Selenium is an integral part of more than about 30 known proteins. These proteins are called selenium-containing proteins or selenoproteins, of which about 15 have been purfied to allow characterization of their biological function. Selnium is incorporated into these selenoproteins as the 21st amino acid, selenocysteine.

In addition to incorporation as selenocysteine, selenium can replace sulfur in methionine, forming selenomethionine. This compound can be incorproated non-specifically into proteins in place of met. Finally, selenium can be tightly bound by certain proteins, known as selenium-bnding proteins, to distinguish them from true selenoproteins. Selenium is found in human and animal tissues as L-selenomethionine or L-selenocysteine.

Selenoproteins

Selenoproteins are comprised of four glutatione peroxidases, three idothyronine deiodinases, three thioredoxin reductases, selenoprotein P, selenoprotein W and selenophosphate synthetase. Over half of the Se in plasma is in the form of selenoprotein P.

Selenoproteins perform a variety of physiological role. The glutatione peroxidases, and possibly selenoprotein P and selenoprotein W, are antioxidant proteins that reduce potentially damaging reactive oxygen species (ROS) such as hydrogen peroxide and lipid hydroperoxides, to harmless products – water and alchols- by coupling their reduction with oxidation of glutathione.

Glutathione in its reduced form (GSH) is the single most important protective and regulatory antioxidant in cells. As it is oxidized it becomes oxidized glutathione (GSSG), and the intracellular ratio of GSH:GSSG is reportedly a very good measure of the cell’s overall antioxidant status. T helper cells infected with HIV-1 reportedly deterioated in GSH status and progressively lost their functional capacity.

Only a few mammalian selenoproteins have well understood roles; these include several forms of glutathione peroxidase (GPX) and the type I 5–iodothyronine deiodinase involved in conversion of T4 thyroid hormone to T3. Glutathione Peroxidase 1 (GPX1 or cGPX) is one of the most thoroughly studied selenoproteins. It catalyzes glutathione-dependent reduction of hydrogen peroxide and various organiz hydroperoxides. The enzyme is a homotetramer of ~22kd subunits and it is located in the cytosol.

Estimates of the total number of selenoproteins encoded in the genomes of mammals range from 25 to 100. These estimate are based on 75Se-labeling experiments, which detect selenoprotein spots on 2D gels.

Selenocystein: biosynthesis and characterization 

Selenocystein (Sec) is recognized as the 21st amino acid, as it has its own codon and selenocysteine-specific ciosynthetic and insertion machinery. The 3′ untranslated region of all mammalian selenoprotein mRNAs contains a region of conserved secondary structure, the Sec insertion sequence (SECIS element). This element is required for reocgnition of UGA condos as Sec, and serves as the binding site of the SECIS element binding protein-2. SBP2 binds to a conserved, non-Watson-Crick base-paired region in the stem of the SECIS element and remains bound through multiple cycles of selenoprotein translation. SBP2 also binds to a selenoprotein-specific elongation factor, eEFSec (rather then the standard elongation factor, eEFIA) which exhibits specificity for both the unique tRNA structure and the amino acid. Recruitment of the Sec-tRNA-EFsec complex to the ribosome occurs via its interaction with the SECIS binding protein 2, a protein exhibiting specificity for the SECIS elements in selenoprotein mRNAs.

The tRNA is first aminoacylated with serine, which serves as the backbone for the biosynthesis of Sec. Sec tRNA is therefore designated tRNA[Ser]Sec. The Sec condon is deciphered by a unique tRNA possessing a UCA anticodon. In short, in the presence of a downstream stem-loop structure, the UGA condon in mRNA, instead of behaving as a stop condon, specifies the insertion of a selenocysteine moeity in the protein synthesis to give a selenoprotein. In summary, a unique tRNA, designated tRNA[Ser][Sec] is charged with L-serine, which is then converted through at least two steps to selenocysteine. With the aid of a unique translation factor, the selenocysteinyltRNA[Ser][Sec recongizes specific UGA condons in mRNA to insert selenocysteine into the primary structure of selenoproteins.

