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International Journal of Molecular... Jun 2023Selenocysteine is a catalytic residue at the active site of all selenoenzymes in bacteria and mammals, and it is incorporated into the polypeptide backbone by a... (Review)
Review
Selenocysteine is a catalytic residue at the active site of all selenoenzymes in bacteria and mammals, and it is incorporated into the polypeptide backbone by a co-translational process that relies on the recoding of a UGA termination codon into a serine/selenocysteine codon. The best-characterized selenoproteins from mammalian species and bacteria are discussed with emphasis on their biological function and catalytic mechanisms. A total of 25 genes coding for selenoproteins have been identified in the genome of mammals. Unlike the selenoenzymes of anaerobic bacteria, most mammalian selenoenzymes work as antioxidants and as redox regulators of cell metabolism and functions. Selenoprotein P contains several selenocysteine residues and serves as a selenocysteine reservoir for other selenoproteins in mammals. Although extensively studied, glutathione peroxidases are incompletely understood in terms of local and time-dependent distribution, and regulatory functions. Selenoenzymes take advantage of the nucleophilic reactivity of the selenolate form of selenocysteine. It is used with peroxides and their by-products such as disulfides and sulfoxides, but also with iodine in iodinated phenolic substrates. This results in the formation of Se-X bonds (X = O, S, N, or I) from which a selenenylsulfide intermediate is invariably produced. The initial selenolate group is then recycled by thiol addition. In bacterial glycine reductase and D-proline reductase, an unusual catalytic rupture of selenium-carbon bonds is observed. The exchange of selenium for sulfur in selenoproteins, and information obtained from model reactions, suggest that a generic advantage of selenium compared with sulfur relies on faster kinetics and better reversibility of its oxidation reactions.
Topics: Animals; Selenocysteine; Selenium; Selenoproteins; Glutathione Peroxidase; Sulfur; Mammals
PubMed: 37373256
DOI: 10.3390/ijms241210109 -
Journal of Peptide Science : An... Feb 2020The chalcogen elements oxygen, sulfur, and selenium are essential constituents of side chain functions of natural amino acids. Conversely, no structural and biological... (Review)
Review
The chalcogen elements oxygen, sulfur, and selenium are essential constituents of side chain functions of natural amino acids. Conversely, no structural and biological function has been discovered so far for the heavier and more metallic tellurium element. In the methionine series, only the sulfur-containing methionine is a proteinogenic amino acid, while selenomethionine and telluromethionine are natural amino acids that are incorporated into proteins most probably because of the tolerance of the methionyl-tRNA synthetase; so far, methoxinine the oxygen analogue has not been discovered in natural compounds. Similarly, the chalcogen analogues of tryptophan and phenylalanine in which the benzene ring has been replaced by the largely isosteric thiophene, selenophene, and more recently, even tellurophene are fully synthetic mimics that are incorporated with more or less efficiency into proteins via the related tryptophanyl- and phenylalanyl-tRNA synthetases, respectively. In the serine/cysteine series, also selenocysteine is a proteinogenic amino acid that is inserted into proteins by a special translation mechanism, while the tellurocysteine is again most probably incorporated into proteins by the tolerance of the cysteinyl-tRNA synthetase. For research purposes, all of these natural and synthetic chalcogen amino acids have been extensively applied in peptide and protein research to exploit their different physicochemical properties for modulating structural and functional properties in synthetic peptides and rDNA expressed proteins as discussed in the following review.
