Methylseleninate is a substrate rather than an inhibitor of mammalian thioredoxin reductase. Implications for the antitumor effects of selenium.
Biochemical and clinical evidence indicates that monomethylated selenium compounds are crucial for the tumor preventive effects of the trace element selenium and that methylselenol (CH(3)SeH) 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 microm, k(cat) of 23 s(-1)), which is reduced by the enzyme according to the equation 2 NADPH + 2 H(+) + CH(3)SeO(2)H --> 2 NADP(+) + 2 H(2)O + CH(3)SeH. The selenium-containing product of this reaction was identified by mass spectrometry. Nascent methylselenol was found to efficiently reduce both H(2)O(2) 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.
Gromer
Stephan
S
Biochemistry Center, Heidelberg University, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany. Stephan.Gromer@gmx.de
Gross
Jurgen H
JH
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002384:Catalysis; D004228:Dithionitrobenzoic Acid / Q000494:pharmacology; D004331:Drosophila melanogaster / Q000201:enzymology; D019803:Glutathione Disulfide / Q000737:chemistry; D005980:Glutathione Reductase / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007700:Kinetics; D013058:Mass Spectrometry; D051379:Mice; D008954:Models, Biological; D008956:Models, Chemical; D016566:Organoselenium Compounds / Q000737:chemistry* / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D010963:Plasmodium falciparum / Q000201:enzymology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012643:Selenium / Q000494:pharmacology*; D017279:Selenocysteine / Q000737:chemistry; D012834:Silver / Q000737:chemistry; D013379:Substrate Specificity; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013879:Thioredoxins / Q000378:metabolism; D013997:Time Factors
D000970:Antineoplastic Agents; D016566:Organoselenium Compounds; D017279:Selenocysteine; D012834:Silver; D013879:Thioredoxins; C008493:methylselenic acid; D004228:Dithionitrobenzoic Acid; D006861:Hydrogen Peroxide; D009195:Peroxidase; D005980:Glutathione Reductase; D013880:Thioredoxin-Disulfide Reductase; D012643:Selenium; D019803:Glutathione Disulfide