Basic Facts About Selenium Chemistry and Biochemistry
At the Selenium Nutritional Research Center, we are concerned with the biochemistry of selenium. However, the biochemistry of selenium begins with the chemistry and physics of selenium itself. While the beneficial effects of selenium in the body are brought about by organic selenium compounds, the reason these compounds function as they do is due to the atomic structure of the selenium atoms contained within these compounds.
Why do we need selenium? Wouldn't sulfur do the job? What does selenium bring to the table that other elements don't? Couldn't nature just make other sulfur-containing compounds do the job without resorting to using another element? No! The atoms of the element selenium provide nature with a neat tool to build molecules that are powerful and versatile reducing agents. An oxygen free radical can react with a lipid (fat) molecule to form a lipid peroxide which, like hydrogen peroxide, is not a free radical but a reactive oxygen species (ROS) that can cause harm to body components, especially cell membranes.
Some selenium compounds can stop some Reactive Oxygen Species (ROS) chain reactions and even repair free radical damage. For example, the family of selenium-containing compounds called glutathione peroxidases repair phospholipid peroxide damage in membranes, thus breaking the peroxidation chain reactions that damage cells. Also, another family of selenium-containing compounds repair epoxide damage in DNA, thus repairing abnormal DNA and preventing mutations that can lead to cancer. Meanwhile, various selenium compounds have several other biochemical functions as well.
The following paragraph is not essential to your understanding of why selenium is unique and especially beneficial for our bodies, so you may skip it if you choose. But if you are scientifically inclined, you will want to read it.
On the periodic chart, selenium is found in group 16 (formerly known as group VIA) just beneath sulfur. This means that both sulfur and selenium atoms have outer electronic shells that contain six electrons. Thus, their chemical reactions are very similar. Selenium, however, is in the next lower period and is a metalloid, whereas sulfur is a nonmetal. As a metalloid, selenium can behave as a metal by donating electrons during a chemical reaction and behave as a nonmetal by accepting electrons. Selenium atoms have a ground state electronic shell distribution of [Ar]3d(10)4s(2)4p(4) compared to sulfur's [Ne]3s(2)3p(4). This electronic shell structure gives selenium the versatility to readily accept or donate electrons and makes the selenium atom an ideal catalytic center and a great semiconductor. More important for us, the selenium atoms in organic selenium-containing compounds can function as redox centers.
Having the same number of electrons in the outer electronic shells of selenium and sulfur means that they can have similar chemical reactions. Plus, they have similar atomic sizes, bond energies, ionization potentials, electron affinities, and electronegativities. This explains why selenium is sometimes mistakenly incorporated into proteins by plants and animals.
Still, nature needs selenium for reasons that sulfur can't fulfill. Please keep in mind that selenium is the only trace element that our genes specify to form an amino acid that is then incorporated into proteins. The codon UGA species selenocysteine, the 21st amino acid. Selenocysteine is not an accident and is the keystone compound needed to make several selenium-containing proteins (selenoproteins).
Basic information on the element selenium
The following links provide excellent information on the atomic, nuclear, chemical, electrical and physical properties of selenium.
The dietary essentiality of selenium was not established until 1973 when Dr. J. T. Rotruck and his colleagues at the University of Wisconsin determined selenium was a component of glutathione peroxidase (GPX). (Rotruck et al., Science 1973) GPX is an antioxidant enzyme produced in cell membranes to protect cells against free radicals that can destroy cells or impair cell function, mutate DNA and initiate many of the diseases associated with aging. GPX repairs peroxide damage in membranes, thus breaking the peroxidation chain reactions that damage cell components. Since that time, several more glutathione peroxidases and other selenoproteins (Sep) have been identified.
Selenium does not function directly in the body in its elemental or ionic form. Selenium atoms do function as reducing centers in organic compounds and as components of proteins. Selenium atoms in their oxidized forms are reduced by body pathways from their oxidized states (with the most oxidized state possible being plus 6) to the most reduced state, which is negative 2. Selenium in the most reduced (negative 2) oxidation state is defined as a selenide.
Selenium is an essential component of several important compounds that have wide-ranging functions in the body. Selenium-containing compounds are involved in the life processes ranging from apoptosis, to immune function, to the protection and repair of DNA. Many of these selenium-containing compounds are selenoproteins that incorporate the selenium-containing amino acid selenocysteine as the penultimate amino acid. Selenocysteine, the 21st amino acid identified as being a component of human proteins, can also be termed a selenide or selenol. Selenocysteine is genetically expressed by the codon UGA.
Some of the seleno proteins are selenoenzymes that have important enzymic functions. In selenoenzymes, selenocysteine is generally at the active site where the selenium atom functions as a redox center. One extremely important role for selenoenzymes is to maintain the intracellular redox milieu. The cellular redox-milieu involves several metabolic, antioxidative and regulatory aspects that are maintained and regulated largely by two enzyme-based systems: the glutathione and thioredoxin systems. (Gromer et al.) The thioredoxin and glutathione systems constitute a balanced redox network. The thioredoxin system may influence virtually all phases of tumorgenesis via its involvement in transcription and translation (Gromer et al.)
The family of selenoenzymes called thioredoxin reductases catalyze the NADPH-dependent reduction of oxidized thioredoxin, hyperoxides, dehydroascorbate, ubiquinol and other substrates. (May et al., J. Biol. Chem. 1997) The action of thioredoxin reductases in recycling dehydroascorbate to ascorbate (vitamin C) now explain the synergistic action of selenium and vitamin C discovered by Dr. Passwater in the early 1960s and described in the patent US 6,090,414. The same mechanism recycles ubiquinol to ubiquinone (Coenzyme Q-10). The thioredoxin system is also capable of regenerating proteins inactivated by ROS.
