Roger A. Sunde

Bio: Roger A. Sunde is an academic researcher from University of Wisconsin-Madison. The author has contributed to research in topics: Glutathione peroxidase & Selenoprotein. The author has an hindex of 37, co-authored 79 publications receiving 5144 citations. Previous affiliations of Roger A. Sunde include University of Missouri & University of Arizona.

Effect of dietary selenium on erythrocyte and liver glutathione peroxidase in the rat

Abstract: Experiments were conducted with male rats to quantitate the relation ship between dietary selenium (Se) intake and the amount of the enzyme glutathione peroxidase (GSH-Px) in erythrocytes and liver. Weanling male rats were fed torula yeast-based diets with 0, 0.05, 0.1, 0.5, 1.0, or 5.0 ppm Se supplemented as sodium selenite. Liver GSH-Px fell to undetectable levels (<1% of that found in the weanling rats) within 24 days in the O ppm Se group; feeding 0.1 ppm Se, or greater, caused liver GSH-Px to increase above that found in the weanling rats. The erythrocyte GSH-Px response to lack of dietary Se was somewhat smaller in magnitude and more gradual; however, only 21% of initial erythrocyte GSH-Px activity remained in the unsupplemented group after 66 days. Increased dietary Se resulted in corresponding increases of erythrocyte GSH-Px activity. Resupplementing with 0.1, 0.5, or 5.0 ppm Se elevated the depressed erythrocyte GSH-Px levels of the deficient rats. Increased dietary Se provided for both faster elevation, and higher maximal GSH-Px activity which in all cases was achieved 60 to 90 days after resupplementation. The results suggest that tissue GSH-Px can be used as an indicator of animal Se status, but other factors such as age, sex, and dietary vitamin E may have to be considered. Lack of GSH-Px in livers of Se-deficient rats may explain the liver necrosis observed when the diet is also deficient in vitamin E and sulfur-containing amino acids. J. Nutr. 104: 580-587,

Tissue-specific regulation of selenoenzyme gene expression during selenium deficiency in rats.

Abstract: Regulation of synthesis of the selenoenzymes cytosolic glutathione peroxidase (GSH-Px), phospholipid hydroperoxide glutathione peroxidase (PHGSH-Px) and type-1 iodothyronine 5'-deiodinase (5'IDI) was investigated in liver, thyroid and heart of rats fed on diets containing 0.405, 0.104 (Se-adequate), 0.052, 0.024 or 0.003 mg of Se/kg. Severe Se deficiency (0.003 mg of Se/kg) caused almost total loss of GSH-Px activity and mRNA in liver and heart. 5'IDI activity decreased by 95% in liver and its mRNA by 50%; in the thyroid, activity increased by 15% and mRNA by 95%. PHGSH-Px activity was reduced by 75% in the liver and 60% in the heart but mRNA levels were unchanged; in the thyroid, PHGSH-Px activity was unaffected by Se depletion but its mRNA increased by 52%. Thus there is differential regulation of the three mRNAs and subsequent protein synthesis within and between organs, suggesting both that mechanisms exist to channel Se for synthesis of a particular enzyme and that there is tissue-specific regulation of selenoenzyme mRNAs. During Se depletion, the levels of selenoenzyme mRNA did not necessarily parallel the changes in enzyme activity, suggesting a distinct mechanism for regulating mRNA levels. Nuclear run-off assays with isolated liver nuclei showed severe Se deficiency to have no effect on transcription of the three genes, suggesting that there is post-transcriptional control of the three selenoenzymes, probably involving regulation of mRNA stability.

