Gerald F. Combs, Jr., PhD

Selenium (Se) was discovered in 1817 by the Swedish chemist Jöns Jakob Berzelius, who found the element associated with tellurium. He named the new element selenium (from the Greek word selene, meaning moon) because it tends to be found in the earth along with tellurium (which had been named after the Latin word tellus, meaning earth). Not until the late 1950s, however, was selenium thought to play a role in normal metabolism. Until that time, the biomedical significance of selenium had been recognized only for its toxic properties. In 1957 it was discovered that trace amounts of Se could alleviate necrotic liver disease and capillary leakage in vitamin E–deficient animals, suggesting that Se spared the need for that fat-soluble vitamin (Schwarz and Foltz, 1957; Schwarz et al., 1957). Research in the 1970s revealed the basis of this interaction: Se is an essential constituent of the antioxidant enzyme glutathione peroxidase 1 (GPX1) (Rotruck et al., 1973). Since that time, an increasing understanding has emerged of the metabolic functions and health implications of this trace element, now known to be an essential constituent of some 25 selenoproteins, including the GPXs, each of which contains covalently linked selenium in the form of selenocysteine (SeCys). This previously unrecognized selenoamino acid, SeCys, was found to be incorporated into the selenoproteins cotranslationally by a process signaled by the TGA codon in DNA (UGA in mRNA), which normally functions as a stop codon. Because many, if not all, selenoproteins appear to have redox functions, selenium is now regarded as being important in the metabolic protection from cellular oxidative stress. In addition, selenium has been shown to have a role in anticarcinogenesis.

Chemistry of Selenium

Selenium is in group 16 (chalcogens) of the periodic table of elements. This group includes the nonmetallic elements sulfur and oxygen in the periods above Se, and the metallic elements tellurium and polonium in the periods below. Within period 3 of the periodic table, Se lies between the metal arsenic and the nonmetal bromine. Thus Se is often considered a metalloid, having both metallic and nonmetallic properties.

Inorganic selenium biochemistry involves mainly that of its nonmetallic anionic forms Se2– (selenide, -2 oxidation state, H2Se, hydrogen selenide), SeO32− (selenite, +4 oxidation state, H2SeO3, selenous acid) and SeO42− (selenate; +6 oxidation state, H2SeO4, selenic acid). Selenide (mainly in the anionic form of HSe at pH 7) plays a pivotal role in metabolism, being the obligate precursor for cotranslational synthesis of SeCys.

The major forms of selenium in cells are the selenoamino acids, in which selenium forms covalent bonds with carbon atoms. Selenium also forms covalent bonds with sulfur atoms. The selenoamino acids include SeCys, which is encoded in a special manner by DNA/mRNA and is cotranslationally synthesized, and the selenide-containing amino acid selenomethionine (SeMet, a selenoether), which originates in plants and microorganisms that use elemental selenium in place of sulfur for synthesis of sulfur (seleno) amino acids. SeMet can be incorporated into proteins in the body nonspecifically in place of methionine (Met). The selenium compounds of greatest relevance in biology are listed in Table 39-1.

Although selenium has many similarities to sulfur, selenium compounds are more nucleophilic and more acidic than the corresponding sulfur compounds. For example the pKa1 of H2Se is 3.9 compared to 7.0 for H2S, and the pKa of the selenol group of selenocysteine (R-SeH) is 5.5 compared to 8.5 for the thiol group of cysteine (R-SH). Thus, whereas thiols such as cysteine (Cys) tend to be protonated at physiological pH, selenols such as SeCys tend to be dissociated under the same conditions. This may have important implications for reaction chemistry catalyzed by selenoproteins.

In addition, the higher redox potentials of selenium compounds, compared with their sulfur analogs, cause selenium metabolism to be inclined toward reduction, whereas sulfur metabolism is generally oxidative. Thus sulfide is oxidized to sulfate but selenate is reduced to selenide.

Selenite (SeO32−) readily accepts electrons and is therefore easily reduced. At low pH, it is readily reduced by such agents as ascorbic acid and SO2. Selenite can readily react with nonprotein thiols (e.g., reduced glutathione, GSH) or with protein-sulfhydryl groups to be reduced to selenide via sequential formation of RSSeSR products called selenotrisulfides (e.g., GSSeSG) and RSSeH products called selenodisulfides (GSSeH).

