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Angewandte Chemie (International Ed. in... Dec 2017Selenocysteine, the selenium-containing analogue of cysteine, is the twenty-first proteinogenic amino acid. Since its discovery almost fifty years ago, it has been... (Review)
Review
Selenocysteine, the selenium-containing analogue of cysteine, is the twenty-first proteinogenic amino acid. Since its discovery almost fifty years ago, it has been exploited in unnatural systems even more often than in natural systems. Selenocysteine chemistry has attracted the attention of many chemists in the field of chemical biology owing to its high reactivity and resulting potential for various applications such as chemical modification, chemical protein (semi)synthesis, and protein folding, to name a few. In this Minireview, we will focus on the chemistry of selenium and selenocysteine and their utility in protein chemistry.
Topics: Animals; Humans; Protein Folding; Proteins; Selenium; Selenocysteine
PubMed: 28857389
DOI: 10.1002/anie.201706876 -
Biochimica Et Biophysica Acta. General... Nov 2018Interest in selenium research has considerably grown over the last decades owing to the association of selenium deficiencies with an increased risk of several human... (Review)
Review
BACKGROUND
Interest in selenium research has considerably grown over the last decades owing to the association of selenium deficiencies with an increased risk of several human diseases, including cancers, cardiovascular disorders and infectious diseases. The discovery of a genetically encoded 21 amino acid, selenocysteine, is a fascinating breakthrough in molecular biology as it is the first addition to the genetic code deciphered in the 1960s. Selenocysteine is a structural and functional analog of cysteine, where selenium replaces sulfur, and its presence is critical for the catalytic activity of selenoproteins.
SCOPE OF REVIEW
The insertion of selenocysteine is a non-canonical translational event, based on the recoding of a UGA codon in selenoprotein mRNAs, normally used as a stop codon in other cellular mRNAs. Two RNA molecules and associated partners are crucial components of the selenocysteine insertion machinery, the Sec-tRNA devoted to UGA codon recognition and the SECIS elements located in the 3'UTR of selenoprotein mRNAs.
MAJOR CONCLUSIONS
The translational UGA recoding event is a limiting stage of selenoprotein expression and its efficiency is regulated by several factors.
GENERAL SIGNIFICANCE
The control of selenoproteome expression is crucial for redox homeostasis and antioxidant defense of mammalian organisms. In this review, we summarize current knowledge on the co-translational insertion of selenocysteine into selenoproteins, and its layers of regulation.
PubMed: 29751099
DOI: 10.1016/j.bbagen.2018.05.010 -
International Journal of Molecular... Sep 2018The selenium content of the body is known to control the expression levels of numerous genes, both so-called selenoproteins and non-selenoproteins. Selenium is a trace... (Review)
Review
The selenium content of the body is known to control the expression levels of numerous genes, both so-called selenoproteins and non-selenoproteins. Selenium is a trace element essential to human health, and its deficiency is related to, for instance, cardiovascular and myodegenerative diseases, infertility and osteochondropathy called Kashin⁻Beck disease. It is incorporated as selenocysteine to the selenoproteins, which protect against reactive oxygen and nitrogen species. They also participate in the activation of the thyroid hormone, and play a role in immune system functioning. The synthesis and incorporation of selenocysteine occurs via a special mechanism, which differs from the one used for standard amino acids. The codon for selenocysteine is a regular in-frame stop codon, which can be passed by a specific complex machinery participating in translation elongation and termination. This includes a presence of selenocysteine insertion sequence (SECIS) in the 3'-untranslated part of the selenoprotein mRNAs. Nonsense-mediated decay is involved in the regulation of the selenoprotein mRNA levels, but other mechanisms are also possible. Recent transcriptional analyses of messenger RNAs, microRNAs and long non-coding RNAs combined with proteomic data of samples from Keshan and Kashin⁻Beck disease patients have identified new possible cellular pathways related to transcriptional regulation by selenium.