Glutathione Peroxidase and Phospholipid Hydroperoxide Glutathione Peroxidase Are Differentially Regulated in Rats by Dietary Selenium

Abstract: Phospholipid hydroperoxide glutathione peroxidase (PHGPX) and classical glutathione peroxidase (GPXI) are encoded by separate genes with only about 40% amino acid and nucleic acid sequence identity. To determine the response of tissue PHGPX expression to dietary Se level and to compare these responses with those for GPXI, weanling male rats were fed amino acid diets containing from 2 (-Se) to 130 (+Se) μg Se/kg diet or a torula diet containing 5 and 190 μg Se/kg diet as Na 2 SeO 3 for 28 d. Tissues were analyzed for PHGPX and GPXI activity and mRNA. There was no effect of Se on growth. In -Se rats, GPXI activity was reduced to 1% in liver and 4-9% in heart, kidney and lung compared with +Se rats ; PHGPX activity was reduced only to 25-50% in these four tissues. The Se response curves indicated that the dietary Se requirement to reach plateau liver PHGPX activity was half that required for plateau GPX activity. In -Se rats, liver and heart GPXI mRNA levels were reduced to 6 and 12%, respectively, whereas PHGPX mRNA was not significantly affected by Se deficiency. Notably, 65 μg Se/ kg diet resulted in plateau liver GPXI mRNA levels but not plateau GPX activity. Testis had the lowest GPX activity and GPXI mRNA of all tissues examined, but had 15-fold higher PHGPX activity and 45-fold higher PHGPX mRNA levels when compared with liver. There was no significant effect of dietary Se on testis GPXI and PHGPX mRNA levels. This study demonstrates that these two selenoperoxidases are differentially regulated by dietary Se. Differences in Se regulation of mRNA levels in liver and heart were even more pronounced than for enzyme activity. The lack of any significant effect of reduced dietary Se on PHGPX mRNA levels suggests that there are detailed underlying molecular mechanisms whereby Se status regulates GPXI mRNA levels but not PHGPX mRNA levels.

Molecular Biology of Selenoproteins

Abstract: Article de synthese sur la biologie moleculaire des selenoproteines. Etude du metabolisme du selenium (Se), des quatre classes de selenoproteines, de la glutathion peroxidase (GPX) Se-dependante et non dependante, de la phospholipide hydroperoxide GPX, de la GPX plasmatique, de seleno-proteines de mammiferes (rats). Etude de la regulation de l'expression de la GPX par le Se chez les eucaryotes

Selenoprotein Gene Nomenclature

Abstract: The human genome contains 25 genes coding for selenocysteine-containing proteins (selenoproteins). These proteins are involved in a variety of functions, most notably redox homeostasis. Selenoprotein enzymes with known functions are designated according to these functions: TXNRD1, TXNRD2, and TXNRD3 (thioredoxin reductases), GPX1, GPX2, GPX3, GPX4, and GPX6 (glutathione peroxidases), DIO1, DIO2, and DIO3 (iodothyronine deiodinases), MSRB1 (methionine sulfoxide reductase B1), and SEPHS2 (selenophosphate synthetase 2). Selenoproteins without known functions have traditionally been denoted by SEL or SEP symbols. However, these symbols are sometimes ambiguous and conflict with the approved nomenclature for several other genes. Therefore, there is a need to implement a rational and coherent nomenclature system for selenoprotein-encoding genes. Our solution is to use the root symbol SELENO followed by a letter. This nomenclature applies to SELENOF (selenoprotein F, the 15-kDa selenoprotein, SEP15), SELENOH (selenoprotein H, SELH, C11orf31), SELENOI (selenoprotein I, SELI, EPT1), SELENOK (selenoprotein K, SELK), SELENOM (selenoprotein M, SELM), SELENON (selenoprotein N, SEPN1, SELN), SELENOO (selenoprotein O, SELO), SELENOP (selenoprotein P, SeP, SEPP1, SELP), SELENOS (selenoprotein S, SELS, SEPS1, VIMP), SELENOT (selenoprotein T, SELT), SELENOV (selenoprotein V, SELV), and SELENOW (selenoprotein W, SELW, SEPW1). This system, approved by the HUGO Gene Nomenclature Committee, also resolves conflicting, missing, and ambiguous designations for selenoprotein genes and is applicable to selenoproteins across vertebrates.