Selenate (SeO42−) is much more resistant to reduction, and activation of selenate to adenosine-5′-phosphoselenate appears to be required as a first step in its physiological reduction.

Selenium has five naturally occurring stable isotopes: 80Se, the most abundant form, along with 74Se, 76Se, 77Se, and 78Se. Some of these stable isotopes of selenium have been employed in metabolic studies in humans. These can be detected by mass spectrometry. Thirteen radioisotopes of selenium can be produced by neutron activation or radionuclear decay, and some of these have found applications as well. Because of its emission of γ-radiation and its relatively long half-life (120 days), 75Se has been widely employed in biological experimentation and in medical diagnostic work. The short-lived 77mSe (t½ = 17.5 sec) has been used in the neutron activation analysis of Se in biological materials.

Selenium in Foods

The selenium contents of foods vary widely, primarily because of variability in the soluble selenium content of the soil for plant species and in the biologically available selenium content of livestock diets. Because of the intimate relationship between plants and animals in the food chain, the selenium contents of foods from both plant and animal origins tend to be greatly influenced by the local soil selenium environment. The major forms of selenium in soil are selenite and selenate.

Foods of all types tend to show geographic patterns of variation in selenium content reflecting, in general, local soil selenium conditions. Variation in the selenium content of foods is readily seen by comparing the selenium contents of like foods from different countries (Combs and Combs, 1986). For example, whole wheat grain may contain more than 2 to 5 mg Se/kg (air-dried) if produced in the western parts of North and South Dakota in the United States or in Saskatchewan and Alberta in Canada. However, whole wheat grain may contain as little as 0.1 mg Se/kg if produced in Kansas or New Zealand, and only 0.005 mg Se/kg if produced in Shaanxi Province, China. On a global basis, foods with the lowest selenium contents are found in the provinces of Heilongjiang, northern Shaanxi, and Sichuan in China. Ironically, foods containing the greatest concentrations of selenium have also been found in China, though in different locales.

Most of the selenium taken up by plants is incorporated into organoselenium compounds such as SeMet, Se-methylselenocysteine, SeCys, and other related metabolites (Rayman et al., 2008). The selenoamino acids are synthesized

by plants and microorganisms when Se2− replaces S2− in the biosynthetic pathways for sulfur-amino acid synthesis. The selenoamino acids, particularly SeMet, then are incorporated into proteins. SeMet is the most abundant form of selenium in cereal grains and legumes, due mainly to the nonspecificity of the methionyl-tRNA synthetase which will use SeMet in place of Met for aminoacylation of the tRNAMet.

Certain plant species called selenium accumulator plants, if grown on high-Se soils, can accumulate very large amounts of Se as non-protein selenoamino acids such as Se-methylselenocysteine, γ-glutamyl-Se-methylselenocysteine, and selenocystathionine. It is thought that these forms are less toxic because their formation prevents excess selenoamino acid incorporation into proteins. Se-methylselenocysteine is a major selenocompound in Se-enriched garlic, onions, broccoli florets, and broccoli sprouts, but γ-glutamyl-Se-methylselenocysteine becomes the major form when these vegetables are grown in soil with high selenium levels.

Animals ingest various forms of selenium, especially SeMet, in their diets. However, they do not have pathways for synthesis of cysteine or methionine from inorganic sulfur and hence do not incorporate large amounts of inorganic selenium into selenoamino acids. Of course, SeCys is synthesized cotranslationally in animals and is incorporated into selenoproteins at specific sites. However, animals can non-specifically incorporate SeMet from the diet into proteins in place of Met. SeMet is the dominant selenoamino acid in tissues of animals that are given high levels of SeMet in their feed, due to the nonspecific incorporation of SeMet in addition to selenoprotein synthesis. On the other hand, animals given selenite or selenate instead of SeMet incorporate selenium mostly as SeCys residues in selenoproteins because this is the only route for de novo selenoamino acid synthesis in animals. Thus, the total concentration of selenium in tissues of animals given selenite or selenate as the source of selenium is lower than that in tissues of animals given SeMet as the source of selenium. Because SeCys and SeMet are found mainly as part of proteins, the selenium content of foods tends to be correlated with protein content.

