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Articles 1 - 14 of 14
Full-Text Articles in Biochemistry, Biophysics, and Structural Biology
Selenoproteins Mediate T Cell Immunity Through An Antioxidant Mechanism, Rajeev K. Shrimali, Robert D. Irons, Bradley A. Carlson, Yasuyo Sano, Vadim N. Gladyshev, Jin Mo Park, Dolph L. Hatfield
Selenoproteins Mediate T Cell Immunity Through An Antioxidant Mechanism, Rajeev K. Shrimali, Robert D. Irons, Bradley A. Carlson, Yasuyo Sano, Vadim N. Gladyshev, Jin Mo Park, Dolph L. Hatfield
Vadim Gladyshev Publications
Selenium is an essential dietary element with antioxidant roles in immune regulation, but there is little understanding of how this element acts at the molecular level in host defense and inflammatory disease. Selenium is incorporated into the amino acid selenocysteine (Sec), which in turn is inserted into selenoproteins in a manner dependent on Sec tRNA[Ser]Sec. To investigate the molecular mechanism that links selenium to T cell immunity, we generated mice with selenoprotein-less T cells by cell type-specific ablation of the Sec tRNA[Ser]Sec gene (trsp). Herein, we show that these mutant mice exhibit decreased pools of …
Platyhelminth Mitochondrial And Cytosolic Redox Homeostasis Is Controlled By A Single Thioredoxin Glutathione Reductase And Dependent On Selenium And Glutathione, Mariana Bonilla, Ana Denicola, Sergey V. Novoselov, Anton A. Turanov, Anna Protasio, Darwin Izmendi, Vadim N. Gladyshev, Gustavo Salinas
Platyhelminth Mitochondrial And Cytosolic Redox Homeostasis Is Controlled By A Single Thioredoxin Glutathione Reductase And Dependent On Selenium And Glutathione, Mariana Bonilla, Ana Denicola, Sergey V. Novoselov, Anton A. Turanov, Anna Protasio, Darwin Izmendi, Vadim N. Gladyshev, Gustavo Salinas
Vadim Gladyshev Publications
Platyhelminth parasites are a major health problem in developing countries. In contrast to their mammalian hosts, platyhelminth thiol-disulfide redox homeostasis relies on linked thioredoxin-glutathione systems, which are fully dependent on thioredoxin-glutathione reductase (TGR), a promising drug target. TGR is a homodimeric enzyme comprising a glutaredoxin domain and thioredoxin reductase (TR) domains with a C-terminal redox center containing selenocysteine (Sec). In this study, we demonstrate the existence of functional linked thioredoxin-glutathione systems in the cytosolic and mitochondrial compartments of Echinococcus granulosus, the platyhelminth responsible for hydatid disease. The glutathione reductase (GR) activity of TGR exhibited hysteretic behavior regulated by the …
Molybdoproteomes And Evolution Of Molybdenum Utilization, Yan Zhang, Vadim N. Gladyshev
Molybdoproteomes And Evolution Of Molybdenum Utilization, Yan Zhang, Vadim N. Gladyshev
Vadim Gladyshev Publications
The trace element molybdenum (Mo) is utilized in many life forms, where it is a key component of several enzymes involved in nitrogen, sulfur, and carbon metabolism. With the exception of nitrogenase, Mo is bound in proteins to a pterin, thus forming the molybdenum cofactor (Moco) at the catalytic sites of molybdoenzymes. Although a number of molybdoenzymes are well characterized structurally and functionally, evolutionary analyses of Mo utilization are limited. Here, we carried out comparative genomic and phylogenetic analyses to examine occurrence and evolution of Mo utilization in bacteria, archaea, and eukaryotes at the level of (i) Mo transport and …
Structure And Catalytic Mechanism Of Eukaryotic Selenocysteine Synthase, Oleg M. Ganichkin, Xue-Ming Xu, Bradley A. Carlson, Heiko Mix, Dolph L. Hatfield, Vadim N. Gladyshev, Markus C. Wahl
Structure And Catalytic Mechanism Of Eukaryotic Selenocysteine Synthase, Oleg M. Ganichkin, Xue-Ming Xu, Bradley A. Carlson, Heiko Mix, Dolph L. Hatfield, Vadim N. Gladyshev, Markus C. Wahl
Vadim Gladyshev Publications