In prokaryotes, the biosynthesis of Sec is as follows: Sec tRNA is first aminoacylated with serine, the serine moiety is in turn modified to an aminoarcrylyl interdiate onto RNA by Sec synthase and then the itnermediate serves as the accepter for activated selenium. The selenium donor is selenophosphate which is synthesized by selenophosphate synthetase. Many of these steps are apparently similar in mammals.

Nature may have taken advantage of utilizing Sec at critical sites in certain enzymes due to the unique redox proterties of selenium. Although Sec is structurally similar to , selenium is a better nucleophile than sulfur and selenocysteines are ionized at physiological pH, while cysteins typically are protonated.

The approach of identifying Sec insertion sequence elements in nucleotide databases has been applied in the HIV genome. SECIS elements are characterized by the presence of a highly conserved ATGAN[10-12 nucleotides]AAN[16-26 nucleotides]NGAN sequence, which forms stem-loop structures with AAN located in the loop, and TGAN and NGAN forming the non-Watson-Crick quartet interaction.

Recommended Dietary Allowance (RDA) 

A daily Se intake of up to 400 ug is considered safe and clinical manifestations of Se intoxication (selenosis) in humans appear only when it exceeds 900 ug. The prinicipal indicator of the amount of Se in the organism is its blood level. Blood contains Se mainly in the form of GPx. The optimal activity of of this anti-oxidative enzyme can be reached only when the level of Se in serum or plasma is at least 90 ug/L.

Selenite (inorganic form) and selenomethionine (organic form) are chemical forms of selenium mostly used in supplments and fortified food. Selenomethionine is generally considered to be the best absorbed and utilized form of selenium. It is also available in high selenium yeasts. Most of the selenium in these yeast is in the form of selenomethionine. Selenium has been supplied both as inorganic forms such as selenate or selenite and organic forms such as selenomethionine or as selenium yeast.

Where do you find Selenium? Foods which are good sources of selenium

Se is highly absorbable. It occurs naturally in plants as selenomethionine, Se-methyl-selenomethionine, selenocysteine, and selenocystine. Selenite (commercially available as sodium selenite) is greater than 80-percent bioavailable and selenomethionine or selnate can be greater than 90% bioavailable.

Absorption from food is also efficient. Se is mainly found in wheat and other cereals, beef and pultry, fish and other seafood. Human food contains Se in the form of selenoamino acids, selenometionine and selenocysteine (considered the 21st amino acid). Selemonethionine is the major organic selno-cpound in creal grains, grassland legumes and soybeans, as well as in selenium-enriched eyast used for slenium supplementation.

Brazil nuts are rich in selenium.

Immune System Effects of Selenium

Most, if not all, of the beneficial effects of selenium on human health are medaited by selenoproteins.

Lymphocytes from subjects supplemented with Se (as Na2SeO3) at 200 ug/d showed an enhanced response to antigen stimulation and an increased ability to develop into cytotoxic lymphocytes and destroy tumour cells. NK activity as also increased.

The main mechism by which Se boosts cell immunity is the stimulation of expression of the high-affinity IL-2 receptor on activated T lymphocytes and NK cells. This facilitates their interaction with IL-2, which is crucial for their clone expansion and differentiation into CTL.

Se also has anti-oxidative and anti-inflammatory effects that derive from the ability of Se (especially its key anti-oxidative compound GPx) to reduce hydrogen preroxid and hpspholipid hydroperoxides and thereby stop the production of free radicals andr eactive forms of oxygen.