Small amounts of inorganic selenium compounds, especially selenate, are present in foods. Minor quantities of inorganic selenium are found in the drinking water, although the level depends on characteristics and the selenium concentration of the soil through which the water passes. Larger intakes of inorganic selenium occur only when selenium supplements in the form of selenate or selenite salts are taken.

The selenium content of foods of animal origin depends largely on the amount and form of selenium consumed by livestock. Food animals raised in regions with feeds of low selenium content deposit relatively low concentrations of selenium in their edible tissues and products (e.g., milk, eggs), whereas animals raised with relatively high selenium nutriture yield food products with much greater selenium concentrations, particularly if the feed contains SeMet. Because livestock need selenium to prevent debilitating deficiency syndromes, it is used as a feed supplement, usually as sodium selenite or sodium selenate, in animal agriculture in many parts of the world. This practice has reduced what would otherwise be a stronger geographic variation in the selenium content of animal food products. Within the normal ranges of selenium in livestock diets, muscle meats from most species tend to contain 0.3 to 0.5 mg Se/kg (fresh weight). Organ meats usually contain higher (4 to 15 times) concentrations of Se.

Selenium in Human Diets

The average daily selenium intake of adults is estimated to vary widely among different regions. In most human diets, the dominant food sources of selenium are cereals, meats, and fish. The dominance of cereal-based foods as core


Selenium-Accumulator Plants

Though the selenium contents of most plants generally reflect the selenium contents of the soil in which they are grown, certain species can accumulate appreciable amounts of the element. Cruciferous vegetables, for example, which are naturally rich in sulfur, can accumulate nutritionally significant amounts of selenium (up to 1 to 10 mg/kg, air-dried) if grown on high-Se soils or if fertilized with selenite or selenate salts. Others can accumulate much more selenium under such conditions. Species in the genera Aster, Astriplex, Castilleja, Comandra, Grindelia, Gutierrezia, Machaeranthera, and Mentzelia can accumulate as much as 25 to 100 mg Se/kg. Other plants in the genera Astragalus, Machaeranthera, Haplopappus, and Stanleya can accumulate hundreds to thousands of milligrams Se per kilogram. One species, Astragalus bisulcatus, has been found to accumulate as much as 10 g Se/kg (see Rosenfeld and Beath, 1964). Species in this latter group, referred to as Se-accumulator plants, were identified as causing “blind staggers” (a neuropathy apparently involving selenosis and, perhaps, plant alkaloids) among livestock grazing on seleniferous soils in northwestern Nebraska and western regions of North and South Dakota. Selenium-accumulator plants have been proposed for use in bioremediation of seleniferous soils.

More than a dozen selenium metabolites have been reported in the tissues of Se-accumulator plants, the dominant one being Se-methylselenocysteine (Shrift, 1969). The non-specific integration of the selenoamino acids into proteins is believed to be the major contributor of selenium toxicity in plants. The ability of Se-accumulator plants to convert these selenoamino acids into non-protein amino acids such as Se-methylselenocysteine (MeSeCys), γ-glutamyl-Se-methylselenocysteine (GGMeSeCys), and selenocystathionine reduces the incorporation of selenoamino acids into proteins and thus minimizes selenium toxicity. Non-accumulator plants, which are incapable of this metabolism, are sensitive to high soil Se levels. For this reason, the presence of Se-accumulator plants has been used to identify seleniferous rangeland.

sources of selenium means that, in many countries, selenium intakes can be affected by factors that influence the importation of grain from the world market, most of which is grown in areas of the United States, Canada, and Australia where the soil is rich in selenium.

Milk and milk products contribute small amounts of selenium to the total intake in most countries, although these foods may contribute a large proportion of total selenium intake in countries where their consumption is relatively high or where the rest of the diet provides little selenium, or both (e.g., New Zealand). Vegetables and fruits are uniformly low in selenium (fresh weight) and provide only small amounts (<8% of total Se intake) of the mineral in most human diets.

An analysis of American diets based on the U.S. Department of Agriculture 1977–1978 Nationwide Food Consumption Survey and published selenium contents of American foods revealed that a core of only 22 foods provided 80% of the total dietary selenium intake (Schubert et al., 1987). Five foods contributed half of total selenium in the “typical” American diet; these foods were beef, white bread, pork, chicken, and eggs.