In eukaryotes and Archaea, selenocysteine synthase (SecS) converts O-phospho-L-seryl-tRNA[Ser]Sec into selenocysteyltRNA[Ser]Sec using selenophosphate as the selenium donor compound. The molecular mechanisms underlying SecS activity are presently unknown. We have delineated a 450-residue core of mouse SecS, which retained full selenocysteyl-tRNA[Ser]Sec synthesis activity, and determined its crystal structure at 1.65Å resolution. SecS exhibits three domains that place it in the fold type I family of pyridoxal phosphate (PLP)-dependent enzymes. Two SecS monomers interact intimately and together build up two identical active sites around PLP in a Schiff-base linkage with lysine 284. Two SecS dimers further …
Comparative Analysis Of Selenocysteine Machinery And Selenoproteome Gene Expression In Mouse Brain Identifies Neurons As Key Functional Sites Of Selenium In Mammals, Yan Zhang, You Zhou, Ulrich Schweizer, Nicolai E. Savaskan, Deame Hua, Jonathan Kipnis, Dolph L. Hatfield, Vadim N. Gladyshev
Comparative Analysis Of Selenocysteine Machinery And Selenoproteome Gene Expression In Mouse Brain Identifies Neurons As Key Functional Sites Of Selenium In Mammals, Yan Zhang, You Zhou, Ulrich Schweizer, Nicolai E. Savaskan, Deame Hua, Jonathan Kipnis, Dolph L. Hatfield, Vadim N. Gladyshev
Vadim Gladyshev Publications
Although dietary selenium (Se) deficiency results in phenotypes associated with selenoprotein depletion in various organs, the brain is protected from Se loss. To address the basis for the critical role of Se in brain function, we carried out comparative gene expression analyses for the complete selenoproteome and associated biosynthetic factors. Using the Allen Brain Atlas, we evaluated 159 regions of adult mouse brain and provided experimental analyses of selected selenoproteins. All 24 selenoprotein mRNAs were expressed in the mouse brain. Most strikingly, neurons in olfactory bulb, hippocampus, cerebral cortex, and cerebellar cortex were exceptionally rich in selenoprotein gene expression, in …
A Functional Link Between Housekeeping Selenoproteins And Phase Ii Enzymes, Aniruddha Sengupta, Bradley A. Carlson, James A. Weaver, Sergey V. Novoselov, Dmitri E. Fomenko, Vadim N. Gladyshev, Dolph Hatfield
A Functional Link Between Housekeeping Selenoproteins And Phase Ii Enzymes, Aniruddha Sengupta, Bradley A. Carlson, James A. Weaver, Sergey V. Novoselov, Dmitri E. Fomenko, Vadim N. Gladyshev, Dolph Hatfield
Vadim Gladyshev Publications
Sec (selenocysteine) is biosynthesized on its tRNA and incorporated into selenium-containing proteins (selenoproteins) as the 21st amino acid residue. Selenoprotein synthesis is dependent on Sec tRNA and the expression of this class of proteins can be modulated by altering Sec tRNA expression. The gene encoding Sec tRNA (Trsp) is a single-copy gene and its targeted removal in liver demonstrated that selenoproteins are essential for proper function wherein their absence leads to necrosis and hepatocellular degeneration. In the present study, we found that the complete loss of selenoproteins in liver was compensated for by an enhanced expression of several phase II …
Functional Characterization Of Alternatively Spliced Human Secisbp2 Transcript Variants, Laura V. Papp, Junning Wang, Derek Kennedy, Didier Boucher, Yan Zhang, Vadim N. Gladyshev, Ravindra N. Singh, Kum Kum Khanna
Functional Characterization Of Alternatively Spliced Human Secisbp2 Transcript Variants, Laura V. Papp, Junning Wang, Derek Kennedy, Didier Boucher, Yan Zhang, Vadim N. Gladyshev, Ravindra N. Singh, Kum Kum Khanna
Vadim Gladyshev Publications
