NaSeO were 0.15, 0.30 and 0.60 mg/kg bw/day, with additional dose of 0.45 mg/kg L-SeMc (All dose calculated as Se). Symptoms like growling, hair loss and significant weight loss were found at 0.60 mg/kg of L-SeMc, but not in other groups. At the dose of 0.60 mg/kg, females in NaSeO, SeY and L-SeMc groups showed significant elevations in ALT and/or ALP. Pathologic manifestations such as bile duct hyperplasia and cholestasis were predominantly found in females at 0.6 mg/kg of L-SeMc and SeY groups, and in males at same dose of L-SeMc group showed marked testicular atrophy. 0.60 mg/kg of SeY and NaSeO, and 0.30, 0.45, 0.60 mg/kg of L-SeMc induced significant reductions in sperm motility rates, rapid movement and amount. In conclusion, the NOAEL of SeP, SeY, L-SeMc, NaSeO was all 0.30 mg/kg for female, and 0.60, 0.30, 0.15 and 0.30 mg/kg for male respectively. Liver and reproductive organs are possible toxic target organs of hyper selenium.
Topics: Male; Female; Rats; Animals; Rats, Sprague-Dawley; Selenium; Sperm Motility; Dietary Supplements; Sodium Selenite; Saccharomyces cerevisiae
PubMed: 37758048
DOI: 10.1016/j.fct.2023.114059 -
Journal of Hazardous Materials Sep 2023Cadmium (Cd), a widespread and highly toxic environmental contaminant, has seriously impacted the growth of rice and the quality of its products. Hence, it is crucial to...
Cadmium (Cd), a widespread and highly toxic environmental contaminant, has seriously impacted the growth of rice and the quality of its products. Hence, it is crucial to monitor and employ robust means to reduce Cd levels in rice, and selenium (Se) has been proven to chelate cadmium ion (Cd) in rice with rational use. Herein, for the first time, the reported selenocysteine (Sec) probe NN-Sec and the newly designed Cd probe SCP were chosen as visualization tools to monitor Sec-inhibited Cd uptake in rice. Specifically, reduced fluorescence of rice precultured with Cd was observed by SCP after Se application, while similarly decreased fluorescence of rice pretreated with Se was observed by NN-Sec after Cd addition. The diminished fluorescence indicated the formation of Cd-Se complexes reduced the Cd content in rice. Additionally, it was Cd and Se that entered the rice causing the fluorescence generation, as demonstrated by inductively coupled plasma mass spectrometry (ICP-MS). To conclude, the two probes successfully visualized Se inhibited Cd uptake in rice, which could provide a robust tool for supporting the development of novel organic fertilizers and reagents to reduce Cd content in rice and the environment.
Topics: Selenium; Cadmium; Oryza; Fluorescent Dyes; Soil Pollutants
PubMed: 37267647
DOI: 10.1016/j.jhazmat.2023.131748 -
Plant Physiology and Biochemistry : PPB Jun 2024Ostreococcus spp. are unicellular organisms with one of the simplest cellular organizations. The sequencing of the genomes of different Ostreococcus species has... (Review)
Review
Ostreococcus spp. are unicellular organisms with one of the simplest cellular organizations. The sequencing of the genomes of different Ostreococcus species has reinforced this status since Ostreococcus tauri has one most compact nuclear genomes among eukaryotic organisms. Despite this, it has retained a number of genes, setting it apart from other organisms with similar small genomes. Ostreococcus spp. feature a substantial number of selenocysteine-containing proteins, which, due to their higher catalytic activity compared to their selenium-lacking counterparts, may require a reduced quantity of proteins. Notably, O. tauri encodes several ammonium transporter genes, that may provide it with a competitive edge for acquiring nitrogen (N). This characteristic makes it an intriguing model for studying the efficient use of N in eukaryotes. Under conditions of low N availability, O. tauri utilizes N from abundant proteins or amino acids, such as L-arginine, similar to higher plants. However, the presence of a nitric oxide synthase (L-arg substrate) sheds light on a new metabolic pathway for L-arg in algae. The metabolic adaptations of O. tauri to day and night cycles offer valuable insights into carbon and iron metabolic configuration. O. tauri has evolved novel strategies to optimize iron uptake, lacking the classic components of the iron absorption mechanism. Overall, the cellular and genetic characteristics of Ostreococcus contribute to its evolutionary success, making it an excellent model for studying the physiological and genetic aspects of how green algae have adapted to the marine environment. Furthermore, given its potential for lipid accumulation and its marine habitat, it may represent a promising avenue for third-generation biofuels.