Glutathione peroxidase activity in selenium-deficient rat liver☆

Abstract: Glutathione peroxidase activity in the liver supernatant from rats fed a Se-deficient diet for 2 weeks was 8% of control when measured with H 2 O 2 but 42% of control when assayed with cumene hydroperoxide. Two peaks of glutathione peroxidase activity were present in the Sephadex G-150 gel filtration chromatogram of rat liver supernatant when 1.5 mM cumene hydroperoxide was used as substrate. Only the first peak was detected when 0.25 mM H 2 O 2 was used as substrate. The first peak was absent from chromatograms of Se-deficient rat liver supernatants; but the second peak, which eluted at a position corresponding to M.W. = 39,000, appeared unchanged. The second peak thus represents a second glutathione peroxidase activity which catalyzes the destruction of organic hydroperoxides but has little activity toward H 2 O 2 and which persists in severe selenium deficiency.

Structural and Functional Aspects of Metal Sites in Biology

Abstract: For present purposes, a protein-bound metal site consists of one or more metal ions and all protein side chain and exogenous bridging and terminal ligands that define the first coordination sphere of each metal ion. Such sites can be classified into five basic types with the indicated functions: (1) structural -- configuration (in part) of protein tertiary and/or quaternary structure; (2) storage -- uptake, binding, and release of metals in soluble form: (3) electron transfer -- uptake, release, and storage of electrons; (4) dioxygen binding -- metal-O{sub 2} coordination and decoordination; and (5) catalytic -- substrate binding, activation, and turnover. The authors present here a classification and structure/function analysis of native metal sites based on these functions, where 5 is an extensive class subdivided by the type of reaction catalyzed. Within this purview, coverage of the various site types is extensive, but not exhaustive. The purpose of this exposition is to present examples of all types of sites and to relate, insofar as is currently feasible, the structure and function of selected types. The authors largely confine their considerations to the sites themselves, with due recognition that these site features are coupled to protein structure at all levels. In themore » next section, the coordination chemistry of metalloprotein sites and the unique properties of a protein as a ligand are briefly summarized. Structure/function relationships are systematically explored and tabulations of structurally defined sites presented. Finally, future directions in bioinorganic research in the context of metal site chemistry are considered. 620 refs.« less

Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases.

Abstract: The goal of this review is to place the exciting advances that have occurred in our understanding of the molecular biology of the types 1, 2, and 3 (D1, D2, and D3, respectively) iodothyronine deiodinases into a biochemical and physiological context. We review new data regarding the mechanism of selenoprotein synthesis, the molecular and cellular biological properties of the individual deiodinases, including gene structure, mRNA and protein characteristics, tissue distribution, subcellular localization and topology, enzymatic properties, structure-activity relationships, and regulation of synthesis, inactivation, and degradation. These provide the background for a discussion of their role in thyroid physiology in humans and other vertebrates, including evidence that D2 plays a significant role in human plasma T3 production. We discuss the pathological role of D3 overexpression causing “consumptive hypothyroidism” as well as our current understanding of the pathophysiology of iodothyronine deiodination during illness and amiodarone therapy. Finally, we review the new insights from analysis of mice with targeted disruption of the Dio2 gene and overexpression of D2 in the myocardium. (Endocrine Reviews 23: 38–89, 2002)

Organoselenium and Organotellurium Compounds: Toxicology and Pharmacology

Abstract: The organoselenium and organotellurium compounds have been described as promising pharmacological agents in view of their unique biological properties. Glutathione peroxidase mimic, antioxidant activity and thioredoxin reductase inhibition are some of the properties reviewed here. On the other hand, little is known about the molecular toxicological effects of organoselenium and organotellurium compounds. Most of our knowledge arose from research on inorganic selenium and tellurium. However, the ability to oxidize sulfhydryl groups from biological molecules can be involved both in their pharmacological properties and in their toxicological effects. In fact, exposition to high doses of organoselenium or to low doses of organotellurium causes the depletion of endogenous reduced glutathione in a variety of tissues. Thus, the design of compounds that cause low depletion of glutathione and react with specific targeted proteins, controlling specific metabolic pathways, will represent an important progress in understanding the field of organochalcogen compounds. Furthermore, the development of new organochalcogens with higher thiol-peroxidase activity that can use other non-toxic thiol reducing agents, such as N-acetylcysteine instead of glutathione, will permit the investigation of the co-administration of organochalcogens and thiols as a formulation for antioxidant therapy.

