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Abstract

The intraerythrocytic Plasmodium falciparum parasite converts most of host hemoglobin heme into a nontoxic heme crystal. Erythrocyte zinc protoporphyrin IX, normally present at 0.5 microM, which is a ratio of 1:40,000 hemes, can elevate 10-fold in some of the anemias associated with malaria disease protection. This work examines a binding mechanism for zinc protoporphyrin IX inhibition of heme crystallization similar to the antimalarial quinolines. Zinc protoporphyrin IX neither forms crystals alone nor extends on preformed heme crystals. Inhibition of both seed heme crystal formation and crystal extension occurs with an inhibitory concentration (IC)50 of 5 microM. Field emission in-lens scanning electron microscopy depicts the transition and inhibition of heme monomer aggregates to heme crystals with and without seeding of preformed hemozoin templates. In vitro zinc protoporphyrin IX, like the quinolines, binds to heme crystals in a saturable, specific, pH, and time-dependent manner. The ratio at saturation is approximately 1 zinc protoporphyrin IX per 250 hemes of the crystal. Unlike the quinolines, zinc protoporphyrin IX binds measurably in the absence of heme. Isolated ring and trophozoite stage parasites have an elevated zinc protoporphyrin IX to heme ratio 6 to 10 times that in the erythrocyte cytosol, which also corresponds to elevated ratios found in heme crystals purified from Plasmodium parasites. This work implicates protection from malaria by a mechanism where elevated zinc protoporphyrin IX in anemic erythrocytes binds to heme crystals to inhibit further crystallization. In endemic malaria areas, severe iron deficiency anemia should be treated with antimalarials along with iron replenishment.

Influence of host iron status on Plasmodium falciparum infection

“…This results in zinc protoporphoryin IX levels ten times higher in iron deficient as compared to iron-replete RBCs (Wong et al, 1996 ). As zinc protoporphoryin IX inhibits hemozoin extension in vitro ; it is reasonable to hypothesize that that elevated zinc protoporphoryin IX in iron deficient erythrocytes provides protection against malaria infection by impeding parasite growth (Iyer et al, 2003 ).…”

Dynamic control of hepatic Plasmodium numbers by hepcidin despite elevated liver iron during iron supplementation

“…The greatly elevated ZnPPIX/heme ratio raised the question if this by itself might protect from lethal murine bloodstage malaria by the ability of ZnPPIX to inhibit heme crystallization similar to the quinolones [39]. For analysis of this bloodstage response in contrast to the liver stage response studied as above, we injected 10 million lethal P. yoelii XL in both groups and by day 4 both hbd and wild type mice had similar 30% parasitemias.…”

Iron Status and Associated Malaria Risk Among African Children

“…Furthermore, ID has also been shown to upregulate nitric oxide, which has antiparasitic properties against Plasmodium [34]. Another possible explanation is that during ID, zinc is incorporated in place of iron during heme synthesis, leading to formation of zinc protoporphyrin that, in turn, is thought to inhibit formation of hemozoin (the parasite survival pigment) in a manner similar to quinolines [35].…”