The mRNA of several T cell associated genes (IL2 receptor alpha subunit, CD4) have the theoretical capacity to encode functional selenoproteins, suggesting that the roles of Se in the immune system may be quite diverse. HLA-DR is an important marker for activated T cells. Thus, if the gene for its invariant chain also encodes a selenoprotein with 10 SeC residues (suggesting a substantial Se requirement), Se may be an esential lymphocyte nutritional factor that plays a significant role in T cell function and proliferation. This is consistent with reports that Se supplementation in culture increases the cytotoxicity of killer T cells as well as the proliferation of T cells in response to mitogens and antigens, whereas Se deficiency does the opposit and is associated with impaired immune function.

Se may be able to reverse age related declines in immune responses in the elderly. In a group of 22 institutionalized elderly subjects supplemented with 100 ug Se-enriched yeast or placebo for 6 months, response to mitogen challenge in those receiving the Se was restored to the level of that in healthy young individuals.

Effect on Viral Infection: Se deficiency induces progression of some viral diseases not only by reducing the function of the IS, but also by increasing the virulence of the infectious agents. Se also appears to be a key nutrient in counteracting certain viral infections. In Se-deficint host harmless viruses can become virulent. A case in point for this was a study using a mouse model. Coxsackieviruses are small RNA enteroviruses in the Picornaviridae which are known to infect the heart and can cause myocarditis, or inflamatory heart disease. Mice are well-established models for coxsackievirus-induced myocarditis and develop a pattern of heart inflammation similar to that found in human.Both myocarditic and amyocarditic mice are available.

In this study, mice were fed a diet deficient in Se begining at the time of weaning. After a period of 4 weeks, glutathione peroxide activity, a marker of Se status, was 1/5 of the activity in Se-adequate mice. Se-deficient an d Se-adequate mice were infected with a normally amyocarditic strain of coxsackievirus B 3 (CVB3/0). At various times post infection, the mice were killed and tissues removed for study. Se-adequate mice did not develop myocarditis when infected with the amyocarditic strain of virus. However, the Se-deficient animals did develop a moderate level of myocarditis, characterized by inflammatory foci scattered through the myocardium. Heart virus titers also revealed that the De-deficient mice had a 10-100 fold higer levels of virus in the heart post infection compared with the Se-adequate mice. The immune response of the Se-deficient mice was also found to be altered. Although the production of neutralizing antibody resposnes was not affected, the proliferative response of T cells to both mitogen and antigen were decreased. Because inflammation is the hallmark of coxsakieviru-indued myocarditis, expression of mRNA for several inflammatory chemokines was examined. MCP-1 was highly expressed at day 10 in the De deficient animals as compared with the Se-adequate animals which could explain the inflammation found in the infected Se-deficient mice. In addition, expression of mRNA for y-interferonwas greatly decreased in the Se-deficient mice.

This important study meant that either an altered immune response might have been responsible for the myocarditis that developed in the Se-deficient mice infected with an amyocarditic strain of CVB3 or the viral pathogen might have been affected or both. To determine if host factors alone were responsible for the devleopment of myocarditis in the Se-deficient CVB3/0 infected mice, a passage experiment was performed. Se-adequate and Se-deficient mice were infected wtih CDB3/0. Seven days later, their hearts were removed and the virus isolated. This isolated virus was then passed back into Se-adequate mice. If the inductin of myocarditis was due solely to host conditions, then the Se-adequate mice should not devlop myocarditis from infection from either the virus isolated from the Se-adequate or deficient mice. Surprisingly however, Se-adequate mice infection with the virus isolated from Se-deficient aniamls developed myocarditis wehreas the Se-adequate mice infected with the Se-adeqaute passed virus did not. These resutls strongly suggested that the virus that replicated in the Se-deficient mice underwent a genomic change. To confirm that a change in viral genome had occured, viruses recovered from both Se-adequate and Se-deficient mice were sequenced. The sequence of the virus recvoered form Se-adequate mice was identical to the orignal stock virus used to inculate the mice. However, the sequence of the virus recovered from Se-deficient mice had 6 point muations. Thus replication of coxsackievirus in a Se-deficient host leads to changes in the viral genome. Once these genomic changes occur, even mice with normal nutriture are susceptible to the newly pathogenic strain of virus.