The selenoenzyme, thioredoxin glutathione reductase (TGR) was originally thought to be a typical thioredoxin reductase, but is now considered to be a testis specific combination glutathione reductase and thioredoxin reductase enzyme.
In the 1980s, Passwater and Olson determined that relatively small, readily absorbable selenium-containing compounds can mimic the function of enzymes including GPX, a glutathione-S-transferase (GST) which was originally called epoxide reductase, and mimics their function in repairing epoxide damage in DNA. The repair of damaged DNA prevents mutations that can lead to cancer. These selenium-containing compounds include selenides, such as triphenyl phosphine selenide, and 3-methylbenzothiazole-2-selenone, and isoselenocyanates, and have the general formulas of R3P=Se and R2C=Se. These selenides also include tris(methylseleno)methane, and allylselenocysteine, and methylselenocysteine, and diselenides such as diallyldiselenide. (European Union Patent issued July 28, 2003 and US Patent Application filed June 7, 1995.)
Another important family of selenoproteins is the Iodothyronine Deiododinases, which has three known members that catalyze the activation and deactivation of the thyroid hormones that play important roles in regulating various metabolic processes and are important for the normal development of the fetal brain.
Selenophosphate synthetase (SPS) forms selenophosphate (SePO3H3) from ATP and selenide. (Allan, Lacourciere and Stadtman, Annu. Rev. Nutr. 1999;19:1-16.) SPS generates selenophosphate from selenite reacting with a disulfide bond to yield a selenotrisulfide, which then reacts through the selenium enzyme SPS with phosphate to generate the selenophosphate. This molecule is very similar to triphenylphosphine selenide, since both contain a P=Se bond.
Selenoproteins include Sep A, Sep P, Sep R, Sep T, Sep W, Sep 15, Sep 18 and at least 35 other selenoproteins (Behne et al., l0th International Symposium on Trace Elements in Man and Animals, 2000). There are probably many more than suggested by these studies. There are also eight selenoproteins in artery walls, eight selenoproteins in brain tissue and nine selenoproteins in testis. (Qu et al., Biolog. Trace Element Res. 2000) Comparatively little is known about the functions of these selenoproteins at this time.
Selenium deficiency in animals can result in liver and muscle disorders. In humans, selenium deficiency has been linked to a cardiomyopathy called Keshan Disease. Selenium deficiency also increases the risk of free-radical related diseases associated with aging. The evidence is strong that selenium is protective against many forms of cancer.
In 1980, the official U. S. recommended intake range for selenium in all forms regardless of their nutritional value was 50 to 200 micrograms per day. In 2000, this was reduced to 70 micrograms of selenium per day for men and 55 micrograms per day for women. (Food and Nutrition Board, Institute of Medicine, DRI: dietary reference intakes for vitamin C, vitamin E, selenium and carotenoids. Washington, D.C., National Academy Press 2000; 284-324.) This was done mistakenly on faulty assumptions in our opinion. We believe that this is a case where a little knowledge was extended to draw conclusions that require additional knowledge than what the reviewers examined. Our research suggests that these nutritionally-recommended intakes for selenium are not high enough to activate the full health benefits of selenium. Others have expressed the same concerns.
Dr. Gerald Combs, Jr. concludes that the nutritional requirements should be 175% higher for women and 218% higher for men. (Nutrition and Cancer 40(1) 6-11, 2001)
Dr. Jean Neve stated "… it is more evident that conclusions drawn from the response of one particular selenoprotein do not apply to all biologic functions demonstrated to depend on the element. Moreover, accumulating evidence suggests that selenium has further beneficial effects at doses higher than those regarded as adequate based on the previous criteria. This is, for example, the case for immunostimulant and anticarcinogenic actions of selenium that have consistently associated with supranutritional levels of exposure to the element, i. e., for dietary intakes of 150 -–250 micrograms of selenium per day, or more …" (Nut. Rev. 58(12): 363-369, Dec. 2000)
Dr. Margaret Rayman also disagreed, questioning whether the measure of selenium repletion used should be the amount of selenium needed to achieve plateau concentrations of plasma GPX, or should the measure be the amount needed to achieve GPX saturation in the platelets be used. She suggests the latter, which would equate to around 80 – 100 micrograms of selenium per day" [The Lancet 356(9225): 233-241, July 15, 2000]
Our research has found that all selenium-containing nutrients do not have equal nutritional value or anti-cancer value. The anti-cancer effect of selenium-containing nutrients is not related to their nutritional value or toxicity. With many selenium-containing compounds in the diet, intakes exceeding the levels needed to maximize known plasma selenoproteins may be required to observe anti-cancer effects. There is more to optimal health than merely maintaining adequate levels of selenoproteins in plasma – the anti-cancer effects are also important. With other selenium compounds, significant anti-cancer effects may be reached before plasma selenoproteins are maximized.
There is more than a thousand-fold difference between selenium compounds in preventing cancer when both toxicity and effectiveness are considered. Small changes in chemical structure of selenium compounds cause dramatic changes in biological activity. The most effective anti-cancer selenium compounds are the selenides, such as triphenylphosphine selenide and allylselenocysteine, which have or induce the greatest levels of epoxide-reducing activity. How directly the selenides are provided or the pathways the body uses to process other selenium forms, determine overall effectiveness.
It is not as much a question of "selenium deficiency" or "selenium adequacy" – or even concentrations of any one or two selenoproteins circulating in the blood -- but a question of optimal amounts of certain effective forms of selenium compounds.