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Researchers Reveal Selenium's Metabolism In Life-Giving Amino Acids

(20.07.2009)


Background:
Selenium and its compounds are essential for animals and humans, but its physiological nature is  ambivalent. It can cause disease by deficiency, but it is toxic at levels less than an order of magnitude above those required for optimum healthy conditions. Selenocysteine is the only genetically encoded amino acid in humans whose biosynthesis occurs on
its cognate transfer RNA (tRNA). O-Phosphoseryl-tRNA:selenocysteinyl-tRNA synthase (SepSecS) catalyzes the final step of selenocysteine formation by a poorly understood tRNA-dependent mechanism. 

The new study:
In the July 17 issue of the journal Science, researchers at Yale University and University of Illinois at Chicago detail the molecular mechanisms that govern its metabolism in the human body.

"It must require an intricately regulated uptake system," said Dieter Söll, co-senior author of the paper, Sterling Professor of Molecular Biophysics and Biochemistry at Yale. "There are 25 human selenoproteins, and most of them are probably essential for life."

Selenium is thought to offer protection from diverse human ailments including adverse mood states, cardiovascular disease, viral infections and cancer.

Selenocysteine is the most active metabolite of selenium in humans. It is unique among amino acids because it is the only one synthesized directly on a transfer RNA (tRNA) molecule, which shuttles the amino acids to the protein-making machinery within cells. Proteins that contain selenocysteine are responsible for recycling protective anti- oxidants such as vitamin C and coenzyme Q10.

Figure: Selonocysteine tRNA molecule

Söll's team for the first time captured images of how selenocysteine is created on a super-sized tRNA molecule, which seems to have a highly specialized role in nature. The 20 other amino acids and their associated tRNAs use the same protein vehicle, called an elongation factor, for transport to the ribosome. However, nature has provided this large tRNA molecule with a specialized elongation factor that chauffeurs only selenocysteine to the ribosome.

"This structure reveals most aspects of the mechanism for the formation of selenocysteine and provides an answer to 20 years of biochemical work in the field," said Sotiria Palioura, lead author of the study and an M.D./Ph.D. candidate at Yale.

The findings may lead to greater understanding of autoimmune liver disease. The tRNA complex described in the Science paper is the target of antibodies in patients with Type 1 autoimmune hepatitis. "The region that the antibody is supposed to recognize is at the business end of this molecule, where we see the reaction happening," Palioura said.

"Selenocysteine has been found to be a critical component of enzymes involved in a number of normal and disease processes," said Michael Bender of the National Institutes of Health's National Institute of General Medical Sciences. "This basic study, which has shed light on selenocysteine's unique biosynthetic pathway, could ultimately have an impact on many aspects of human health, including the immune response, neurodegeneration, cardiovascular disease, and cancer."

Other Yale authors on the paper were R. Lynn Sherrer and Thomas A. Steitz. Senior co-author on the paper was Miljan Simonovic of the University of Illinois at Chicago.

Funding for the research was provided by the National Institute for General Medical Sciences, the Department of Energy, and the Howard Hughes Medical Institute at Yale University.

Source: Yale University


The cited study:

Sotiria Palioura, R. Lynn Sherrer, Thomas A. Steitz, Dieter Söll, Miljan Simonovic, The Human SepSecS-tRNASec Complex Reveals the Mechanism of Selenocysteine Formation, Science, 325/5938 (2009) 321-325. doi: 10.1126/science.1173755


Related studies

Caterina Di Cosmo, Neil McLellan, Xiao-Hui Liao, Kum Kum Khanna, Roy E.
Weiss, Laura Papp,  Samuel Refetoff, Clinical and molecular characterization of a novel selenocysteine insertion sequence-binding protein 2 (SBP2) gene mutation (R128X), Clin. Endocrinol. Metab. , published online July 14, 2009. doi:10.1210/jc.2009-0686

  M. Birringer, S. Pilawa, L. Flohe, Trends in selenium biochemistry, Nat. Prod. Rep., 19 (2002) 693-718. doi: 10.1039/b205802m

Dietrich Behne, A. Kyriakopoulos,  Mammalian selenium-containing proteins, Annu. Rev. Nutr., 21 (2001) 453-473. doi:10.1146/annurev.nutr.21.1.453

G.N. Schrauzer, Selenomethionine: A Review of Its Nutritional Significance, Metabolism and Toxicity, J. Nutr., 130 (2000) 1653-1656.

 T.C. Stadtman, Selenosysteine, Annu. Rev. Biochem., 65 (1996) 83-100. doi: 10.1146/annurev.bi.65.070196.000503

A. Böck, K. Forchhammer, J. Heider, C. Baron, Selenoprotein synthesis: an expansion of the genetic code, Trends Biochem. Sci., 16 (1991) 463-467.



Related EVISA Resources

EVISA Link database: Protein-bound selenium and human health
EVISA Link Database: Toxicity of selenium


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last time modified: November 3, 2009



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