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J. Biol. Chem., Vol. 277, Issue 12, 9701-9706, March 22, 2002

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Methylseleninate Is a Substrate Rather Than an Inhibitor of Mammalian Thioredoxin Reductase
IMPLICATIONS FOR THE ANTITUMOR EFFECTS OF SELENIUM^*

Stephan Gromer^§ and Jürgen H. Gross^¶

From the  Biochemistry Center, Heidelberg University, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany and the ^¶ Institute of Organic Chemistry, Heidelberg University, Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany

Biochemical and clinical evidence indicates that monomethylated selenium compounds are crucial for the tumor preventive effects of the trace element selenium and that methylselenol (CH₃SeH) is a key metabolite. As suggested by Ganther (Ganther, H. E. (1999) Carcinogenesis 20, 1657-1666), methylselenol and its precursor methylseleninate might exert their effects by inhibition of the selenoenzyme thioredoxin reductase via the irreversible formation of a diselenide bridge. Here we report that methylseleninate does not act as an inhibitor of mammalian thioredoxin reductase but is in fact an excellent substrate (K_m of 18 µM, k_cat of 23 s¹), which is reduced by the enzyme according to the equation 2 NADPH + 2 H⁺ + CH₃SeO₂H  2 NADP⁺ + 2 H₂O + CH₃SeH. The selenium-containing product of this reaction was identified by mass spectrometry. Nascent methylselenol was found to efficiently reduce both H₂O₂ and glutathione disulfide. The implications of these findings for the antitumor activity of selenium are discussed. Methylseleninate was a poor substrate not only for human glutathione reductase but also for the non-selenium thioredoxin reductases enzymes from Drosophila melanogaster and Plasmodium falciparum. This suggests that the catalytic selenocysteine residue of mammalian thioredoxin reductase is essential for methylseleninate reduction.

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