Biochemistry

             Many properties of the selenium atom are unique. The biochemistry of selenium differs from other dietary minerals and trace elements. Selenium is not a structural component such as in the case of calcium nor is selenium a metal coordination complex such as zinc and cobalt in enzymes or iron in hemoglobin.

            The nutritional role of selenium in animals was recognized in the 1950s. However, human essentiality of selenium was not established until 1973 with the discovery of the selenoprotein cellular glutathione peroxidase. (5)

            Selenocysteine is recognized as the 21st amino acid in human proteins. (6)

The biosynthesis of selenocysteine is regulated by four genes and begins with the aminoacylation of the amino acid serine by the enzyme serine synthetase to produce Ser-tRNASec (7) The serine residue is then used to provide the carbon backbone for selenocysteine. The selenium donor for selenocysteine is from reduced selenide. The selenide is joined to the aminoacrylyl intermediate directed by selenophosphate synthetase (SPS).

Selenoproteins are proteins which contain selenocysteine. However, the electronic properties of the selenium atom determine the unique biochemical properties of the various organic selenium compounds. In all of the selenoenzymes characterized so far, selenium is present as selenocysteine. The active site is selenocysteine in which, at physiological pH, selenium is fully ionized and is a very efficient redox catalyst. (8)

            It is generally recognized that the mammalian genome encodes 25 selenoprotein genes, while the possibility exists that more than 40 selenoprotein genes may exist as determined by SDS-PAGE of 75Se-labeled tissue. Each selenoprotein so specified contains one or more molecules of selenium in the form of the amino acid  selenocysteine cotranslationally inserted into the growing peptide in response to the UGA codon. The functions of only about half of these selenoproteins are understood. There is evidence that several of these proteins may be involved with the mechanism by which selenium provides its anticancer effects, antioxidant and otherwise. (9,10)

            Just as selenium as a nutrient is dramatically different than other nutrient minerals, selenocysteine is dramatically different from any of the other amino acids in human proteins in its mode of incorporation and biochemical steps.

 Genetic regulation of Selenocysteine:

            “Independent” UGA codon in mRNA is a “stop” signal and previously all UGA codons were considered as such. Now it is understood that a specific sequence of signals including the UGA codon is responsible for specifying selenocysteine.

 

            Recognition of the UGA triplet in mRNA for specifying selenocysteine requires an RNA signal sequence, referred to as the Selenocysteine Insertion Sequence (SECIS), located in the 3’ untranslated region of eukaryotic selenoprotein mRNAs. Mammalian cells contain several dedicated molecules involved in the synthesis and regulation of selenoprotein synthesis, and data implicating selenoprotein levels as modifiers of cancer risk and therefore also as the mediators of the anticarcinogenic effects of selenium are now only beginning to emerge. (10)

            Selenoproteins are conventionally grouped as the glutathione peroxidases 1-6, iodothyronine deiodinases 1-3, thioredoxin reductases 1-3, selenoprotein P, and other less understood and even unknown function including selenoproteins H, I, K, M, N, O, R, S, T, V, W and 15. Selenoprotein P functions as a transporter of selenium between the liver and other organs.

            Some of these selenoproteins are enzymes such as the six antioxidant glutathione peroxidases (GPXs) and the three thioredoxin reductases (TR1, TR2, TR3), some are storage, transfer and transport agents such as selenoprotein P, some have direct roles in modulating immune response etc. Neither all of the possible selenoproteins have been identified, nor have all of the roles of the 25 “known” selenoproteins been determined.

            Selenoprotein expression is dependent upon selenium status. Selenoprotein expression is regulated by selenium supply and selenium deficiency causes a non-uniform decrease in the levels of all selenoproteins (11) This regulation occurs in a carefully controlled fashion, with prioritization of the available selenium. (12) There is a hierarchy of selenoprotein expression with respect to maintaining levels of individual selenoproteins and retaining selenium in different organs (13)

 

            The body meets other selenoproteins requirements for immediate survival before delegating selenium for selenoproteins for long term needs such as cancer prevention. Thus, the cancer preventing actions of dietary selenium are not apparent at low selenium intakes.

 

            The activity of selenophosphate synthetase depends on availability of selenium, which indicates a sensitive autoregulation of selenoprotein synthesis. (14)

            All dietary forms of selenium except the elemental can be converted to reduced selenide and then incorporated into selenoproteins via selenophosphate synthetase (SPS). However, not all selenium compounds are equally effective in leading to the pathways involved in cancer prevention, which may or may not involve selenoproteins.