The major forms of selenium in plant and animal tissues are analogs of the sulfur-containing amino acids, SeMet and SeCys. Plants tissues contain mostly SeMet, which plants synthesize. Animal and human tissues contain both SeMet obtained from dietary sources and SeCys in specific selenproteins which animals synthesize in conjunction with a specific tRNA. SeCys is the dominant form of selenium in livestock supplemented with inorganic forms of selenium.

Utilization of Dietary Selenium

Bioavailability of Dietary Selenium

The utilization of dietary selenium by the human body involves the metabolic conversion of a portion of ingested selenium to forms that can be incorporated into selenoproteins (as SeCys residues). Because most food selenium occurs as selenoamino acids in food proteins, the bioavailability of such selenium is determined in part by the digestibility of those proteins; poorly digested selenium-containing proteins, as well as dietary selenium compounds that are insoluble in the luminal environment of the small intestine, will pass through to be eliminated in the feces. Under normal circumstances, there appears to be only a small enterohepatic circulation of absorbed selenium; therefore fecal selenium constitutes mostly unabsorbed dietary selenium.

Selenium Metabolism

Recognition that the metabolic function of selenium is related to that of vitamin E (α-tocopherol) emerged with the demonstration that selenium could prevent pathological conditions in vitamin E–deficient rats (Schwarz and Foltz, 1957) and chicks (Schwarz et al., 1957). From this origin came the view of selenium as an antioxidant nutrient. Indeed, combined deprivation of selenium and vitamin E yields elevated levels of products of free radical attack on polyunsaturated fatty acids that are detectable in tissues (malonyldialdehyde, F2-isoprostanes) and exhaled breath (ethane, pentane). Thus it is clear that selenium and vitamin E function in concert in cellular antioxidant protection. In this system, α-tocopherol functions as a lipid-soluble, chain-breaking antioxidant, whereas selenium is involved as one or more SeCys residues in one or more redox-active selenoproteins. Because the physiological role of selenium is as SeCys residues in selenoproteins, an important aspect of selenium metabolism is the incorporation of dietary selenium into these selenoproteins.

Reduction of Selenate and Selenite to Selenide

The various forms of selenium that are taken up from the gastrointestinal tract are metabolized ultimately to selenide (Ganther, 1999) (Figure 39-1). For the oxidized inorganic forms, this involves reduction. Selenate is converted to selenite via activation to adenosine phosphoselenate and reduction by reactions with reduced glutathione (GSH). Selenite, whether from the diet or formed from selenate, is converted to selenide by reactions that require GSH and NADPH as reductants and involve formation of a glutathione selenopersulfide (GSSeH) intermediate.

Metabolism of Selenomethionine from the Diet

Ingested SeMet can be used in protein synthesis in place of Met, or it can be catabolized ultimately to selenide. It can charge tRNAMet at rates similar to that of Met (Km values: 11 μmol/L for SeMet versus 7 μmol/L for Met) and is thus readily incorporated into proteins according to their Met contents. This nonspecific, protein-bound selenium accounts for most of the selenium in tissues (e.g., 20% to 60% of the selenium in plasma) of individuals fed normal diets containing SeMet. Metabolism of SeMet to selenide occurs by the same pathway used for the transmethylation and transsulfuration of Met to form Cys. This involves activation of SeMet to Se-adenosylselenomethionine, which in turn serves as a methyl donor and is converted to Se-adenosylselenohomocysteine. Se-adenosylselenohomocysteine is further metabolized to selenohomocysteine. Selenohomocysteine is further metabolized by the transsulfuration enzymes (see Figure 14-22 for Met metabolism Chapter 14), cystathionine β-synthase and cystathionine γ-lyase. These reactions yield SeCys, from which selenide is released by a specific γ-lyase. The SeCys produced from metabolism of ingested SeMet is not incorporated directly (i.e., nonspecifically) into proteins in animals. A third prospect for SeMet is metabolism to methylated forms and methylseleno-N-acetyl-galactosamine, which are excretable forms.