Topics: Animals; Gene Expression Regulation; Humans; Nonsense Mediated mRNA Decay; Protein Biosynthesis; Proteins; RNA, Long Noncoding; RNA, Messenger; Selenium; Selenocysteine; Selenoproteins; Transcriptional Activation; Transcriptome
PubMed: 30205557
DOI: 10.3390/ijms19092665 -
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 -
Current Medicinal Chemistry 2022Selenium (Se) has been known for its beneficial biological roles for several years, but interest in this trace element has seen a significant increase in the past couple... (Review)
Review
Selenium (Se) has been known for its beneficial biological roles for several years, but interest in this trace element has seen a significant increase in the past couple of decades. It has been reported to be a part of important bioactive organic compounds, such as selenoproteins and amino acids, including selenocysteine (SeCys), selenomethionine (SeMet), selenazolidine (SeAzo), and selenoneine. The traditional Se supplementations (primarily as selenite and selenomethionine), though have been shown to carry some benefits, also have associated toxicities, thereby paving the way for the organoselenium compounds, especially the selenoproteins and peptides (SePs/SePPs) that offer several health benefits beyond fulfilling the elementary nutritional Se needs. This review aims to showcase the applications of selenium-containing peptides that have been reported in recent decades. This article summarizes their bioactivities, including neuroprotective, antiinflammatory, anticancer, antioxidant, hepatoprotective, and immunomodulatory roles. This will offer the readers a sneak peek into the current advancements to invoke further developments in this emerging research area.
Topics: Humans; Selenium; Selenomethionine; Selenocysteine; Antioxidants; Trace Elements; Selenoproteins; Selenious Acid; Peptides
PubMed: 35156568
DOI: 10.2174/0929867329666220214104010 -
Free Radical Biology & Medicine Nov 2022Selenophosphate synthetases use selenium and ATP to synthesize selenophosphate. This is required for biological utilization of selenium, most notably for the synthesis... (Review)
Review
Selenophosphate synthetases use selenium and ATP to synthesize selenophosphate. This is required for biological utilization of selenium, most notably for the synthesis of the non-canonical amino acid selenocysteine (Sec). Therefore, selenophosphate synthetases underlie all functions of selenoproteins, which include redox homeostasis, protein quality control, hormone regulation, metabolism, and many others. This protein family comprises two groups, SelD/SPS2 and SPS1. The SelD/SPS2 group represent true selenophosphate synthetases, enzymes central to selenium metabolism which are present in all Sec-utilizing organisms across the tree of life. Notably, many SelD/SPS2 proteins contain Sec as catalytic residue in their N-terminal flexible selenium-binding loop, while others replace it with cysteine (Cys). The SPS1 group comprises proteins originated through gene duplications of SelD/SPS2 in metazoa in which the Sec/Cys-dependent catalysis was disrupted. SPS1 proteins do not synthesize selenophosphate and are not required for Sec synthesis. They have essential regulatory functions related to redox homeostasis and pyridoxal phosphate, which affect signaling pathways for growth and differentiation. In this review, we summarize the knowledge about the selenophosphate synthetase family acquired through decades of research, encompassing their structure, mechanism, function, and evolution.
Topics: Adenosine Triphosphate; Cysteine; Hormones; Ligases; Phosphates; Phosphotransferases; Pyridoxal Phosphate; Selenium; Selenium Compounds; Selenocysteine; Selenoproteins
PubMed: 36122644
DOI: 10.1016/j.freeradbiomed.2022.09.007 -
Annual Review of Pharmacology and... Jan 2022The cytosolic selenoprotein thioredoxin reductase 1 (TrxR1, TXNRD1), and to some extent mitochondrial TrxR2 (TXNRD2), can be inhibited by a wide range of electrophilic... (Review)
Review
The cytosolic selenoprotein thioredoxin reductase 1 (TrxR1, TXNRD1), and to some extent mitochondrial TrxR2 (TXNRD2), can be inhibited by a wide range of electrophilic compounds. Many such compounds also yield cytotoxicity toward cancer cells in culture or in mouse models, and most compounds are likely to irreversibly modify the easily accessible selenocysteine residue in TrxR1, thereby inhibiting its normal activity to reduce cytosolic thioredoxin (Trx1, TXN) and other substrates of the enzyme. This leads to an oxidative challenge. In some cases, the inhibited forms of TrxR1 are not catalytically inert and are instead converted to prooxidant NADPH oxidases, named SecTRAPs, thus further aggravating the oxidative stress, particularly in cells expressing higher levels of the enzyme. In this review, the possible molecular and cellular consequences of these effects are discussed in relation to cancer therapy, with a focus on outstanding questions that should be addressed if targeted TrxR1 inhibition is to be further developed for therapeutic use.
Topics: Animals; Humans; Mice; Mitochondria; Neoplasms; Oxidation-Reduction; Reactive Oxygen Species; Selenocysteine; Thioredoxin Reductase 1
PubMed: 34449246
DOI: 10.1146/annurev-pharmtox-052220-102509