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Free Radical Biology & Medicine Aug 2022Glutathione peroxidase 1 (GPx1) is an important cellular antioxidant enzyme that is found in the cytoplasm and mitochondria of mammalian cells. Like most selenoenzymes,... (Review)
Review
Glutathione peroxidase 1 (GPx1) is an important cellular antioxidant enzyme that is found in the cytoplasm and mitochondria of mammalian cells. Like most selenoenzymes, it has a single redox-sensitive selenocysteine amino acid that is important for the enzymatic reduction of hydrogen peroxide and soluble lipid hydroperoxides. Glutathione provides the source of reducing equivalents for its function. As an antioxidant enzyme, GPx1 modulates the balance between necessary and harmful levels of reactive oxygen species. In this review, we discuss how selenium availability and modifiers of selenocysteine incorporation alter GPx1 expression to promote disease states. We review the role of GPx1 in cardiovascular and metabolic health, provide examples of how GPx1 modulates stroke and provides neuroprotection, and consider how GPx1 may contribute to cancer risk. Overall, GPx1 is protective against the development and progression of many chronic diseases; however, there are some situations in which increased expression of GPx1 may promote cellular dysfunction and disease owing to its removal of essential reactive oxygen species.
Topics: Animals; Antioxidants; Glutathione Peroxidase; Mammals; Oxidative Stress; Reactive Oxygen Species; Selenium; Selenocysteine; Glutathione Peroxidase GPX1
PubMed: 35691509
DOI: 10.1016/j.freeradbiomed.2022.06.004 -
Nature Metabolism Jul 2020The micronutrient selenium is incorporated via the selenocysteine biosynthesis pathway into the rare amino acid selenocysteine, which is required in selenoproteins such...
The micronutrient selenium is incorporated via the selenocysteine biosynthesis pathway into the rare amino acid selenocysteine, which is required in selenoproteins such as glutathione peroxidases and thioredoxin reductases. Here, we show that selenophosphate synthetase 2 (SEPHS2), an enzyme in the selenocysteine biosynthesis pathway, is essential for survival of cancer, but not normal, cells. SEPHS2 is required in cancer cells to detoxify selenide, an intermediate that is formed during selenocysteine biosynthesis. Breast and other cancer cells are selenophilic, owing to a secondary function of the cystine/glutamate antiporter SLC7A11 that promotes selenium uptake and selenocysteine biosynthesis, which, by allowing production of selenoproteins such as GPX4, protects cells against ferroptosis. However, this activity also becomes a liability for cancer cells because selenide is poisonous and must be processed by SEPHS2. Accordingly, we find that SEPHS2 protein levels are elevated in samples from people with breast cancer, and that loss of SEPHS2 impairs growth of orthotopic mammary-tumour xenografts in mice. Collectively, our results identify a vulnerability of cancer cells and define the role of selenium metabolism in cancer.
Topics: Amino Acid Transport System y+; Animals; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Female; Ferroptosis; Humans; Inactivation, Metabolic; Mice; Mice, Nude; Neoplasms; Phospholipid Hydroperoxide Glutathione Peroxidase; Phosphotransferases; Selenium; Selenium Compounds; Selenocysteine; Xenograft Model Antitumor Assays
PubMed: 32694795
DOI: 10.1038/s42255-020-0224-7 -
Molecules (Basel, Switzerland) Mar 2013Selenium (Se³⁴₇₉) is a metalloid which is close to sulfur (S) in terms of properties. The Se concentration in soil varies with type, texture and organic matter... (Review)
Review
Selenium (Se³⁴₇₉) is a metalloid which is close to sulfur (S) in terms of properties. The Se concentration in soil varies with type, texture and organic matter content of the soil and with rainfall. Its assimilation by plants is influenced by the physico-chemical properties of the soil (redox status, pH and microbial activity). The presence of Se in the atmosphere is linked to natural and anthropogenic activities. Selenoproteins, in which selenium is present as selenocysteine, present an important role in many body functions, such as antioxidant defense and the formation of thyroid hormones. Some selenoprotein metabolites play a role in cancer prevention. In the immune system, selenium stimulates antibody formation and activity of helper T cells, cytotoxic T cells and Natural Killer (NK) cells. The mechanisms of intestinal absorption of selenium differ depending on the chemical form of the element. Selenium is mainly absorbed in the duodenum and caecum by active transport through a sodium pump. The recommended daily intake of selenium varies from 60 μg/day for women, to 70 μg/day for men. In growing ruminants the requirements are estimated at 100 μg/kg dry matter and 200 μg/Kg for pregnant or lactating females. A deficiency can cause reproductive disorders in humans and animals.