Plasma Forms of Selenium

The circulating plasma pool of selenium comprises two functional, specific selenoproteins (SepP1 and GPX3); the general non-specific SeMet in albumin and other plasma proteins; and a small amount of selenium in forms other than amino acid residues in proteins (e.g., selenosugars). SepP1 and GXP3 accounted for about 34% and 20%, respectively, (or a total of 54%) of the total plasma selenium pool in a group of healthy adult subjects in North Dakota in the United States, a region with relatively high selenium intakes and a mean plasma selenium level of 142 ng/mL (Combs et al., 2011). The proportion of plasma selenium contributed by the two plasma selenoproteins was estimated to be slightly larger (64%) in a group of subjects with plasma total selenium concentrations of 125 ng/mL, which are closer to mean values for the U.S. population (Burk et al., 2006). Maximal expression of the plasma selenoproteins occurs at intakes yielding plasma levels above 70 ng/mL, which is close to the plasma selenium levels estimated to be contributed by maximal expression of SepP1 and GPX3. Higher intakes of foods containing SeMet result in increases in the nonspecific incorporation of SeMet into plasma proteins and thus higher plasma selenium levels. Intake of inorganic forms of selenium does not result in an increase in this component of plasma selenium because animals do not incorporate inorganic selenium into SeMet (Burke et al., 2001).

Selenium Excretion

Metabolic tracer studies have shown that over a 12-day period, Se-adequate adults excrete a total of 17% of selenium from an oral selenite dose, but only 11% of selenium from an oral SeMet dose (Patterson et al., 1989). The primary route of selenium excretion is across the kidney; the dominant urinary metabolite in individuals with low-to-moderate Se intakes is the selenosugar 1β-methylseleno-N-acetyl-galactosamine (Kobayashi et al., 2002). Individuals with relatively high selenium intakes may excrete other compounds such as trimethylselenonium or other selenosugars in the urine and methylselenol in the breath.

Selenium Incorporation into Selenoproteins

Selenium is incorporated as SeCys in some 25 selenoproteins in animals (Kryukov et al., 2003). Neither SeCys from the diet or endogenous protein turnover nor SeCys formed in the body during SeMet catabolism can be used directly for the specific incorporation of SeCys into selenoproteins. Instead, inorganic selenide is activated and added in a cotranslational conversion of serine (Ser) to SeCys while the amino acid is bound to a specific tRNA (tRNA[Ser]SeCys) (Figure 39-2). The selenium in selenoamino acids is used for selenoprotein synthesis only after the selenoamino acids have been catabolized to yield inorganic selenium.


The tRNA[Ser]SeCys in mammals differs from other tRNAs by having 90 nucleotides (compared to the usual 76), a UCA (uracil–cytosine–adenine) anticodon sequence, 2 additional base pairs in the acceptor stem (9 compared to 7), and 11 additional bases (16 compared to 5, including 5 base pairs compared to none) in the D-loop (Carlson et al., 2006). Mammalian tRNA[Ser]SeCys has two isoforms arising from the same gene and differing in the modification of uridine at the 5′ position of the UCA anticodon (i.e., 5-methylcarboxymethyl uridine or 5-methylcarboxymethyl uridine-2′-O-methylribose). The tRNA[Ser]SeCys is charged with Ser at its 3′-terminal adenosine in a reaction catalyzed by seryl-tRNA synthetases, which do not distinguish between tRNASer and tRNA[Ser]SeCys.

Selenophosphate is the immediate Se donor for the conversion of Ser-tRNA[Ser]SeCys to SeCys-tRNA[Ser]SeCys. The formation of selenophosphate is catalyzed by selenophosphate synthetase (SPS) (Salinas et al., 2006). Humans have two SPS genes; one encodes a selenoprotein (SPS2) and the

other encodes a non-selenoprotein (SPS1). SPS2 and SPS1 differ only in the amino acid residue at position 60 (threonine in SPS1, SeCys in SPS2). It is hypothesized that SPS1 may ensure continued synthesis of SeCys, albeit at low levels, under conditions of limited Se supply and diminished activity of SPS2. The reaction uses ATP as a cosubstrate for addition of phosphate to selenide (HSe2–) to form selenophosphate (HSePO32−).

