Abstract
Ferredoxin:NADP+ oxidoreductase from Plasmodium falciparum (PfFNR) catalyzes the NADPH-dependent reduction of ferredoxin (PfFd), which provides redox equivalents for the biosynthesis of isoprenoids and fatty acids in the apicoplast. Like other flavin-dependent electrontransferases, PfFNR is a potential source of free radicals of quinones and other redox cycling compounds. We report here a kinetic study of the reduction of quinones, nitroaromatic compounds and aromatic N-oxides by PfFNR. We show that all these groups of compounds are reduced in a single-electron pathway, their reactivity increasing with the increase in their single-electron reduction midpoint potential (E17). The reactivity of nitroaromatics is lower than that of quinones and aromatic N-oxides, which is in line with the differences in their electron self-exchange rate constants. Quinone reduction proceeds via a ping-pong mechanism. During the reoxidation of reduced FAD by quinones, the oxidation of FADH. to FAD is the possible rate-limiting step. The calculated electron transfer distances in the reaction of PfFNR with various electron acceptors are similar to those of Anabaena FNR, thus demonstrating their similar “intrinsic” reactivity. Ferredoxin stimulated quinone- and nitro-reductase reactions of PfFNR, evidently providing an additional reduction pathway via reduced PfFd. Based on the available data, PfFNR and possibly PfFd may play a central role in the reductive activation of quinones, nitroaromatics and aromatic N-oxides in P. falciparum, contributing to their antiplasmodial action.
Highlights
The emergence of a malarial parasite Plasmodium falciparum resistance to available drugs, e.g., chloroquine or artemisinin ([1] and references therein), results in both a demand for new antimalarial agents and a better understanding of their mechanisms of action
P. falciparum is vulnerable to oxidative stress, which might be caused by its lack of the antioxidant enzymes catalase and glutathione peroxidase [2]
It is commonly accepted that the single-electron reduction of quinones and other classes of prooxidant compounds is performed by flavin-dependent dehydrogenases-electrontransferases
Summary
The emergence of a malarial parasite Plasmodium falciparum resistance to available drugs, e.g., chloroquine or artemisinin ([1] and references therein), results in both a demand for new antimalarial agents and a better understanding of their mechanisms of action. P. falciparum is vulnerable to oxidative stress, which might be caused by its lack of the antioxidant enzymes catalase and glutathione peroxidase [2]. For this reason, redox cycling compounds such as quinones, aromatic nitrocompounds and aromatic N-oxides, which frequently exhibit antiplasmodial in vitro activity at micromolar or lower concentrations, were a subject of great interest for a number of years ([3,4,5,6,7,8] and references therein). It is commonly accepted that the single-electron reduction of quinones and other classes of prooxidant compounds is performed by flavin-dependent dehydrogenases-electrontransferases. Ienletchtirsown oarckc,ewpteoresxtwenitdhedditfhfeersetnutdisetsruocftuPrfeFsN, Rreudsuicntgioanlaprogteenntuiamlsbearnodf neloencptrhoystsaiotilcogcihcaarlgeelse.ctOrounr arcecseuplttsorpsrowviitdhedaiffgeernenertasltriunscitguhretsi,nrteodtuhcetiironrepdoutcetniotinalms aenchdaenliescmtrsosatnadtichcihgharliggehst. tOhuersrpeescuifltisc pferaotvuirdees aofgePnfFeNraRl inresliegvhatnint ttoo tthheeisrerepdrouccetisosnesm. echanisms and highlight the specific features of Pf FNR relevant t2o. tRheessuelptsrocesses
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