Topics: Animals; Environment; Humans; Nutritional Requirements; Selenium; Selenocysteine; Selenoproteins
PubMed: 23486107
DOI: 10.3390/molecules18033292 -
Nature Chemical Biology May 2020We recently described glutathione peroxidase 4 (GPX4) as a promising target for killing therapy-resistant cancer cells via ferroptosis. The onset of therapy resistance...
We recently described glutathione peroxidase 4 (GPX4) as a promising target for killing therapy-resistant cancer cells via ferroptosis. The onset of therapy resistance by multiple types of treatment results in a stable cell state marked by high levels of polyunsaturated lipids and an acquired dependency on GPX4. Unfortunately, all existing inhibitors of GPX4 act covalently via a reactive alkyl chloride moiety that confers poor selectivity and pharmacokinetic properties. Here, we report our discovery that masked nitrile-oxide electrophiles, which have not been explored previously as covalent cellular probes, undergo remarkable chemical transformations in cells and provide an effective strategy for selective targeting of GPX4. The new GPX4-inhibiting compounds we describe exhibit unexpected proteome-wide selectivity and, in some instances, vastly improved physiochemical and pharmacokinetic properties compared to existing chloroacetamide-based GPX4 inhibitors. These features make them superior tool compounds for biological interrogation of ferroptosis and constitute starting points for development of improved inhibitors of GPX4.
Topics: Animals; Cell Line, Tumor; Enzyme Inhibitors; Ferroptosis; Humans; Lipid Peroxidation; Mice, SCID; Molecular Probes; Molecular Targeted Therapy; Nitriles; Oxides; Phospholipid Hydroperoxide Glutathione Peroxidase; Prodrugs; Rats, Wistar; Selenocysteine; Small Molecule Libraries; Structure-Activity Relationship
PubMed: 32231343
DOI: 10.1038/s41589-020-0501-5 -
BMC Genomics Oct 2020Selenium is an essential trace element, and selenocysteine (Sec, U) is its predominant form in vivo. Proteins that contain Sec are selenoproteins, whose special...
BACKGROUND
Selenium is an essential trace element, and selenocysteine (Sec, U) is its predominant form in vivo. Proteins that contain Sec are selenoproteins, whose special structural features include not only the TGA codon encoding Sec but also the SECIS element in mRNA and the conservation of the Sec-flanking region. These unique features have led to the development of a series of bioinformatics methods to predict and research selenoprotein genes. There have been some studies and reports on the evolution and distribution of selenoprotein genes in prokaryotes and multicellular eukaryotes, but the systematic analysis of single-cell eukaryotes, especially algae, has been very limited.
RESULTS
In this study, we predicted selenoprotein genes in 137 species of algae by using a program we previously developed. More than 1000 selenoprotein genes were obtained. A database website was built to record these algae selenoprotein genes ( www.selenoprotein.com ). These genes belong to 42 selenoprotein families, including three novel selenoprotein gene families.
CONCLUSIONS
This study reveals the primordial state of the eukaryotic selenoproteome. It is an important clue to explore the significance of selenium for primordial eukaryotes and to determine the complete evolutionary spectrum of selenoproteins in all life forms.
