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Nutrients Sep 2018Selenium is an essential micronutrient that plays a crucial role in development and a wide variety of physiological processes including effect immune responses. The... (Review)
Review
Selenium is an essential micronutrient that plays a crucial role in development and a wide variety of physiological processes including effect immune responses. The immune system relies on adequate dietary selenium intake and this nutrient exerts its biological effects mostly through its incorporation into selenoproteins. The selenoproteome contains 25 members in humans that exhibit a wide variety of functions. The development of high-throughput omic approaches and novel bioinformatics tools has led to new insights regarding the effects of selenium and selenoproteins in human immuno-biology. Equally important are the innovative experimental systems that have emerged to interrogate molecular mechanisms underlying those effects. This review presents a summary of the current understanding of the role of selenium and selenoproteins in regulating immune cell functions and how dysregulation of these processes may lead to inflammation or immune-related diseases.
Topics: Adaptive Immunity; Animals; Host-Pathogen Interactions; Humans; Immune System; Immune System Diseases; Immunity, Innate; Inflammation; Leukocytes; Neoplasms; Selenium; Selenoproteins; Tumor Escape
PubMed: 30200430
DOI: 10.3390/nu10091203 -
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 -
Molecules (Basel, Switzerland) Apr 2019Selenium is a micronutrient that is essential for the proper functioning of all organisms. Studies on the functions of selenium are rapidly developing. This element is a... (Review)
Review
Selenium is a micronutrient that is essential for the proper functioning of all organisms. Studies on the functions of selenium are rapidly developing. This element is a cofactor of many enzymes, for example, glutathione peroxidase or thioredoxin reductase. Insufficient supplementation of this element results in the increased risk of developing many chronic degenerative diseases. Selenium is important for the protection against oxidative stress, demonstrating the highest activity as a free radical scavenger and anti-cancer agent. In food, it is present in organic forms, as exemplified by selenomethionine and selenocysteine. In dietary supplementation, the inorganic forms of selenium (selenite and selenate) are used. Organic compounds are more easily absorbed by human organisms in comparison with inorganic compounds. Currently, selenium is considered an essential trace element of fundamental importance for human health. Extreme selenium deficiencies are widespread among people all over the world. Therefore, it is essential to supplement the deficiency of this micronutrient with selenium-enriched food or yeast cell biomass in the diet.
Topics: Chemical Phenomena; Diet; Dietary Supplements; Environmental Monitoring; Food Analysis; Humans; Micronutrients; Selenium; Trace Elements
PubMed: 30987088
DOI: 10.3390/molecules24071298 -
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 -
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 -
Proceedings of the National Academy of... Aug 2016Ferroptosis is form of regulated nonapoptotic cell death that is involved in diverse disease contexts. Small molecules that inhibit glutathione peroxidase 4 (GPX4), a...
Ferroptosis is form of regulated nonapoptotic cell death that is involved in diverse disease contexts. Small molecules that inhibit glutathione peroxidase 4 (GPX4), a phospholipid peroxidase, cause lethal accumulation of lipid peroxides and induce ferroptotic cell death. Although ferroptosis has been suggested to involve accumulation of reactive oxygen species (ROS) in lipid environments, the mediators and substrates of ROS generation and the pharmacological mechanism of GPX4 inhibition that generates ROS in lipid environments are unknown. We report here the mechanism of lipid peroxidation during ferroptosis, which involves phosphorylase kinase G2 (PHKG2) regulation of iron availability to lipoxygenase enzymes, which in turn drive ferroptosis through peroxidation of polyunsaturated fatty acids (PUFAs) at the bis-allylic position; indeed, pretreating cells with PUFAs containing the heavy hydrogen isotope deuterium at the site of peroxidation (D-PUFA) prevented PUFA oxidation and blocked ferroptosis. We further found that ferroptosis inducers inhibit GPX4 by covalently targeting the active site selenocysteine, leading to accumulation of PUFA hydroperoxides. In summary, we found that PUFA oxidation by lipoxygenases via a PHKG2-dependent iron pool is necessary for ferroptosis and that the covalent inhibition of the catalytic selenocysteine in Gpx4 prevents elimination of PUFA hydroperoxides; these findings suggest new strategies for controlling ferroptosis in diverse contexts.
Topics: Catalytic Domain; Cell Death; Cell Line, Tumor; Deuterium; Epithelial Cells; Fatty Acids, Unsaturated; Gene Expression Regulation; Glutathione Peroxidase; Green Fluorescent Proteins; Humans; Iron; Lipid Peroxidation; Lipid Peroxides; Lipoxygenases; Phospholipid Hydroperoxide Glutathione Peroxidase; Phosphorylase Kinase; Protein Transport; Recombinant Fusion Proteins; Selenocysteine; Signal Transduction
PubMed: 27506793
DOI: 10.1073/pnas.1603244113 -
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 -
Cell Jan 2018Selenoproteins are rare proteins among all kingdoms of life containing the 21 amino acid, selenocysteine. Selenocysteine resembles cysteine, differing only by the...
Selenoproteins are rare proteins among all kingdoms of life containing the 21 amino acid, selenocysteine. Selenocysteine resembles cysteine, differing only by the substitution of selenium for sulfur. Yet the actual advantage of selenolate- versus thiolate-based catalysis has remained enigmatic, as most of the known selenoproteins also exist as cysteine-containing homologs. Here, we demonstrate that selenolate-based catalysis of the essential mammalian selenoprotein GPX4 is unexpectedly dispensable for normal embryogenesis. Yet the survival of a specific type of interneurons emerges to exclusively depend on selenocysteine-containing GPX4, thereby preventing fatal epileptic seizures. Mechanistically, selenocysteine utilization by GPX4 confers exquisite resistance to irreversible overoxidation as cells expressing a cysteine variant are highly sensitive toward peroxide-induced ferroptosis. Remarkably, concomitant deletion of all selenoproteins in Gpx4 cells revealed that selenoproteins are dispensable for cell viability provided partial GPX4 activity is retained. Conclusively, 200 years after its discovery, a specific and indispensable role for selenium is provided.
Topics: Animals; Apoptosis; Cell Survival; Cells, Cultured; Female; Glutathione Peroxidase; HEK293 Cells; Humans; Hydrogen Peroxide; Interneurons; Lipid Peroxidation; Male; Mice; Mice, Inbred C57BL; Phospholipid Hydroperoxide Glutathione Peroxidase; Seizures; Selenium
PubMed: 29290465
DOI: 10.1016/j.cell.2017.11.048 -
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