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International Journal of Molecular... Oct 2021Selenium is incorporated into selenoproteins as the 21st amino acid selenocysteine (Sec). There are 25 selenoproteins encoded in the human genome, and their synthesis... (Review)
Review
Selenium is incorporated into selenoproteins as the 21st amino acid selenocysteine (Sec). There are 25 selenoproteins encoded in the human genome, and their synthesis requires a dedicated machinery. Most selenoproteins are oxidoreductases with important functions in human health. A number of disorders have been associated with deficiency of selenoproteins, caused by mutations in selenoprotein genes or Sec machinery genes. We discuss mutations that are known to cause disease in humans and report their allele frequencies in the general population. The occurrence of protein-truncating variants in the same genes is also presented. We provide an overview of pathogenic variants in selenoproteins genes from a population genomics perspective.
Topics: Alleles; Animals; Genetic Variation; Genome, Human; Humans; Selenium; Selenocysteine; Selenoproteins
PubMed: 34769022
DOI: 10.3390/ijms222111593 -
Nature Communications Nov 2022The importance of modified peptides and proteins for applications in drug discovery, and for illuminating biological processes at the molecular level, is fueling a...
The importance of modified peptides and proteins for applications in drug discovery, and for illuminating biological processes at the molecular level, is fueling a demand for efficient methods that facilitate the precise modification of these biomolecules. Herein, we describe the development of a photocatalytic method for the rapid and efficient dimerization and site-specific functionalization of peptide and protein diselenides. This methodology, dubbed the photocatalytic diselenide contraction, involves irradiation at 450 nm in the presence of an iridium photocatalyst and a phosphine and results in rapid and clean conversion of diselenides to reductively stable selenoethers. A mechanism for this photocatalytic transformation is proposed, which is supported by photoluminescence spectroscopy and density functional theory calculations. The utility of the photocatalytic diselenide contraction transformation is highlighted through the dimerization of selenopeptides, and by the generation of two families of protein conjugates via the site-selective modification of calmodulin containing the 21 amino acid selenocysteine, and the C-terminal modification of a ubiquitin diselenide.
Topics: Selenocysteine; Peptides; Proteins; Amino Acids
PubMed: 36371402
DOI: 10.1038/s41467-022-34530-z -
The Biochemical Journal Feb 2000The mammalian thioredoxin reductases (TrxRs) are a family of selenium-containing pyridine nucleotide-disulphide oxidoreductases with mechanistic and sequence identity,... (Review)
Review
The mammalian thioredoxin reductases (TrxRs) are a family of selenium-containing pyridine nucleotide-disulphide oxidoreductases with mechanistic and sequence identity, including a conserved -Cys-Val-Asn-Val-Gly-Cys- redox catalytic site, to glutathione reductases. TrxRs catalyse the NADPH-dependent reduction of the redox protein thioredoxin (Trx), as well as of other endogenous and exogenous compounds. The broad substrate specificity of mammalian TrxRs is due to a second redox-active site, a C-terminal -Cys-SeCys- (where SeCys is selenocysteine), that is not found in glutathione reductase or Escherichia coli TrxR. There are currently two confirmed forms of mammalian TrxRs, TrxR1 and TrxR2, and it is possible that other forms will be identified. The availability of Se is a key factor determining TrxR activity both in cell culture and in vivo, and the mechanism(s) for the incorporation of Se into TrxRs, as well as the regulation of TrxR activity, have only recently begun to be investigated. The importance of Trx to many aspects of cell function make it likely that TrxRs also play a role in protection against oxidant injury, cell growth and transformation, and the recycling of ascorbate from its oxidized form. Since TrxRs are able to reduce a number of substrates other than Trx, it is likely that additional biological effects will be discovered for TrxR. Furthermore, inhibiting TrxR with drugs may lead to new treatments for human diseases such as cancer, AIDS and autoimmune diseases.
Topics: Animals; Ascorbic Acid; Cell Division; Disease; Gene Expression Regulation, Enzymologic; Humans; Oxidative Stress; Selenium; Selenocysteine; Thioredoxin-Disulfide Reductase; Tumor Suppressor Protein p53
PubMed: 10657232
DOI: No ID Found -
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 -
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 -
Molecules (Basel, Switzerland) Nov 2021Selenocysteine (Sec) is the 21st non-standard proteinogenic amino acid. Due to the particularity of the codon encoding Sec, the selenoprotein synthesis needs to be... (Review)
Review
Selenocysteine (Sec) is the 21st non-standard proteinogenic amino acid. Due to the particularity of the codon encoding Sec, the selenoprotein synthesis needs to be completed by unique mechanisms in specific biological systems. In this paper, the underlying mechanisms for the biosynthesis and incorporation of Sec into selenoprotein were comprehensively reviewed on five aspects: (i) the specific biosynthesis mechanism of Sec and the role of its internal influencing factors (SelA, SelB, SelC, SelD, SPS2 and PSTK); (ii) the elements (SECIS, PSL, SPUR and RF) on mRNA and their functional mechanisms; (iii) the specificity (either translation termination or translation into Sec) of UGA; (iv) the structure-activity relationship and action mechanism of SelA, SelB, SelC and SelD; and (v) the operating mechanism of two key enzyme systems for inorganic selenium source flow before Sec synthesis. Lastly, the size of the translation initiation interval, other action modes of SECIS and effects of REPS (Repetitive Extragenic Palindromic Sequences) that affect the incorporation efficiency of Sec was also discussed to provide scientific basis for the large-scale industrial fermentation for the production of selenoprotein.