Topics: Adaptation, Physiological; Chlorophyceae; Chlorophyta; Nitrogen; Marine Biology
PubMed: 38735153
DOI: 10.1016/j.plaphy.2024.108661 -
Chemistry (Weinheim An Der Bergstrasse,... Aug 2023Diselenide-selenoester ligations are increasingly used for the synthesis of proteins. Excellent ligation rates, even at low concentrations, in combination with mild and...
Diselenide-selenoester ligations are increasingly used for the synthesis of proteins. Excellent ligation rates, even at low concentrations, in combination with mild and selective deselenization conditions can overcome some of the most severe challenges in chemical protein synthesis. Herein, the versatile multicomponent synthesis and application of a new ligation auxiliary that combines a photocleavable scaffold with the advantages of selenium-based ligation strategies are presented. Its use was investigated with respect to different ligation junctions and describe a novel para-methoxybenzyl deprotection reaction for the selenol moiety. The glycine-based auxiliary enabled successful synthesis of the challenging target protein G-CSF.
Topics: Peptides; Proteins
PubMed: 37265454
DOI: 10.1002/chem.202301253 -
Chemistry (Weinheim An Der Bergstrasse,... Mar 2024A low pKa (5.2), high polarizable volume (3.8 Å), and proneness to oxidation under ambient conditions make selenocysteine (Sec, U) a unique, natural reactive handle...
A low pKa (5.2), high polarizable volume (3.8 Å), and proneness to oxidation under ambient conditions make selenocysteine (Sec, U) a unique, natural reactive handle present in most organisms across all domains of life. Sec modification still has untapped potential for site-selective protein modification and probing. Herein we demonstrate the use of a cyclometalated gold(III) compound, [Au(bnpy)Cl ], in the arylation of diselenides of biological significance, with a scope covering small molecule models, peptides, and proteins using a combination of multinuclear NMR (including Se NMR), and LC-MS. Diphenyl diselenide (Ph-Se) and selenocystine, (Sec) , were used for reaction optimization. This approach allowed us to demonstrate that an excess of diselenide (Au/Se-Se) and an increasing water percentage in the reaction media enhance both the conversion and kinetics of the C-Se coupling reaction, a combination that makes the reaction biocompatible. The C-Se coupling reaction was also shown to happen for the diselenide analogue of the cyclic peptide vasopressin ((Se-Se)-AVP), and the Bos taurus glutathione peroxidase (GPx1) enzyme in ammonium acetate (2 mM, pH=7.0). The reaction mechanism, studied by DFT revealed a redox-based mechanism where the C-Se coupling is enabled by the reductive elimination of the cyclometalated Au(III) species into Au(I).
Topics: Animals; Cattle; Selenium; Gold; Peptides; Glutathione Peroxidase; Selenocysteine; Cystine; Organoselenium Compounds
PubMed: 38197477
DOI: 10.1002/chem.202304050 -
BioRxiv : the Preprint Server For... May 2024Many of the proteins that contain the amino acid selenocysteine are required for optimal defense against cellular stress. As such, one might expect selenoprotein...
BACKGROUND AND AIMS
Many of the proteins that contain the amino acid selenocysteine are required for optimal defense against cellular stress. As such, one might expect selenoprotein synthesis to persist or be induced upon cellular insult. Because selenocysteine is incorporated by a complex post-transcriptional mechanism, monitoring the transcription of selenoprotein genes is not adequate to understand the regulation of selenoprotein synthesis. We aimed to determine whether selenoprotein synthesis is regulated by the induction of hepatotoxic stress.
METHODS
We used hepatotropic clinically relevant drugs to evaluate the regulation of selenoprotein synthesis in human hepatocarcinoma cells.
RESULTS
We found that two drugs, benzbromarone and sorafenib, caused significant inhibition of selenoprotein synthesis. However, the loss of selenoprotein expression was not specific as total protein synthesis was similarly down-regulated only by benzbromarone and sorafenib.
CONCLUSIONS
These results allow us to conclude that these hepatotoxins do not induce or preserve selenoprotein synthesis as a protective mechanism.
HIGHLIGHTS
The treatment of liver cells with hepatotoxic and hepatotropic compounds does not result in increased synthesis of selenoproteins.Compounds that induced the canonical oxidative stress response that features NRF2 activation eliminated selenoprotein synthesis.The downregulation of selenoproteins was accompanied by general inhibition of protein synthesis.
PubMed: 38826422
DOI: 10.1101/2023.05.12.540527