Hierarchy of Selenium Supply in Selenium Deficiency

When Se intake is limited there is a clear hierarchy of Se supply, both to different tissues and to different selenoenzymes within a tissue. Thus, it appears that regulatory mechanisms exist, which ensure that, in Se deficiency, Se levels are maintained in certain priority organs and selenoproteins. Se is well retained by brain, endocrine and reproductive organs, indicating the relative importance of the trace element for the biological functions of these organs. In contrast, Se is lost rapidly from liver and muscle. Within a tissue, iodothyronine deiodinase I and phospholipid hydroperoxide GPX (PHGPX) take priority for expression over cyGPX in Se deficiency (Behne et al., 1988; Bermano et al., 1995).

The mechanisms that regulate the supply of Se to selenoproteins have probably evolved, at least in part, to cope with differing amounts of the micronutrient in the diet. The processes whereby dietary Se finds its way into selenocysteine within specific selenoproteins are complicated, allowing for regulation at many levels. The major portion of Se in the diet is probably in the form of the amino acid selenomethionine. This amino acid is the seleno analogue of methionine and can take part in many of the metabolic pathways for the sulphur-containing amino acid. Se is also found in the diet as selenocysteine and as various inorganic salts, such as selenite and selenate. There is also a large variety of selenosulphur compounds, but quantitatively these may only represent a very small portion of the dietary total Se. Once selenomethionine is absorbed into an animal, it can be metabolized in a similar fashion to methionine and can be incorporated non-specifically into proteins (Fig. 12.2).

The rate of incorporation of selenomethionine is very dependent on the adequacy of methionine levels. Thus, when methionine is limiting, larger portions of selenomethionine are incorporated, due to a mass-action effect. Conversely, when higher levels of methionine are consumed, less selenome-thionine is incorporated. Similarly, it is possible that any selenocysteine absorbed into the animal is also incorporated non-specifically into protein. This non-specific incorporation of Se into protein has no known physiological role, although these amino acids may provide a source of Se for production of specific selenoproteins during Se deficiency.

Incorporation of Se into specific selenoproteins requires the complex mechanism described previously. The selenophosphate synthetases operating in this mechanism produce selenophosphate from ATP and a form of Se, which is chemically similar to selenide. Many of the inorganic Se compounds that are absorbed from the diet would be reduced by molecules such as glutathione to selenide-like compounds (Fig. 12.2). However, Se from selenomethionine has to go through a transamination pathway and then reduction. Thus, in mammalian tissue, there are non-specifically incorporated seleno amino acids and selenocysteine incorporated at the active site of the selenoproteins.

Diet

Animal

Selenocysteine [

Inorganic Se SeOo-/SeO2- etc.

Selenomethionine (SeMet)

Non-specific incorporation into protein i Se in proteins ;

SELENOPROTEINS "

SeMet

Selenocysteine incorporation

  • Ser tRNAx
  • Selenide| ^-> H2PO3Se

cotranslation

Fig. 12.2. Some pathways of selenium (Se) metabolism. The different forms of Se in the diet are absorbed and the major pool of selenomethionine passes either non-specifically into proteins instead of methionine or passes through an inorganic intermediate similar to selenide, which is then specifically incorporated into selenoproteins. Not shown are the pathways for methylation of excess Se, prior to excretion. GSH, glutathione.

Se metabolism is thus a complex process and this is perhaps not surprising, given the potential chemical reactivity of inorganic Se compounds. The Se as selenocysteine at the active site of enzymes is a very efficient biological catalyst and large amounts of non-specific incorporation of the amino acid might lead to inappropriate biochemical reactions within the body. The predominance of selenomethionine as a dietary source of the micronutrient provides a relatively inert source, which through well-regulated metabolic pathways can be specifically incorporated into the active site of the specific selenoproteins (for a review, see Daniels, 1996).

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