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. 2005 Aug;18(8):1287-95.
doi: 10.1021/tx0500530.

Interactions of sodium selenite, glutathione, arsenic species, and omega class human glutathione transferase

Robert A Zakharyan  1 , George Tsaprailis, Uttam K Chowdhury, Alba Hernandez, H Vasken Aposhian
Affiliations

Interactions of sodium selenite, glutathione, arsenic species, and omega class human glutathione transferase

Robert A Zakharyan et al. Chem Res Toxicol. 2005 Aug.

Abstract

Human monomethylarsenate reductase [MMA(V) reductase] and human glutathione S-transferase omega 1-1 (hGSTO1-1) [because MMA(V) reductase and hGSTO1-1 are identical proteins, the authors will utilize the designation "hGSTO1-1"] are identical proteins that catalyze the reduction of arsenate, monomethylarsenate [MMA(V)], and dimethylarsenate [DMA(V)]. Sodium selenite (selenite) inhibited the reduction of each of these substrates by the enzyme in a concentration-dependent manner. The kinetics indicated a noncompetitive inhibition of the MMA(V), DMA(V), or arsenate reducing activity of hGSTO1-1. The inhibition of the MMA(V) reducting activity of hGSTO1-1 by selenite was reversed by 1 mM DL-dithiothreitol (DTT) but not by reduced glutathione (GSH), which is a required substrate for the enzyme. Neither superoxide anion nor hydrogen peroxide was involved in the selenite inhibition of hGSTO1-1. MALDI-TOF and MS/MS analysis demonstrated that five molecules of GSH were bound to one monomer of hGSTO1-1. Four of the five cysteines of the monomer were glutathionylated. Cys-32 in the active center, however, exists mostly in the sulfhydryl form since it was alkylated consistently by iodoacetamide. MALDI-TOF mass spectra analysis of hGSTO1-1 after reaction with GSH and sodium selenite indicated that selenium was integrated into hGSTO1-1 molecules. Three selenium were found to be covalently bonded to the monomer of hGSTO1-1 with three molecules of GSH. It is proposed that the reaction products of the reduction of selenite inhibited the activity of hGSTO1-1 by reacting with disulfides of glutathionylated cysteines to form bis (S-cysteinyl)selenide and S-selanylcysteine and had little or no interaction with the sulfhydryl of Cys-32 in the active site of the enzyme.

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