Synthesis of selenoproteins depends on decoding of the UGA stop codon as the amino acid selenocysteine (Sec). This process requires the presence of a Sec insertion sequence element (SECIS) in the 3’-untranslated region of selenoprotein mRNAs and its interaction with the SECIS binding protein 2 (SBP2). In humans, mutations in the SBP2-encoding gene Sec insertion sequence binding protein 2 (SECISBP2) that alter the amino acid sequence or cause splicing defects lead to abnormal thyroid hormone metabolism. Herein, we present the first in silico and in vivo functional characterization of alternative splicing of SECISBP2. We report a complex splicing …
Selenoproteinless Animals: Selenophosphate Synthetase Sps1 Functions In A Pathway Unrelated To Selenocysteine Biosynthesis, Alexey V. Lobanov, Dolph Hatfield, Vadim N. Gladyshev
Selenoproteinless Animals: Selenophosphate Synthetase Sps1 Functions In A Pathway Unrelated To Selenocysteine Biosynthesis, Alexey V. Lobanov, Dolph Hatfield, Vadim N. Gladyshev
Vadim Gladyshev Publications
Proteins containing the 21st amino acid, selenocysteine (Sec), have been described in all three domains of life, but the composition of selenoproteomes in organisms varies significantly. Here, we report that aquatic arthropods possess many selenoproteins also detected in other animals and unicellular eukaryotes, and that most of these proteins were either lost or replaced with cysteine-containing homologs in insects. As a result of this selective selenoproteome reduction, fruit flies and mosquitoes have three known selenoproteins, and the honeybee, Apis mellifera, a single detected candidate selenoprotein. Moreover, we identified the red flour beetle, Tribolium castaneum, and the silkworm, Bombyx …
Trends In Selenium Utilization In Marine Microbial World Revealed Through The Analysis Of The Global Ocean Sampling (Gos) Project, Yan Zhang, Vadim N. Gladyshev
Trends In Selenium Utilization In Marine Microbial World Revealed Through The Analysis Of The Global Ocean Sampling (Gos) Project, Yan Zhang, Vadim N. Gladyshev
Vadim Gladyshev Publications
Selenium is an important trace element that occurs in proteins in the form of selenocysteine (Sec) and in tRNAs in the form of selenouridine. Recent large-scale metagenomics projects provide an opportunity for understanding global trends in trace element utilization. Herein, we characterized the selenoproteome of the microbial marine community derived from the Global Ocean Sampling (GOS) expedition. More than 3,600 selenoprotein gene sequences belonging to 58 protein families were detected, including sequences representing 7 newly identified selenoprotein families, such as homologs of ferredoxin– thioredoxin reductase and serine protease. In addition, a new eukaryotic selenoprotein family, thiol reductase GILT, was identified. …
Selenodb 1.0 : A Database Of Selenoprotein Genes, Proteins And Secis Elements, Sergi Castellano, Vadim N. Gladyshev, Roderic Guigo, Marla J. Berry
Selenodb 1.0 : A Database Of Selenoprotein Genes, Proteins And Secis Elements, Sergi Castellano, Vadim N. Gladyshev, Roderic Guigo, Marla J. Berry
Vadim Gladyshev Publications
Selenoproteins are a diverse group of proteins usually misidentified and misannotated in sequence databases. The presence of an in-frame UGA (stop) codon in the coding sequence of selenoprotein genes precludes their identification and correct annotation. The in-frame UGA codons are recoded to cotranslationally incorporate selenocysteine, a rare selenium-containing amino acid. The development of ad hoc experimental and, more recently, computational approaches have allowed the efficient identification and characterization of the selenoproteomes of a growing number of species. Today, dozens of selenoprotein families have been described and more are being discovered in recently sequenced species, but the correct genomic annotation is …
Loss Of Housekeeping Selenoprotein Expression In Mouse Liver Modulates Lipoprotein Metabolism, Aniruddha Sengupta, Bradley A. Carlson, Victoria J. Hoffmann, Vadim N. Gladyshev, Dolph L. Hatfield