The addition of selenide to the serine attached to Ser-tRNA[Ser]SeCys to form SeCys-tRNA[Ser]SeCys involves the action of two additional enzymes, a specific O-phosphoseryl-tRNA[Ser]SeCys kinase and selenocysteine synthase. O-phosphoseryl-tRNA[Ser]SeCys kinase catalyzes the phosphorylation of the serine residue of Ser-tRNA[Ser]SeCys, and the pyridoxal phosphate-dependent selenocysteine synthase catalyzes the addition of selenium from selenophosphate to complete the conversion of the Ser attached to the tRNA[Ser]SeCys to a SeCys that is still esterified to the tRNA.

The UGA Codon in Selenoprotein mRNA

Each SeCys center of a selenoprotein is encoded by a TGA in the respective gene, which is transcribed as UGA in the mRNA. This phenomenon, first recognized with the sequencing of the cDNA for GPX1, was unexpected because a UGA in mRNAs typically serves as a stop codon in mammalian protein synthesis. Studies on translation of selenoprotein mRNAs revealed that the 3′-untranslated region (3′-UTR) of the mRNA was necessary for UGA-encoded SeCys incorporation. Berry and colleagues (1991) identified a consensus 87-base stem–loop element necessary for the insertion of Se in two selenoproteins of the rat (iodothyronine 5′-deiodinase-1 and GPX1). This SeCys insertion sequence (SECIS) element has been found in the 3′-UTRs of the mRNAs of all selenoproteins. Most selenoprotein mRNAs contain a single UGA codon encoding a single SeCys residue per polypeptide chain and a single SECIS element. Selenoprotein P is unique in that its mRNA encodes multiple SeCys residues and contains two SECIS elements in its 3′-UTR.

As shown in Figure 39-3, the mammalian SECIS element consists of a stem–loop structure with an apical loop and an internal loop between two helical regions (stems). The apical loop consists of 7 to 10 unpaired bases, including a consensus AA (adenine–adenine) sequence. The helix between the apical and the internal loops contains an AUGA (adenine–uracil–guanine–adenine) sequence 5′ to the apical loop, and a GA (guanine–adenine) sequence 3′ to the apical loop. This AUGA … AA … GA motif is key to functionality, although a few mammalian SECIS elements have been found with a variant motif, AUGA … CC … GA. The conserved UGA and GA sequences form the core of a quartet motif of non–Watson and Crick base pairs (i.e., U-U and G-A), resulting in a greater than 90-degree kink in the stem–loop. Half of mammalian SECIS elements have an additional stem extending from the apical loop; it is thought that these specific secondary structures may affect the rate of SeCys insertion into various selenoproteins.

Archaea have the same SECIS element as eukaryotes. However, the prokaryotic SECIS consists of a 38-nucleotide stem–loop element located in the open reading frame of the selenoprotein mRNA immediately following the UGA codon (Bock et al., 2006). It is thought that constraints of maintaining this secondary structure may limit the capacity of bacterial genes to place SeCys at the active site of enzymes. In bacteria, a single elongation factor is required to bind the SECIS element and the SeCys-tRNA, whereas in eukaryotes and archaea, those roles are filled by different proteins: SECIS-binding protein (SBP2), which appears to bind to the AUGA/GA stem nucleotides, and a SeCys-specific elongation factor (eEFSeCys) that partners with SBP2 for incorporation of UGA-encoded SeCys. That eEFSeCys binds to SeCys-tRNA[Ser]SeCys but not to Ser-tRNASer prevents misincorporation of Ser in place of SeCys. Like other elongation factors, eEFSeCys binds GTP and is dependent upon GTP hydrolysis for activity.

This process of SeCys incorporation into selenoproteins is accomplished by a complex of these proteins on the ribosome: selenoprotein mRNA, SBP2, eEFSeCys–GTP, and SeCys-tRNA[Ser]SeCys. The bases between the UGA and the SECIS element of the selenoprotein mRNA serve as a flexible tether, enabling the complex to orient the anticodon on the tRNA to interact with the approaching acceptor site on the ribosome. Peptide bond formation between SeCys and the nascent polypeptide is catalyzed by peptidyltransferase, as is the case for addition of other amino acids to the growing peptide chain.