Topics: Amino Acids; Animals; Chalcogens; Crystallography, X-Ray; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Immunoglobulin M; Peptides; Protein Domains; Proteins
PubMed: 31856429
DOI: 10.1002/psc.3232 -
Experimental Biology and Medicine... Dec 2022Selenium is a naturally found trace element, which provides multiple benefits including antioxidant, anticancer, and antiaging, as well as boosting immunity. One unique... (Review)
Review
Selenium is a naturally found trace element, which provides multiple benefits including antioxidant, anticancer, and antiaging, as well as boosting immunity. One unique feature of selenium is its incorporation as selenocysteine, a rare 21st amino acid, into selenoproteins. Twenty-five human selenoproteins have been discovered, and a majority of these serve as crucial antioxidant enzymes for redox homeostasis. Unlike other amino acids, incorporation of selenocysteine requires a distinctive UGA stop codon recoding mechanism. Although many studies correlating selenium, selenoproteins, aging, and senescence have been performed, it has not yet been explored if the upstream events regulating selenoprotein synthesis play a role in senescence-associated pathologies. The epitranscriptomic writer alkylation repair homolog 8 (ALKBH8) is critical for selenoprotein production, and its deficiency can significantly decrease levels of selenoproteins that are essential for reactive oxygen species (ROS) detoxification, and increase oxidative stress, one of the major drivers of cellular senescence. Here, we review the potential role of epitranscriptomic marks that govern selenocysteine utilization in regulating the senescence program.
Topics: Humans; Selenium; Antioxidants; Selenocysteine; Selenoproteins; Codon, Terminator; AlkB Homolog 8, tRNA Methyltransferase
PubMed: 36036467
DOI: 10.1177/15353702221116592 -
RNA (New York, N.Y.) Sep 2023Unique chemical and physical properties are introduced by inserting selenocysteine (Sec) at specific sites within proteins. Recombinant and facile production of...
Unique chemical and physical properties are introduced by inserting selenocysteine (Sec) at specific sites within proteins. Recombinant and facile production of eukaryotic selenoproteins would benefit from a yeast expression system; however, the selenoprotein biosynthetic pathway was lost in the evolution of the kingdom Fungi as it diverged from its eukaryotic relatives. Based on our previous development of efficient selenoprotein production in bacteria, we designed a novel Sec biosynthesis pathway in using translation components. tRNA was mutated to resemble tRNA to allow recognition by seryl-tRNA synthetase as well as selenocysteine synthase (SelA) and selenophosphate synthetase (SelD). Expression of these Sec pathway components was then combined with metabolic engineering of yeast to enable the production of active methionine sulfate reductase enzyme containing genetically encoded Sec. Our report is the first demonstration that yeast is capable of selenoprotein production by site-specific incorporation of Sec.
Topics: Codon, Terminator; Saccharomyces cerevisiae; Aeromonas salmonicida; Protein Engineering; RNA, Transfer, Cys; Humans; Nucleic Acid Conformation
PubMed: 37279998
DOI: 10.1261/rna.079658.123 -
Biochemical Society Transactions Jun 2022GPX4 is a selenocysteine-containing protein that plays an essential role in repairing peroxidised phospholipids. Its role in organismal homeostasis has been known for... (Review)
Review
GPX4 is a selenocysteine-containing protein that plays an essential role in repairing peroxidised phospholipids. Its role in organismal homeostasis has been known for decades, and it has been reported to play a pivotal role in cell survival and mammalian embryonic development. In recent years, GPX4 has been associated with a cell death modality dubbed ferroptosis. The framing of this molecular pathway of cell death was essential for understanding the conditions that determine GPX4 dependency and ultimately to the process of lipid peroxidation. Since its discovery, ferroptosis has been gaining momentum as a promising target for yet-incurable diseases, including cancer and neurodegeneration. Given the current interest, in the present review, we provide newcomers in the field with an overview of the biology of GPX4 and cover some of its most recent discoveries.
Topics: Animals; Cell Death; Ferroptosis; Glutathione Peroxidase; Lipid Peroxidation; Mammals; Phospholipid Hydroperoxide Glutathione Peroxidase
PubMed: 35758268
DOI: 10.1042/BST20220682 -
Nature Communications Dec 2023Aortic aneurysms, which may dissect or rupture acutely and be lethal, can be a part of multisystem disorders that have a heritable basis. We report four patients with...
Aortic aneurysms, which may dissect or rupture acutely and be lethal, can be a part of multisystem disorders that have a heritable basis. We report four patients with deficiency of selenocysteine-containing proteins due to selenocysteine Insertion Sequence Binding Protein 2 (SECISBP2) mutations who show early-onset, progressive, aneurysmal dilatation of the ascending aorta due to cystic medial necrosis. Zebrafish and male mice with global or vascular smooth muscle cell (VSMC)-targeted disruption of Secisbp2 respectively show similar aortopathy. Aortas from patients and animal models exhibit raised cellular reactive oxygen species, oxidative DNA damage and VSMC apoptosis. Antioxidant exposure or chelation of iron prevents oxidative damage in patient's cells and aortopathy in the zebrafish model. Our observations suggest a key role for oxidative stress and cell death, including via ferroptosis, in mediating aortic degeneration.
