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.
Lockwood
Thomas D
TD
Department of Pharmacology and Toxicology, School of Medicine, Wright State University, Cox Bldg, 3525 Southern Blvd, Kettering, OH 45429, USA. thomas.lockwood@wright.edu
D000818:Animals; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D007501:Iron / Q000494:pharmacology*; D007700:Kinetics; D010084:Oxidation-Reduction; D010963:Plasmodium falciparum / Q000201:enzymology*; D015800:Protozoan Proteins / Q000378:metabolism
D015800:Protozoan Proteins; D007501:Iron; D003546:Cysteine Endopeptidases