Differential susceptibility of filarial and human erythrocyte glutathione reductase to inhibition by the trivalent organic arsenical melarsen oxide

Sylke Müller, Rolf D. Walter, Alan H. Fairlamb

    Research output: Contribution to journalArticlepeer-review

    18 Citations (Scopus)

    Abstract

    The glutathione reductases (GR) from two cattle filariae (Setaria digitata and Onchocerca gutturosa) have been isolated and their properties have been compared to those of human erythrocyte GR. In general, the enzymes appear to be very similar with respect to substrate-specificity for glutathione disulfide and NADPH, molecular mass (97 kDa vs. 98 kDa) and oligomeric organisation (subunit size of 51 kDa vs. 50 kDa). However, studies on the inhibition of the enzymes by the trivalent melaminophenyl arsenical melarsen oxide revealed that the human GR is less susceptible to inhibition by the arsenical than the filarial enzymes. Further, it was found that the mechanism of inactivation differs for the host and filarial enzymes. The human enzyme is inhibited by melarsen oxide in a competitive manner with a Ki of 23.7 μM, whereas the filarial GRs are inhibited in two stages: an immediate partial inactivation followed by a time-dependent stage with saturable pseudo-first-order kinetics. Ki values for the S. digitata and O. gutturosa GRs are 38.3 μM and 4.5 μM, respectively, with maximum second-stage inactivation rates of 1.0 × 10-4 s-1 and 24.3 × 10-4 s-1, respectively. These differences between host and parasite enzyme might reflect differences in the primary and secondary structure of the proteins which might be exploitable for the design of new specific macrofilaricidal drugs.

    Original languageEnglish
    Pages (from-to)211-219
    Number of pages9
    JournalMolecular and Biochemical Parasitology
    Volume71
    Issue number2
    DOIs
    Publication statusPublished - May 1995

    Keywords

    • Arsenical drug
    • Chemotherapy
    • Filariasis
    • Glutathione reductase

    ASJC Scopus subject areas

    • Parasitology
    • Molecular Biology

    Fingerprint

    Dive into the research topics of 'Differential susceptibility of filarial and human erythrocyte glutathione reductase to inhibition by the trivalent organic arsenical melarsen oxide'. Together they form a unique fingerprint.

    Cite this