Responsiveness of parasite Cys His proteases to iron redox

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 Fe(3+). 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 Fe(3+) but not Fe(2+) in the presence of excess GSH or DTT. Initial inhibition of falcipain-2 by Fe(3+) (1-50 microM) was reversed in temporal correlation with the 12-14 min half-time of Fe(3+) reduction to Fe(2+) 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. Fe(3+)/Fe(2+) 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.