            Inorganic selenium compounds (selenium salts) contain selenium in the oxidized state. Selenites are Se+4 and selenates are Se+6 oxidation states. When inorganic selenium compounds are absorbed, the higher oxidation states of selenium are reduced to the selenide, Se+2. The reducing equivalents to do this are obtained from reduced glutathione (GSH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH).

 

            The selenium in organic selenium-containing compounds is already in the reduced selenide (Se+2) oxidation state. The release of selenide from organic compounds is via catabolism. Selenomethionine can be inadvertently incorporated into proteins accidentally in place of the structurally similar methionine.  Thus, selenomethionine can initially be “tied up” without undergoing catabolism. However, some of the selenide can be eventually recovered upon later catabolism of such proteins.

 

            It is also important to note that dietary selenocysteine itself is not incorporated into de novo selenoproteins. All selenium-containing compounds – with the above mentioned exception of some of selenomethionine – is catabolized to selenide which is then inserted into a serine-derived amino acid backbone to form the selenocysteine within de novo synthesized selenoproteins.

            Selenide can follow either of two pathways – incorporation into selenoproteins or entering into methylation or sugar derivation and eventual excretion. The excretionary pathway involves metabolism into methylselenol (CH3SeH) and conversion to dimethylselenide ([CH3]2SeH) (which can be excreted via the lungs) and trimethylselenonium ion ([CH3]3Se+) and 1-ß-methylseleno-N-acetyl-D-galactosamine (CH3Se-GalN) (both of which are excreted via the kidneys).

            Selenophosphate synthetase (SPS) is critical for the biosynthesis selenoproteins, which contain selenocysteine as their active site. Selenophosphate synthetase catalyzes the reaction of selenides with AMP to form selenophosphate. Selenophosphate becomes the selenium donor for the production of selenocysteine. So far, two selenophosphate synthetases (1 & 2) have been identified, one being the SPS 2, which has selenocysteine as its active site, the other being SPS 1, which has threonine as its active site. SPS forms selenophosphate (SePO3H3) from ATP and selenide.

            Sex differences in selenium biochemistry have been observed. Estrogen appears to up-regulate some selenoproteins and may help account for a lower requirement for selenium in women in addition to blood-volume variance.

3.     Huang HY, Caballero B, Chang S, Alberg A, Semba R, Schneyer C, Wilson RF,          Cheng TY, Prokopowicz G, Barnes II GJ, Vassy J, Bass EB.       Multivitamin/Mineral Supplements and Prevention of Chronic Disease. Evidence         Report/Technology Assessment No. 139. (Prepared by The Johns Hopkins      University Evidence-based Practice Center under Contract No. 290-02-0018). AHRQ Publication No. 06-E012. Rockville, MD: Agency for Healthcare         Research and Quality. May 2006.

4.     Ip, C.  Lessons from Basic Research in Selenium and Cacner Prevention. J Nutr.           128(11) November 1998; 1845-54)

5.     Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG and Hoekstra WG. Selenium: biochemical role as a component of glutathione peroxidase.         Science 1973 Feb 9;179(73):588-90.

6.     Stadtman, T.C. Selenium biochemistry Ann. Rev. Biochem. 1990:59;111-127.

7.     Leinfelder, W., Forchhammer, K., Veprek, B., et al., In vitro synthesis of          selenocysteinyl-tRNA (UCA) from seryl-tRNA (UCA): involvement and            characterization of the selD gene product. Proc. Natl. Acad. Sci. USA         1990:87;543-547.

8.     Reilly, C. in Selenium in Food and Health, 2nd ed. Springer, New York 2006     p124.

9.     Diwadkar-Navsariwala V., Prins GS, Swanson SM, Birch LA, Ray VH, Hedayat         S, Lantvit DL, and Diamond AM. Selenoprotein deficiency accelerates prostate    carcinogenesis in a transgenic model.  Proc Natl Acad Sci U S A. 2006 May 23;          103(21): 8179–8184.

10.   Diwadkar-Navsariwala V and Diamond AM. The Link between Selenium and Chemoprevention: A Case for Selenoproteins. J. Nutr. 134:2899-2902, November            2004

11.   Burk, R. and Hill, K.E. Regulation of selenoproteins. Ann. Rev. Nutr 1993:13;65-         81.

12.   Hesketh, J.E. and Villette, S. Intracellular trafficking of micronutrients: from gene            regulation to nutrient requirements. Proc. Nutr. Soc 2002:61;405-414.

13.   Hatfield, D.L. and Gladyshev, V.N. How selenium has altered our understanding           of the genetic code. Mol. Cell Biol. 2002:22;3565-3576.

14.   Guimaraes, M.J., Peterson, D., Vicari, A., et al., Is there an autoregulatory        mechanism in selenocysteine metabolism? Proc. Natl. Acad. Sci. USA.    1996:93;15086-15091.