Diphenyl diselenide [(PhSe)2] inhibits Drosophila melanogaster δ-aminolevulinate dehydratase (δ-ALA-D) gene transcription and enzyme activity

The main objective of the present study was to compare the inhibitory effect of diphenyl diselenide (PhSe)(2) and Pb2+ on mice and fruit fly delta-Aminolevulinate dehydratase (delta-ALA-D). Optimum pH was quite different for mice (pH 6.5) and flies (pH 8.5). At pH 8.5, the inhibitory potency of (PhSe)(2) was higher for the fruit flies (IC50 8.2 mu mol/l) than for mice (IC50 19.5 mu mol/l). Pb2+ inhibited mice delta-ALA-D at pH 6.5 (IC50 6.2 mu mol/l) and 8.5 (IC50 5.6 mu mol/l) with higher potency than the fly enzyme (IC50 43.7 mu mol/l). delta-ALA-D transcription was reduced by 15% in flies exposed to 0.3 mmol/kg (PhSe)(2), which is similar to the reduction observed in activity measured in the presence of dithiothreitol. The three-dimensional prediction by SWISS-PROT mouse and fly delta-ALA-D revealed differences in the number of hydrogen bonds and turns for the 2 enzymes. Sulfhydryl groups (-SH) that could be oxidized by (PhSe)(2) are conserved in the two sources of enzyme. Distinct responsiveness to pH, (PhSe)(2) and Pb2+ of these enzymes may be related to subtle differences in tertiary or quaternary structure of mouse and fly delta-ALA-D. Furthermore, mechanism underlying enzyme inhibition after in vivo exposure seems to be different for Drosophila melanogaster and rodent enzymes. (c) 2007 Elsevier Inc. All rights reserved.