Responsiveness of parasite Cys His proteases to iron redox
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Plasmodium falciparum growth can be opposed in erythrocyte culture or in vivo by nonselective inhibitors of CysHis proteases or pro-oxidative drugs, which elevate erythrocyte Fe3+. However, no relationship between Fe redox and CysHis protease inhibition has been suggested. Here, mature falcipain-2 was found to be inhibited by relevant concentrations of Fe3+ but not Fe2+ in the presence of excess GSH or DTT. Initial inhibition of falcipain-2 by Fe3+ (1–50 μM) was reversed in temporal correlation with the 12–14 min half-time of Fe3+ reduction to Fe2+ caused by GSH or DTT (6 mM). The metal–redox responses of cathepsin B from mammal, cruzain from Trypanosoma cruzi, and falcipain-2 from P. falciparum were similar. Fe3+/Fe2+ speciation has features consistent with a natural redox switch modifying the reaction rate of mature CysHis proteases in virtually all cell types. Pro-oxidative antimalarial therapy might intervene in a natural mechanism normally modifying CysHis protease reaction rates via redox state of Fe pools.