Nebraska Redox Biology Center Educational Portal


Selenium (Se) is an essential micronutrient in mammals that exerts its function in the context of selenocysteine (Sec)-containing proteins (selenoproteins) [ 1 ]. Selenocysteine, the 21st amino acid in the genetic code, is a functional analog of cysteine (Cys) where sulfur is replaced with a Se atom. More than 90% of the Se pool in mammals is present in selenoprotein form at low, suboptimal, and optimal dietary Se supplementation, which classifies selenoproteins as a major biological form of Se [ 1, 2, 3, 4, 5, 6 ]. Twenty-five human and 24 mouse selenoproteins have been predicted and experimentally confirmed [ 6 ].

Dietary Se Sources and Requirements. Various inorganic (elemental Se, selenites, selenides) and organic (selenomethionine, methylated selenocompounds, selenoproteins, etc.) forms of Se are present in the environment [ 1 ]. Different regions of the world are characterized by significant variations of Se content in the soil, resulting in variation of Se content in natural diet. Seleniferous soils, the most Se-rich type of soils, are widespread in North and South America, Russia, and China [ 1, 7 ]. At the same time, significant regional variations of Se in soils have been demonstrated. The Midwest area of the U.S. is characterized by very high Se content in the soil, and people in this area have the highest selenium intakes in the country [ 1, 7 ]. The recommended dietary allowances of Se in the U.S. is estimated at 40-55 μg/day for adults, and adequate intake for children is 20-30 μg/day [ 1, 7 ]. Se supplementation during pregnancy and lactation is recommended at 60 and 70 μg/day, respectively. The upper tolerable intake level is set at 400 μg/day [ 1, 7 ]. The amount of Se needed to achieve maximal expression of selenoproteins is not clearly defined. Se deficiency has been associated with a 20-fold increase in the mortality of individuals infected with the human immunodeficiency virus [ 8 ], as well as with the development of cardiomyopathy, male reproductive problems [ 9 ], and immunological disorders [ 10, 11 ]. The effect of Se toxicity has been reported for several regions of the U.S. Midwest [ 12, 13 ].

Map of soil selenium content in the U.S. (red = high selenium areas). Courtesy of U.S. Department of the Interior, U.S. Geological Survey, Mineral Resources.

Toxic concentration of Se in groundwater was demonstrated in two regions of India's Punjab province [ 14 ]. Various plants differ in their ability to metabolize and accumulate Se: non-Se accumulators (<100 mg Se/kg DW), Se-accumulators (100-1000 mg Se/kg DW) and Se hyperaccumulators (>1,000 mg Se/kg DW). Moreover, Se hyperaccumulation work as mechanism of protection from herbivores and pathogens in some plants [ 15, 16, 17, 18 ]. Crop plants and animal food are among the major sources of Se in human diet. For example, Se content in Brazil nuts is 0.54 mg/oz [ 1, 19 ]. Some plants may accumulate up to 3 mg of Se per gram and may be extremely toxic as dietary components [ 1, 15 ]. Crop plants from Se-rich soil regions could be considered as significant sources of Se, and the upper tolerable intake level of Se could be easily exceeded by using such agricultural products. In addition, about 19% of the U.S. population regularly consumes Se-containing dietary supplements [ 1, 20 ]. Due to lack of both regulations and U.S. Food and Drug Administration oversight, a wide range of different supplement formulations are available in the market, and Se content varies between 10 and 200 μg/day [ 1, 21 ]. Selenium supplements are also available in the form of high Se yeast, with a Se content of 2 mg/g [ 1 ]. Taken together, the use of high Se dietary supplements in Se-rich regions may cause health problems due Se overconsumption and toxicity.

Selenium, selenoproteins and thiol dependent processes. Thiol-dependent redox processes are among the major, but insufficiently investigated, biological phenomena directly related to Se metabolism. Thiol-dependent redox control involves structurally distinct but mechanistically similar families of enzymes called thiol oxidoreductases [ 6, 22 ]. Thiol oxidoreductases have catalytic Cys in their active sites [ 6, 22, 23 ]. and regulate a variety of biological functions, such as protection against oxidative stress, signal transduction, and protein folding, modification, and regulation. In rare cases, the catalytic Cys is replaced by Sec [ 22, 23 ]. Thiol oxidoreductases are widely distributed, and the associated thiol-dependent processes are essential and occur in all branches of life In rare cases, the catalytic Cys could be replaced by selenocysteine (Sec), which is a Cys analog with selenium in place of sulfur. All Cys/Sec replacements have thus far been observed only in active sites of various thiol oxidoreductases [ 22, 23 ].

Chemical structure of cysteine and selenocysteine.

In contrast to the many functions of Cys, Sec is always (at least in functionally characterized selenoproteins) located in the active sites of redox proteins and serves as the catalytic group in these enzymes [ 6, 22, 23 ]. The reason such replacement evolved is most likely related to the more pronounced nucleophilic properties of Se, making Sec a more efficient catalyst compared to Cys [ 24, 25 ]. Also, most selenoproteins have close Cys-containing homologs whose catalytic Cys are highly conserved. While all selenoproteins characterized to date exhibit diverse functions, they all appear to contribute to antioxidant and redox processes. There are more than 60 functionally distinct selenoprotein families and about half of them belongs to thioredoxin forld oxidoreductases [ 6, 22, 23 ].

Se regulates selenoprotein expression. Dietary Se regulates the expression of selenoproteins and the abundance of their mRNAs [ 1, 26 ]. For example, Se deficiency is shown to result in up to a 99% decrease in the activity of glutathione peroxidase 1 (GPx1) and in up to a 90% decrease in the abundance of GPx1 mRNA in the livers of rats and mice. Intake of Se in some regions of the world does not appear to be adequate for full expression of some selenoproteins. It has been observed that GPx1 activity and expression become saturated at dietary levels of Se only several times greater than levels considered adequate [ 27 ]. Other studies indicate the expression of other selenoproteins, such as selenoprotein W [ 28 ]. and thioredoxin reductase 1 [ 29 ], may still be responsive to Se levels as high as 10 times more than thought adequate. Recent data suggest saturation of the major plasma selenoprotein, Selenoprotein P, requires a much higher amount of Se [ 1, 29, 30 ]. Thus, Se supplementation is supposed to regulate selenoprotein content and redox homeostasis in the cell.

Human selenoproteome. Thioredoxin fold selenoproteins are shown on blue background. Selenoproteins evolved by C-terminal extention mechanism are shown on orange background. Secondary structure end Sec insertion sites are shown at the right part of the table. β-sheets are shown in blue and α-helices in orange [ 6, 22, 23 ].

The selenophosphate can be used as Se donor for the biosynthesis of 5-methylaminomethyl-2-selenouridine (mnm5Se2U or SeU) in some prokaryotic organisms. Selenouridine is located at the wobble position of the anticodons of tRNALys, tRNAGlu, and tRNAGln [ 1, 31, 32 ]. The proposed function of Selenouridine in these tRNAs is related to codon-anticodon interactions [ 1, 31, 33 ].

In addition to Sec and selenouridine, Se can serve as cofactor in some molibdenum containing enzymes such as nicotinic acid hydroxylase and xanthine dehydrogenase [ 34, 35, 36, 37 ]. Se is covalently bound to Mo in the active site in these enzymes, but exact structure and function of the Se cofactor is not known.

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