Topics: Nucleic Acid Conformation; RNA, Messenger; Selenium; Selenocysteine; Selenoproteins; Structure-Activity Relationship
PubMed: 34885702
DOI: 10.3390/molecules26237120 -
RNA Biology 2018Posttranslational modification (PTM) is a key mechanism for regulating diverse protein functions, and thus critically affects many essential biological processes.... (Review)
Review
Posttranslational modification (PTM) is a key mechanism for regulating diverse protein functions, and thus critically affects many essential biological processes. Critical for systematic study of the effects of PTMs is the ability to obtain recombinant proteins with defined and homogenous modifications. To this end, various synthetic and chemical biology approaches, including genetic code expansion and protein chemical modification methods, have been developed. These methods have proven effective for generating site-specific authentic modifications or structural mimics, and have demonstrated their value for in vitro and in vivo functional studies of diverse PTMs. This review will discuss recent advances in chemical biology strategies and their application to various PTM studies.
Topics: Acetylation; Chemistry Techniques, Synthetic; Codon, Terminator; Genetic Code; Glycosylation; Humans; Lysine; Methylation; Nitrates; Phosphorylation; Protein Processing, Post-Translational; Proteome; Selenocysteine; Sulfates; Ubiquitination
PubMed: 28901832
DOI: 10.1080/15476286.2017.1360468 -
EMBO Reports May 2004In the genetic code, the UGA codon has a dual function as it encodes selenocysteine (Sec) and serves as a stop signal. However, only the translation terminator function...
In the genetic code, the UGA codon has a dual function as it encodes selenocysteine (Sec) and serves as a stop signal. However, only the translation terminator function is used in gene annotation programs, resulting in misannotation of selenoprotein genes. Here, we applied two independent bioinformatics approaches to characterize a selenoprotein set in prokaryotic genomes. One method searched for selenoprotein genes by identifying RNA stem-loop structures, selenocysteine insertion sequence elements; the second approach identified Sec/Cys pairs in homologous sequences. These analyses identified all or almost all selenoproteins in completely sequenced bacterial and archaeal genomes and provided a view on the distribution and composition of prokaryotic selenoproteomes. In addition, lineage-specific and core selenoproteins were detected, which provided insights into the mechanisms of selenoprotein evolution. Characterization of selenoproteomes allows interpretation of other UGA codons in completed genomes of prokaryotes as terminators, addressing the UGA dual-function problem.
Topics: Amino Acid Sequence; Archaea; Bacteria; Base Sequence; Codon, Terminator; Computational Biology; Databases, Factual; Euryarchaeota; Genes, Archaeal; Molecular Sequence Data; Nucleic Acid Conformation; Proteins; Proteome; Selenocysteine; Selenoproteins; Sequence Alignment
PubMed: 15105824
DOI: 10.1038/sj.embor.7400126 -
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 -
Archaea (Vancouver, B.C.) Aug 2010Methanogenic archaea are a group of strictly anaerobic microorganisms characterized by their strict dependence on the process of methanogenesis for energy conservation.... (Review)
Review
Methanogenic archaea are a group of strictly anaerobic microorganisms characterized by their strict dependence on the process of methanogenesis for energy conservation. Among the archaea, they are also the only known group synthesizing proteins containing selenocysteine or pyrrolysine. All but one of the known archaeal pyrrolysine-containing and all but two of the confirmed archaeal selenocysteine-containing protein are involved in methanogenesis. Synthesis of these proteins proceeds through suppression of translational stop codons but otherwise the two systems are fundamentally different. This paper highlights these differences and summarizes the recent developments in selenocysteine- and pyrrolysine-related research on archaea and aims to put this knowledge into the context of their unique energy metabolism.
Topics: Archaeal Proteins; Codon, Terminator; Energy Metabolism; Euryarchaeota; Lysine; Methane; Phylogeny; Selenocysteine
PubMed: 20847933
DOI: 10.1155/2010/453642