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Differing views of the role of selenium in thioredoxin reductase

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Abstract

This review covers three different chemical explanations that could account for the requirement of selenium in the form of selenocysteine in the active site of mammalian thioredoxin reductase. These views are the following: (1) the traditional view of selenocysteine as a superior nucleophile relative to cysteine, (2) the superior leaving group ability of a selenol relative to a thiol due to its significantly lower pK a and, (3) the superior ability of selenium to accept electrons (electrophilicity) relative to sulfur. We term these chemical explanations as the “chemico-enzymatic” function of selenium in an enzyme. We formally define the chemico-enzymatic function of selenium as its specific chemical property that allows a selenoenzyme to catalyze its individual reaction. However we, and others, question whether selenocysteine is chemically necessary to catalyze an enzymatic reaction since cysteine-homologs of selenocysteine-containing enzymes catalyze their specific enzymatic reactions with high catalytic efficiency. There must be a unique chemical reason for the presence of selenocysteine in enzymes that explains the biological pressure on the genome to maintain the complex selenocysteine-insertion machinery. We term this biological pressure the “chemico-biological” function of selenocysteine. We discuss evidence that this chemico-biological function is the ability of selenoenzymes to resist inactivation by irreversible oxidation. The way in which selenocysteine confers resistance to oxidation could be due to the superior ability of the oxidized form of selenocysteine (Sec-SeO2 −, seleninic acid) to be recycled back to its parent form (Sec-SeH, selenocysteine) in comparison to the same cycling of cysteine-sulfinic acid to cysteine (Cys-SO2 − to Cys-SH).

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Notes

  1. There are in fact 25 genes for selenocysteine-containing proteins in the human genome. The actual number of proteins is somewhat larger due to alternatively spliced transcripts.

  2. There is considerable confusion in the literature in calculating the oxidation number of sulfur and selenium compounds. For the compounds shown in Fig. 8, we have chosen to base the oxidation number on that of sulfuric acid (S = +6). Using this as a reference compound, the S atom in methyl phenyl sulfoxide has an oxidation number of +4 and the S atom in methyl phenyl sulfone has an oxidation number of +6. This convention has the benefit of having the valence number equal to the oxidation number.

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Acknowledgments

The authors would like to express deep gratitude to Hans J. Reich for the many hours of conversation spent on this subject and for his help in guiding our hypotheses. This work was supported by National Institutes of Health Grant GM070742 to RJH.

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  1. Department of Biochemistry, College of Medicine, University of Vermont, 89 Beaumont Ave, Given Building Room B413, Burlington, VT, 05405, USA

    Robert J. Hondal & Erik L. Ruggles

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Hondal, R.J., Ruggles, E.L. Differing views of the role of selenium in thioredoxin reductase. Amino Acids 41, 73–89 (2011). https://doi.org/10.1007/s00726-010-0494-6

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