A second case in point is a similar study done with influenza virus. Influenza virus is a segmented RNA virus in the Orthomyxoviridae family. These viruses are responsible for many deaths each year and older adults are particularly susceptible. Influenza viruses alter their surface proteins in order to escape early detection by the immune system. To determine if a deficiency in Se affects the pathogenicity of an influenza virus, Se-deficient and Se-adquate mice were infected with a mild strain of influenza (A/Bangkok/1/29). At various times post infection, mice were killed and tissues harvested. Again, Se-deficient mice developed much more severe lung inflammation post influenza infection when compared with the infected Se-adequate mice. Se-deficient mice also had decreased percetnages of CD8+ cells infiltrating the lungs, compared with Se-adequate mice. In the draining lymph nodes, Se-deficient mice had an increased in the production of proinflammatory cytokines and chemokines. In addition, the Th2-like as opposed to the more Th1 like found in infected Se adequate animals. What was even more interesting, sequencing of the mRNA segments that code for viral surface prtoeins (HA-hemagluttinin and NA-neurominidase) revelealed little diference between Se deficient and adequate naimals. However, the mRNA that codes for teh amtrix protein revealed 29 nucleotide chagnes of which sex led to amino acid changes. Virus recovered from Se adequa

te animals, on the other hand, had two nucletoide chagnes of which one led to an amino acid chagne.

The relationship between selenium and AIDS is well documented with progressive depletion of Se in AIDS related complex (ARC) and AIDS patietns, depletion of thyroid T3, impairment of glutatione function and low whole blood and plasma GSH-Px activity. Selenium is a critical part of the antioxidant enzyme glutathione peroxidase. In a study of  infected drug using men and women in Miami, low plasma levels of selenium were association with a 10 fold higher risk of death and a 3 fold increase of risk for development of mycobacterial disease. Several small intervention studies also provide evidence of the beneficial effects of selenium supplementation. For example, in one randomized trial in Florida (n=186), selenium (200 ug/d) resulted in significant decrease in total hospital admission rates (P=0.002) and in the percentage of hospitalizations due to infections (P=.001). However, fewer placebo treated participants were using antiretroviral drugs at baseline. In another study among 949 HIV-1 infected Tanzanian women who were pregnant, 306 of 949 women died over a 5.7 year median follow up time. Lower plasma selenium levels were significantly associated with an increased in mortality (P=.01). Plasma selenium levels were not associated with time to progression to CD4 count <200 cells/mm3 but were weakly and positively related to CD4 cell count in the first years of follow up. Thus while there is a body of oberservational evidence and several small trials which implicate selenium deficiency as an independent predictor for the accelerated progression of HIV disease, more data is needed from randomized controlled trials.

The high tunover rate in T cells in HIV infected subjects could significantly contribute to the observed decline in plasma Se levels. The mRNA of several T cell assocaited genes (CD4, CD8, HLA-DRP33) may encode selenoproteins. If this is true, bhte billions of CD4+ T cells lost daily in AIDS pateints may contribute to the progressive Se depletion.

In AIDS patients, selenium deficiency may be associated with myopaty, cardiomyopathy and immune dysfunction including oral candidiasis, imparied phagocytic function and decreased CD4 T cells.

Effect of Selenium supplementation:

Supplementation with selenium, even in selenium-replete individuals has reported immunostimulant effects. This includes an enhancement of activated T cell proliferation. For example, lymphocytes from volulnteers supplemented with Se at 200 ug per day showed an enhanced response to antigen stimulation and an increased ability tod evelop into cytotoxic lymphocytes. NK cell activity was also reportedly increased. The mechanism appears to be related to upregulation of receptors for the growth regulatory cytokine IL-2 on the surface of activated lymphocytes and NK cells.

Se supplementation inhibits both the activation of HIV1 by oxidative stress, and the activaiton of NF-kB, an important cellular transactivator of HIV-1.