The Selenoproteins

Genomic screening for selenoproteins has been accomplished by searching for conserved SECIS elements, conserved appropriate secondary structures, open reading frames containing in-frame TGA codons, and homologs in other species containing Cys (Kryukov et al., 2003). Most selenoproteins appear to be enzymes, or to have been derived from enzyme families, with their SeCys residues located in variants of the CxxC (where C = Cys and x = any amino acid) motif found in many redox proteins (Gladyshev, 2006). The selenoproteins appear to have a scattered phylogenetic distribution; most have homologs containing Cys instead of SeCys. For example, GPX6 is a selenoprotein (contains SeCys) in humans and swine but not in rodents. Other cross-species examples include methionine-R-sulfoxide reductase, which is a selenoprotein in green algae but not in vertebrates; and protein U, which contains SeCys in fish but exists as Cys-containing homologs in humans and worms. In general, the substitution of SeCys for Cys in the enzyme active site enhances its catalytic efficiency.

Selenoproteins are present in bacteria, archaea, and eukaryota, but not in all members of these domains. In addition, the size of the selenoproteome varies among domain members. For example, in eukaryotes, the highest number of selenoproteins is observed in aquatic organisms (e.g., more than 30 selenoproteins in many fishes and algae) whereas no selenoproteins have been identified in fungi and higher plants (Lobanov et al., 2009). In addition to use of selenium for synthesis of proteins that are translated with SeCys residues, some bacterial and archaeal cells use selenium for synthesis of selenouridine-modified tRNAs and/or posttranslational maturation of selenium-molybdenum-cofactor containing enzymes such as xanthine dehydrogenase and purine hydroxylase (Haft and Self, 2008). The incorporation of selenium into these latter compounds also appears to require the conversion of selenide to selenophosphate by selenophosphate synthetase.

The human selenoproteome consists of 25 selenoproteins broadly classified as antioxidant enzymes (Reeves and Hoffman, 2009) (Table 39-2). Of these, the first to be recognized, and thus the best studied, are the GPXs. Other well-studied selenoproteins include the iodothyronine 5′-deiodinases (DIs), the thioredoxin reductases (TRRs), and selenoproteins P (SepP) and W (SepW). Many selenoenzymes exist as multiple isoforms.

TABLE 39-2

The Major Selenoproteins

Glutathione peroxidases Antioxidant enzymes catalyzing the reduction of hydroperoxides using reducing equivalents from reduced glutathione (GSH) GPX1 Cytosol, mitochondrial matrix space Sensitive to dietary Se deprivation
GPX2 Cytosol; mostly gastrointestinal cells Relatively resistant to dietary Se deprivation
GPX3 Plasma, milk Sensitive to dietary Se deprivation
GPX4 Cell membranes; mammalian sperm mid-piece Relatively resistant to dietary Se deprivation
Thioredoxin reductases Antioxidant flavoenzymes catalyzing the reduction of thioredoxin using reducing equivalents from NADPH TRR1 Cytosol  
TRR2 Mitochondria Relatively resistant to dietary Se deprivation
TRR3 Cytosol; mostly testes  
Deiodinases Enzymes essential for thyroid hormone function; catalyze activation of T4 to T3 DI1 Cytosol; mostly liver, muscle Catalyzes 5′-deiodination of T4 outer ring; also can catalyze 5-deiodination of inner ring
DI2 Cytosol; brain, pituitary, brown adipose, skin, placenta Catalyzes 5′-deiodination of T4 outer ring
DI3 Cytosol; brain, skin, placenta Catalyzes 5-deiodination of inner ring for conversion of T3 to T2 and T4 to reverseT3
Selenoprotein P Major transporter for Se to peripheral tissues SepP Plasma; cytosol of most cells Has 5–6 Se atoms per molecule
Selenoprotein W Presumed to function in protecting muscle from oxidative damage SepW Cytosol; muscle, brain Upregulated by supranutritional Se levels
Selenoprotein 15 Thought to be involved in protein folding Sep15 Endoplasmic reticulum; most cells A thiol-disulfide oxidase
Selenoprotein R Reduces methionine R-sulfoxide (oxidized methionine) SepR Cytosol and nucleus; most cells Also called methionine-R-sulfoxide reductase
Selenophosphate synthetase 2 Catalyzes ATP-dependent activation of selenide in the cotranslational synthesis of tRNA-bound SeCys SPS2 Cytosol; most cells Functions in the synthesis of all selenoproteins

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Feb 26, 2017 | Posted by in PHARMACY | Comments Off on Selenium

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