Loss Of Housekeeping Selenoprotein Expression In Mouse Liver Modulates Lipoprotein Metabolism, Aniruddha Sengupta, Bradley A. Carlson, Victoria J. Hoffmann, Vadim N. Gladyshev, Dolph L. Hatfield
Vadim Gladyshev Publications
Selenium is incorporated into proteins as selenocysteine (Sec), which is dependent on its specific tRNA, designated tRNA [Ser]Sec. Targeted removal of the tRNA [Ser]Sec gene (Trsp) in mouse hepatocytes previously demonstrated the importance of selenoproteins in liver function. Herein, analysis of plasma proteins in this Trsp knockout mouse revealed increases in apolipoprotein E (ApoE) that was accompanied by elevated plasma cholesterol levels. The expression of genes involved in cholesterol biosynthesis, metabolism and transport were also altered in knockout mice. Additionally, in two transgenic Trsp mutant mouse lines (wherein only housekeeping selenoprotein synthesis was restored), the expression …
Comparative Genomic Analyses Of Copper Transporters And Cuproproteomes Reveal Evolutionary Dynamics Of Copper Utilization And Its Link To Oxygen, Perry Ridge, Yan Zhang, Vadim N. Gladyshev
Comparative Genomic Analyses Of Copper Transporters And Cuproproteomes Reveal Evolutionary Dynamics Of Copper Utilization And Its Link To Oxygen, Perry Ridge, Yan Zhang, Vadim N. Gladyshev
Vadim Gladyshev Publications
Copper is an essential trace element in many organisms and is utilized in all domains of life. It is often used as a cofactor of redox proteins, but is also a toxic metal ion. Intracellular copper must be carefully handled to prevent the formation of reactive oxygen species which pose a threat to DNA, lipids, and proteins. In this work, we examined patterns of copper utilization in prokaryotes by analyzing the occurrence of copper transporters and copper-containing proteins. Many organisms, including those that lack copper-dependent proteins, had copper exporters, likely to protect against copper ions that inadvertently enter the cell. …
Reduced Reliance On The Trace Element Selenium During Evolution Of Mammals, Alexey Lobanov, Dolph Hatfield, Vadim N. Gladyshev
Reduced Reliance On The Trace Element Selenium During Evolution Of Mammals, Alexey Lobanov, Dolph Hatfield, Vadim N. Gladyshev
Vadim Gladyshev Publications
Background: Selenium (Se) is an essential trace element that occurs in proteins in the form of selenocysteine (Sec). It is transported throughout the body in the form of Sec residues in Selenoprotein P (SelP), a plasma protein of unclear origin recently proposed as an experimental marker of dietary Se status.
Results: Here, we report that the amino-terminal domain of SelP is distantly related to ancestral bacterial thiol oxidoreductases of the thioredoxin superfamily, and that its carboxy-terminal Se transport domain may have originated in early metazoan evolution by de novo accumulation of Sec residues. Reconstruction of evolutionary changes in the Se …
In Silico Identification Of Genes Involved In Selenium Metabolism: Evidence For A Third Selenium Utilization Trait, Yan Zhang, Anton Turanov, Dolph Hatfield, Vadim N. Gladyshev
In Silico Identification Of Genes Involved In Selenium Metabolism: Evidence For A Third Selenium Utilization Trait, Yan Zhang, Anton Turanov, Dolph Hatfield, Vadim N. Gladyshev
Vadim Gladyshev Publications
Background: Selenium (Se) is a trace element that occurs in proteins in the form of selenocysteine (Sec) and in tRNAs in the form of selenouridine (SeU). Selenophosphate synthetase (SelD) is required for both utilization traits. However, previous research also revealed SelDs in two organisms lacking Sec and SeU, suggesting a possible additional use of Se that is dependent on SelD.
Results: In this study, we conducted comparative genomics and phylogenetic analyses to characterize genes involved in Se utilization. Candidate genes identified included SelA/SelB and YbbB that define Sec and SeU pathways, respectively, and NADH oxidoreductase that is predicted to generate …