Topics: Codon, Terminator; Eukaryota; Evolution, Molecular; Proteome; Selenium; Selenocysteine; Selenoproteins
PubMed: 33028229
DOI: 10.1186/s12864-020-07101-z -
Antioxidants & Redox Signaling Sep 2020Bioinformatics has brought important insights into the field of selenium research. The progress made in the development of computational tools in the last two decades,... (Review)
Review
Bioinformatics has brought important insights into the field of selenium research. The progress made in the development of computational tools in the last two decades, coordinated with growing genome resources, provided new opportunities to study selenoproteins. The present review discusses existing tools for selenoprotein gene finding and other bioinformatic approaches to study the biology of selenium. The availability of complete selenoproteomes allowed assessing a global distribution of the use of selenocysteine (Sec) across the tree of life, as well as studying the evolution of selenoproteins and their biosynthetic pathway. Beyond gene identification and characterization, human genetic variants in selenoprotein genes were used to examine adaptations to selenium levels in diverse human populations and to estimate selective constraints against gene loss. The synthesis of selenoproteins is essential for development in mice. In humans, several mutations in selenoprotein genes have been linked to rare congenital disorders. And yet, the mechanism of Sec insertion and the regulation of selenoprotein synthesis in mammalian cells are not completely understood. Omics technologies offer new possibilities to study selenoproteins and mechanisms of Sec incorporation in cells, tissues, and organisms.
Topics: Animals; Computational Biology; Humans; Protein Biosynthesis; Research; Selenocysteine; Selenoproteins
PubMed: 32031018
DOI: 10.1089/ars.2020.8044 -
EMBO Molecular Medicine Aug 2023Ferroptosis has emerged as an attractive strategy in cancer therapy. Understanding the operational networks regulating ferroptosis may unravel vulnerabilities that could...
Ferroptosis has emerged as an attractive strategy in cancer therapy. Understanding the operational networks regulating ferroptosis may unravel vulnerabilities that could be harnessed for therapeutic benefit. Using CRISPR-activation screens in ferroptosis hypersensitive cells, we identify the selenoprotein P (SELENOP) receptor, LRP8, as a key determinant protecting MYCN-amplified neuroblastoma cells from ferroptosis. Genetic deletion of LRP8 leads to ferroptosis as a result of an insufficient supply of selenocysteine, which is required for the translation of the antiferroptotic selenoprotein GPX4. This dependency is caused by low expression of alternative selenium uptake pathways such as system Xc . The identification of LRP8 as a specific vulnerability of MYCN-amplified neuroblastoma cells was confirmed in constitutive and inducible LRP8 knockout orthotopic xenografts. These findings disclose a yet-unaccounted mechanism of selective ferroptosis induction that might be explored as a therapeutic strategy for high-risk neuroblastoma and potentially other MYCN-amplified entities.
Topics: Humans; Cell Line, Tumor; Ferroptosis; N-Myc Proto-Oncogene Protein; Neuroblastoma; Selenocysteine; Animals
PubMed: 37435859
DOI: 10.15252/emmm.202318014 -
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 -
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 -
Croatian Medical Journal Dec 2012Selenocysteine, the 21st amino acid, has been found in 25 human selenoproteins and selenoenzymes important for fundamental cellular processes ranging from selenium... (Review)
Review
Selenocysteine, the 21st amino acid, has been found in 25 human selenoproteins and selenoenzymes important for fundamental cellular processes ranging from selenium homeostasis maintenance to the regulation of the overall metabolic rate. In all organisms that contain selenocysteine, both the synthesis of selenocysteine and its incorporation into a selenoprotein requires an elaborate synthetic and translational apparatus, which does not resemble the canonical enzymatic system employed for the 20 standard amino acids. In humans, three synthetic enzymes, a specialized elongation factor, an accessory protein factor, two catabolic enzymes, a tRNA, and a stem-loop structure in the selenoprotein mRNA are critical for ensuring that only selenocysteine is attached to selenocysteine tRNA and that only selenocysteine is inserted into the nascent polypeptide in response to a context-dependent UGA codon. The abnormal selenium homeostasis and mutations in selenoprotein genes have been causatively linked to a variety of human diseases, which, in turn, sparked a renewed interest in utilizing selenium as the dietary supplement to either prevent or remedy pathologic conditions. In contrast, the importance of the components of the selenocysteine-synthetic machinery for human health is less clear. Emerging evidence suggests that enzymes responsible for selenocysteine formation and decoding the selenocysteine UGA codon, which by extension are critical for synthesis of the entire selenoproteome, are essential for the development and health of the human organism.
Topics: Health; Humans; Selenium; Selenocysteine; Selenoproteins
PubMed: 23275319
DOI: 10.3325/cmj.2012.53.535