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Frontiers in Endocrinology 2023Selenium, a non-metallic element, is a micronutrient essential for the biosynthesis of selenoproteins containing selenocysteine. In adults, the thyroid contains the... (Review)
Review
Selenium, a non-metallic element, is a micronutrient essential for the biosynthesis of selenoproteins containing selenocysteine. In adults, the thyroid contains the highest amount of selenium per gram of tissue. Most known selenoproteins, such as glutathione peroxidase, are expressed in the thyroid and are involved in thyroid hormone metabolism, redox state regulation, and maintenance of cellular homeostasis. Some clinical studies have shown that lack of selenium will increase the prevalence of several kinds of thyroid diseases. Selenium treatment in patients with Graves' orbitopathy has been shown to delay disease progression and improve the quality of life. Selenium supplementation in Hashimoto's thyroiditis was associated with the decreased levels of anti-thyroid peroxidase antibody and improved thyroid ultrasound structure. In thyroid cancer, various selenium supplements have shown variable anticancer activity. However, published results remain the conflicting and more clinical evidence is still needed to determine the clinical significance of selenium. This article reviews the strong association between selenium and thyroid disease and provides new ideas for the clinical management of selenium in thyroid disease.
Topics: Humans; Selenium; Quality of Life; Graves Ophthalmopathy; Thyroid Diseases; Selenoproteins
PubMed: 37033262
DOI: 10.3389/fendo.2023.1133000 -
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 -
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 -
Inflammopharmacology Jun 2020Selenium is an essential immunonutrient which holds the human's metabolic activity with its chemical bonds. The organic forms of selenium naturally present in human body... (Review)
Review
Selenium is an essential immunonutrient which holds the human's metabolic activity with its chemical bonds. The organic forms of selenium naturally present in human body are selenocysteine and selenoproteins. These forms have a unique way of synthesis and translational coding. Selenoproteins act as antioxidant warriors for thyroid regulation, male-fertility enhancement, and anti-inflammatory actions. They also participate indirectly in the mechanism of wound healing as oxidative stress reducers. Glutathione peroxidase (GPX) is the major selenoprotein present in the human body, which assists in the control of excessive production of free radical at the site of inflammation. Other than GPX, other selenoproteins include selenoprotein-S that regulates the inflammatory cytokines and selenoprotein-P that serves as an inducer of homeostasis. Previously, reports were mainly focused on the cellular and molecular mechanism of wound healing with reference to various animal models and cell lines. In this review, the role of selenium and its possible routes in translational decoding of selenocysteine, synthesis of selenoproteins, systemic action of selenoproteins and their indirect assimilation in the process of wound healing are explained in detail. Some of the selenium containing compounds which can acts as cancer preventive and therapeutics are also discussed. These compounds directly or indirectly exhibit antioxidant properties which can sustain the intracellular redox status and these activities protect the healthy cells from reactive oxygen species induced oxidative damage. Although the review covers the importance of selenium/selenoproteins in wound healing process, still some unresolved mystery persists which may be resolved in near future.
Topics: Animals; Antioxidants; Humans; Inflammation; Oxidation-Reduction; Reactive Oxygen Species; Selenium; Selenoproteins
PubMed: 32144521
DOI: 10.1007/s10787-020-00690-x -
Frontiers in Pharmacology 2023Maintaining the balance of a cell's redox function is key to determining cell fate. In the critical redox system of mammalian cells, glutathione peroxidase (GPX) is the... (Review)
Review
Maintaining the balance of a cell's redox function is key to determining cell fate. In the critical redox system of mammalian cells, glutathione peroxidase (GPX) is the most prominent family of proteins with a multifaceted function that affects almost all cellular processes. A total of eight members of the GPX family are currently found, namely GPX1-GPX8. They have long been used as antioxidant enzymes to play an important role in combating oxidative stress and maintaining redox balance. However, each member of the GPX family has a different mechanism of action and site of action in maintaining redox balance. GPX1-4 and GPX6 use selenocysteine as the active center to catalyze the reduction of HO or organic hydroperoxides to water or corresponding alcohols, thereby reducing their toxicity and maintaining redox balance. In addition to reducing HO and small molecule hydroperoxides, GPX4 is also capable of reducing complex lipid compounds. It is the only enzyme in the GPX family that directly reduces and destroys lipid hydroperoxides. The active sites of GPX5 and GPX7-GPX8 do not contain selenium cysteine (Secys), but instead, have cysteine residues (Cys) as their active sites. GPX5 is mainly expressed in epididymal tissue and plays a role in protecting sperm from oxidative stress. Both enzymes, GPX7 and GPX8, are located in the endoplasmic reticulum and are necessary enzymes involved in the oxidative folding of endoplasmic reticulum proteins, and GPX8 also plays an important role in the regulation of Ca in the endoplasmic reticulum. With an in-depth understanding of the role of the GPX family members in health and disease development, redox balance has become the functional core of GPX family, in order to further clarify the expression and regulatory mechanism of each member in the redox process, we reviewed GPX family members separately.
PubMed: 36937839
DOI: 10.3389/fphar.2023.1147414 -
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 -
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 -
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