Mammalian selenoproteins

The vast majority of research focused on selenium in biology (primarily in the fields of molecular biology, cell biology, and biochemistry) over the past 20 years has centered on identification and characterization of specific selenoproteins, or proteins that contain selenium in the form of selenocysteine. In addition, studies to determine the unique machinery necessary for incorporation of a nonstandard amino acid (L-selenocysteine) during translation also have been central to our understanding of how cells can utilize this metalloid. This process has been studied in bacterial models (primarily Escherichia colt) and more recently in mammals in vitro cell culture and animal models). In this work, we will review the biosynthesis of selenoproteins in bacterial systems, and only briefly review what is currently known about parallel pathways in mammals, since a comprehensive review in this area has been recently published. Moreover, we summarize the global picture of the nonspecific and specific use of selenium from a broader perspective, one that includes lesser known pathways for selenium utilization into modified nucleosides in tRNA and a labile selenium cofactor. We also review recent research on newly identified mammalian selenoproteins and discuss their role in mammalian cell biology. 

A recently discovered human selenoprotein is a thioredoxin reductase which is present in the T cells of the immune system as well as in placenta and other tissues.189 547-549 The 55-kDa protein has one selenocysteine as the penultimate C-terminal residue. Another mammalian selenoprotein, of uncertain function, is the 57-kDa selenoprotein P. It contains over 60% of the... 

It is clear that mammalian selenoproteins play critical roles in many vital cellular functions and are, therefore, essential for disease prevention [221]. There is an extensive amount of research into the use of organoselenium compounds for cancer prevention [222-224]. 

Kortokov KV, Novoselov SV, Hateield DV and Gladyshev VN (2002) Mammalian selenoprotein in which selenocysteine (Sec) incorporation is supported by a new Sec insertion sequence element. Mol Cell Biol 22 1402-1411. 

The precise functional roles of selenoproteins P and W are not well understood. Selenoprotein P contains more selenium (up to 10 atoms per molecule) than any other mammalian selenoprotein, and it can form equimolar selenium-mercury complexes, thereby probably helping to detoxify mercury. It is the major selenoprotein fovmd in plasma and may also act as a selenium transport protein and selenium reserve. Selenoprotein W is found in muscle, and its decline may help explain the molecular basis of white muscle disease in selenium-deficient sheep. 

Glutathione peroxide was the first selenium-containing mammalian enzyme identified over 35 years ago," the same year that the selenoprotein A was identified in C. sticklandtL With the advent of the human genome sequence we now know that there are 25 selenoproteins encoded in humans, " with similar numbers encoded by other mammals. Some of the best-studied selenoproteins include five isoenzymes of thioredoxin reductase, three... 

Selenium plays a special role in development and protection of spermatozoa (Chapter 15). Tire selenoprotein phospholipid hydroperoxide glutathione peroxidase (PHGPx Eq. 15-58, Table 15-4) has a high activity in the testis and in spermatids. However, in mature spermatozoa it forms an enzymatically inactive oxidatively crosslinked capsular material around the midpiece of the cell perhaps providing mechanical stability.268 A similar 34-kDa selenoprotein is present in sperm nuclei and may be essential for condensation of DNA.269 Sperm tails contain specialized cytoskele-tal proteins which form "outer dense fibers."270 In contrast to mammalian spermatozoa, nematode sperm move by ameboid motility that depends upon a specialized actin-like molecule.271 Sperm cells are unusually rich in polyamines, most of which are bound to RNA and DNA (Chapter 24). 

A. Characterization of mSelB, a novel mammalian elongation 74. factor for selenoprotein translation. EMBO J. 2000 19 4796 805. 

This is an area which has only very recently attracted intensive study. In fact, as recently pointed out by Stadtman detailed studies of the specific biochemical role of selenium at the enzyme level dates only from 1972. However, research is progressing rapidly. To put this into perspective, a 1979 report stated that there are at least three, and possibly four , selenoproteins. A 1980 article listed eight known selenoproteins Table 2 lists these selenoproteins and their source. Interestingly, the form of selenium which has been determined in all animal and bacterial proteins examined thus far appears to be selenocysteine. Both bacterial and mammalian enzymes apparently are involved in redox reactions (an exception may be thiolase see below). Selenomethionine, as mentioned previously, is a predominant form of selenium in many grains and grasses, but it has not been detected in mammalian enzymes. 

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