The Mononuclear Molybdenum Enzymes

Abstract: Molybdenum is the only second-row transition metal required by most living organisms, and is nearly universally distributed in biology. Enzymes containing molybdenum in their active sites have long been recognized,1 and at present over 50 molybdenum-containing enzymes have been purified and biochemically characterized; a great many more gene products have been annotated as putative molybdenum-containing proteins on the basis of genomic and bioinformatic analysis.2 In certain cases, our understanding of the relationship between enzyme structure and function is such that we can speak with confidence as to the detailed nature of the reaction mechanism and, with the availability of high-resolution X-ray crystal structures, the specific means by which transition states are stabilized and reaction rate is accelerated within the friendly confines of the active site. At the same time, our understanding of the biosynthesis of the organic cofactor that accompanies molybdenum (variously called molybdopterin or pyranopterin), the manner in which molybdenum is incorporated into it, and then further modified as necessary prior to insertion into apoprotein has also (in at least some cases) become increasingly well understood. It is now well-established that all molybdenum-containing enzymes other than nitrogenase (in which molybdenum is incorporated into a [MoFe7S9] cluster of the active site) fall into three large and mutually exclusive families, as exemplified by the enzymes xanthine oxidase, sulfite oxidase, and DMSO reductase; these enzymes represent the focus of the present account.3 The structures of the three canonical molybdenum centers in their oxidized Mo(VI) states are shown in Figure 1, along with that for the pyranopterin cofactor. The active sites of members of the xanthine oxidase family have an LMoVIOS-(OH) structure with a square-pyramidal coordination geometry. The apical ligand is a Mo=O ligand, and the equatorial plane has two sulfurs from the enedithiolate side chain of the pyranopterin cofactor, a catalytically labile Mo–OH group, and most frequently a Mo=S. Nonfunctional forms of these enzymes exist in which the equatorial Mo=S is replaced with a second Mo=O; in at least one member of the family the Mo=S is replaced by a Mo=Se, and in others it is replaced by a more complex –S–Cu–S–Cys to give a binuclear center. Members of the sulfite oxidase family have a related LMoVIO2(S–Cys) active site, again square-pyramidal with an apical Mo=O and a bidentate enedithiolate Ligand (L) in the equatorial plane but with a second equatorial Mo=O (rather than Mo–OH) and a cysteine ligand contributed by the protein (rather than a Mo=S) completing the molybdenum coordination sphere. The final family is the most diverse structurally, although all members possess two (rather than just one) equiv of the pyranopterin cofactor and have an L2MoVIY(X) trigonal prismatic coordination geometry. DMSO reductase itself has a catalytically labile Mo=O as Y and a serinate ligand as X completing the metal coordination sphere of oxidized enzyme. Other family members have cysteine (the bacterial Nap periplasmic nitrate reductases), selenocysteine (formate dehydrogenase H), –OH (arsenite oxidase), or aspartate (the NarGHI dissimilatory nitrate reductases) in place of the serine. Some enzymes have S or even Se in place of the Mo=O group. Members of the DMSO reductase family exhibit a general structural homology to members of the aldehyde:ferredoxin oxidoreductase family of tungsten-containing enzymes;4 indeed, the first pyranopterin-containing enzyme to be crystallographically characterized was the tungsten-containing aldehyde:ferredoxin oxidoreductase from Pyrococcus furiosus,5 a fact accounting for why many workers in the field prefer “pyranopterin” (or, perhaps waggishly, “tungstopterin”) to “molybdopterin”. The term pyranopterin will generally be used in the present account. Open in a separate window Figure 1 Active site structures for the three families of mononuclear molybdenum enzymes. The structures shown are, from left to right, for xanthine oxidase, sulfite oxidase, and DMSO reductase. The structure of the pyranopterin cofactor common to all of these enzymes (as well as the tungsten-containing enzymes) is given at the bottom.