Topics: Humans; Male; Mice; Animals; Zebrafish; Selenocysteine; Muscle, Smooth, Vascular; Aortic Aneurysm; Selenoproteins; Myocytes, Smooth Muscle
PubMed: 38042913
DOI: 10.1038/s41467-023-43851-6 -
International Journal of Molecular... Oct 2023Selenoproteins are a group of proteins containing selenium in the form of selenocysteine (Sec, U) as the 21st amino acid coded in the genetic code. Their synthesis... (Review)
Review
Selenoproteins are a group of proteins containing selenium in the form of selenocysteine (Sec, U) as the 21st amino acid coded in the genetic code. Their synthesis depends on dietary selenium uptake and a common set of cofactors. Selenoproteins accomplish diverse roles in the body and cell processes by acting, for example, as antioxidants, modulators of the immune function, and detoxification agents for heavy metals, other xenobiotics, and key compounds in thyroid hormone metabolism. Although the functions of all this protein family are still unknown, several disorders in their structure, activity, or expression have been described by researchers. They concluded that selenium or cofactors deficiency, on the one hand, or the polymorphism in selenoproteins genes and synthesis, on the other hand, are involved in a large variety of pathological conditions, including type 2 diabetes, cardiovascular, muscular, oncological, hepatic, endocrine, immuno-inflammatory, and neurodegenerative diseases. This review focuses on the specific roles of selenoproteins named after letters of the alphabet in medicine, which are less known than the rest, regarding their implications in the pathological processes of several prevalent diseases and disease prevention.
Topics: Humans; Selenium; Diabetes Mellitus, Type 2; Selenoproteins; Selenocysteine; Antioxidants
PubMed: 37895024
DOI: 10.3390/ijms242015344 -
Biomimetics (Basel, Switzerland) Jan 2023Selenium exists in the form of selenocysteines in selenoproteins and plays a pivotal role in the catalytic process of the antioxidative enzymes. In order to study the... (Review)
Review
Selenium exists in the form of selenocysteines in selenoproteins and plays a pivotal role in the catalytic process of the antioxidative enzymes. In order to study the structural and functional properties of selenium in selenoproteins, explore the significance of the role of selenium in the fields of biology and chemistry, scientists conducted a series of artificial simulations on selenoproteins. In this review, we sum up the progress and developed strategies in the construction of artificial selenoenzyme. Using different mechanisms from different catalytic angles, selenium-containing catalytic antibodies, semi-synthetic selenonezyme, and the selenium-containing molecularly imprinted enzymes have been constructed. A variety of synthetic selenoenzyme models have been designed and constructed by selecting host molecules such as cyclodextrins, dendrimers, and hyperbranched polymers as the main scaffolds. Then, a variety of selenoprotein assemblies as well as cascade antioxidant nanoenzymes were built by using electrostatic interaction, metal coordination, and host-guest interaction. The unique redox properties of selenoenzyme glutathione peroxidase (GPx) can be reproduced.
PubMed: 36810385
DOI: 10.3390/biomimetics8010054 -
Nutrients Jan 2022In the last two years, there has been a surge in the number of publications on the trace element selenium (Se) and selenocysteine-containing selenoproteins in human...
In the last two years, there has been a surge in the number of publications on the trace element selenium (Se) and selenocysteine-containing selenoproteins in human health, largely due to the pandemic and the multiple roles that this micronutrient and Se-dependent selenoproteins play in various aspects of the disease [...].
Topics: COVID-19; Humans; Nutritional Status; SARS-CoV-2; Selenium; Selenocysteine; Selenoprotein P; Selenoproteins; Post-Acute COVID-19 Syndrome
PubMed: 35057464
DOI: 10.3390/nu14020283