Involvement of lipids in ferriprotoporphyrin IX polymerization in malaria

Fitch, Coy D.; Cai, Guang-zuan; Chen, Yifeng; Shoemaker, James D.

doi:10.1016/s0925-4439(99)00017-4

Cited by 150 publications

(143 citation statements)

References 18 publications

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“…Next, we examined whether aptamers interfere with hemozoin formation in vitro using 1-mono-oleoylglycerol (MOG) (30) as an initiator. In these assays, MOG and heme were co-incubated in pH 5.2 buffer and the nucleic acid concentration titrated to attain the desired final concentration.…”

Section: Resultsmentioning

confidence: 99%

Inhibiting Plasmodium falciparum growth and heme detoxification pathway using heme-binding DNA aptamers

Niles¹,

DeRisi

Marletta

2009

Proc. Natl. Acad. Sci. U.S.A.

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The human parasite Plasmodium falciparum enzymatically digests hemoglobin during its intra-erythrocytic developmental stages in acidic food vacuole compartments. The released heme is rapidly detoxified by polymerization into the chemically inert pigment, hemozoin. Several heme-binding anti-malarial compounds, such as chloroquine, efficiently inhibit this process, and this is believed to be the predominant mechanism by which these drugs induce parasite toxicity. In an effort to expand the biochemical tools available for exploration of this pathogen's basic biology, we chose this heme-detoxification pathway as a model system for exploring the suitability of DNA aptamers for modulating this essential parasite biochemical pathway. In this report, we demonstrate that heme-binding DNA aptamers efficiently inhibit in vitro hemozoin formation catalyzed by either a model lipid system or parasite-derived extracts just as or more potently than chloroquine. Furthermore, when parasites are grown in red cells loaded with heme-binding aptamers, their growth is significantly inhibited relative to parasites exposed to non-heme-binding DNA oligonucleotides. Both the timing of parasite-induced toxicity and the concentration of heme-binding aptamer required for inducing toxicity correlate well with the uptake of red cell cytosolic components by the parasite, and the requirement for compounds with similar in vitro hemozoin inhibitory potency to preconcentrate within the parasite before observing toxicity. Thus, these hemebinding aptamers recapitulate the in vitro hemozoin inhibition activity and induce parasite toxicity in a manner consistent with inhibition of this pathway. Altogether, these data demonstrate that aptamers can be versatile tools with applicability in functionally dissecting important P. falciparum-specific pathways both in vitro and in vivo.

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Section: Resultsmentioning

confidence: 99%

Inhibiting Plasmodium falciparum growth and heme detoxification pathway using heme-binding DNA aptamers

Niles¹,

DeRisi

Marletta

2009

Proc. Natl. Acad. Sci. U.S.A.

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“…among these are the family of unusual histidine rich protein, HRP I-IV, (Sullivan et al, 1996a;Choi et al, 1998)which bind large quantities of heme. In addition, glycoproteins and lipids have been suggested to mediate malaria pigment formation (Arese et al, 1999;Fitch et al, 1999). Clearly the reactions outlined in equation 1 and 2 can generate aggregated heme phases without catalysis, but the role of macromolecular catalysis of these reactions remains an important research effort.…”

Section: Figurementioning

confidence: 99%

Phase homogeneity and crystal morphology of the malaria pigment β-hematin

Ad²,

Pw³

2002

Acta Crystallogr D Biol Cryst

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Hemoglobin digestion in the intraerythrocytic trophozoite stages of the malaria parasite releases large quantities of heme, which is then detoxified by crystallization into regular crystallites, which are subsequently secreted into the host vascular network as malaria pigment. This crystalline product is isostructural with the synthetic phase β-hematin, and its structure, solved from its powder diffraction pattern, (Pagola et al., 2000), corresponds to a hydrogen bonded chain of propionate linked dimers, Figure 1. This is an example where the crystalline phase is the macromolecule of direct biological interest, particularly in light of the currently accepted hypothesis for the quinoline antimalarial drug action being the inhibition of β-hematin formation and biosynthesis. A surprisingly array of spectroscopically similar closely related phases can also form during the reactions which are used to synthesize β-hematin. Scanning electron microscopy and X-ray powder diffraction have been used to characterize these materials. Taken together these results indicate that infrared spectroscopy, in itself, is insufficient to identify synthetic analogs to malaria pigment and that a combination of electron microscopy and powder diffraction are required to unambiguously characterize these heme aggregates.

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“…This raised the possibility of oriented nucleation, although the clustering and alignment might have occurred after the nucleation step. Fitch et al (2) have proposed that neutral lipids play a role in inducing crystallization of hemozoin within the digestive vacuole (DV). The presence of lipid bodies a few hundred nm in diameter, composed of mono-and diacylglycerols close to the outer surface of the DV, has been reported by Jackson et al (3).…”

mentioning

confidence: 99%

Aligned hemozoin crystals in curved clusters in malarial red blood cells revealed by nanoprobe X-ray Fe fluorescence and diffraction

Kapishnikov

Berthing

Hviid

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The human malaria parasite Plasmodium falciparum detoxifies the heme byproduct of hemoglobin digestion in infected red blood cells by sequestration into submicron-sized hemozoin crystals. The crystal is composed of heme units interlinked to form cyclic dimers via reciprocal Fe─O (propionate) bonds. Templated hemozoin nucleation was envisaged to explain a classic observation by electron microscopy of a cluster of aligned hemozoin crystals within the parasite digestive vacuole. This dovetails with evidence that acylglycerol lipids are involved in hemozoin nucleation in vivo, and nucleation of β-hematin, the synthetic analogue of hemozoin, was consistently induced at an acylglycerol-water interface via their {100} crystal faces. In order to ascertain the nature of hemozoin nucleation in vivo, we probed the mutual orientations of hemozoin crystals in situ within RBCs using synchrotron-based X-ray nanoprobe Fe fluorescence and diffraction. The X-ray patterns indicated the presence of hemozoin clusters, each comprising several crystals aligned along their needle c axes and exposing {100} side faces to an approximately cylindrical surface, suggestive of nucleation via a common lipid layer. This experimental finding, and the associated nucleation model, are difficult to reconcile with recent reports of hemozoin formation within lipid droplets in the digestive vacuole. The diffraction results are verified by a study of the nucleation process using emerging tools of three-dimensional cellular microscopy, described in the companion paper.crystal nucleation | optical birefringence | X-ray diffraction | submicrofocus X-ray fluorescence | lipid-induced precipitation

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Involvement of lipids in ferriprotoporphyrin IX polymerization in malaria

Cited by 150 publications

References 18 publications

Inhibiting Plasmodium falciparum growth and heme detoxification pathway using heme-binding DNA aptamers

Inhibiting Plasmodium falciparum growth and heme detoxification pathway using heme-binding DNA aptamers

Phase homogeneity and crystal morphology of the malaria pigment β-hematin

Aligned hemozoin crystals in curved clusters in malarial red blood cells revealed by nanoprobe X-ray Fe fluorescence and diffraction

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