Formation of haemozoin/β‐haematin under physiological conditions is not spontaneous

Pandey, Amit V.; Tekwani, Babu L.

doi:10.1016/0014-5793(96)00881-2

Cited by 59 publications

(31 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, recently published results by us and other groups (34 -36) show that under physiological conditions heme polymerization could not occur as a spontaneous chemical process. Our studies on heme polymerization under different experimental conditions demonstrate that no hemozoin could be formed in the absence of malarial parasite extract (34,41). A product formed spontaneously in the absence of parasite material has been characterized by us and other workers (22,31,34) as a heme-acetate adduct that may be formed by the linking of a central ferric iron of heme and a carboxylate group of acids in the buffer used for the assay of heme polymerization.…”

Section: Discussionmentioning

confidence: 90%

“…Our studies on heme polymerization under different experimental conditions demonstrate that no hemozoin could be formed in the absence of malarial parasite extract (34,41). A product formed spontaneously in the absence of parasite material has been characterized by us and other workers (22,31,34) as a heme-acetate adduct that may be formed by the linking of a central ferric iron of heme and a carboxylate group of acids in the buffer used for the assay of heme polymerization. However, these products could still be differentiated by their solubility characteristics in SDS/bicarbonate buffer (21,22,24,34).…”

Section: Discussionmentioning

confidence: 90%

“…A product formed spontaneously in the absence of parasite material has been characterized by us and other workers (22,31,34) as a heme-acetate adduct that may be formed by the linking of a central ferric iron of heme and a carboxylate group of acids in the buffer used for the assay of heme polymerization. However, these products could still be differentiated by their solubility characteristics in SDS/bicarbonate buffer (21,22,24,34). Fitch and Chou (36) have recently shown that no spontaneous heme polymerization occurs under any concentration of heme or acetate.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Artemisinin, an Endoperoxide Antimalarial, Disrupts the Hemoglobin Catabolism and Heme Detoxification Systems in Malarial Parasite

Pandey

Tekwani

Singh

et al. 1999

Journal of Biological Chemistry

225

156

View full text Add to dashboard Cite

Endoperoxide antimalarials based on the ancient Chinese drug Qinghaosu (artemisinin) are currently our major hope in the fight against drug-resistant malaria. Rational drug design based on artemisinin and its analogues is slow as the mechanism of action of these antimalarials is not clear. Here we report that these drugs, at least in part, exert their effect by interfering with the plasmodial hemoglobin catabolic pathway and inhibition of heme polymerization. In an in vitro experiment we observed inhibition of digestive vacuole proteolytic activity of malarial parasite by artemisinin. These observations were further confirmed by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with artemisinin, suggesting inhibition of hemoglobin degradation. We found artemisinin to be a potent inhibitor of heme polymerization activity mediated by Plasmodium yoelii lysates as well as Plasmodium falciparum histidine-rich protein II. Interaction of artemisinin with the purified malarial hemozoin in vitro resulted in the concentration-dependent breakdown of the malaria pigment. Our results presented here may explain the selective and rapid toxicity of these drugs on mature, hemozoin-containing, stages of malarial parasite. Since artemisinin and its analogues appear to have similar molecular targets as chloroquine despite having different structures, they can potentially bypass the quinoline resistance machinery of the malarial parasite, which causes sublethal accumulation of these drugs in resistant strains.

show abstract

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Artemisinin, an Endoperoxide Antimalarial, Disrupts the Hemoglobin Catabolism and Heme Detoxification Systems in Malarial Parasite

Pandey

Tekwani

Singh

et al. 1999

Journal of Biological Chemistry

225

156

View full text Add to dashboard Cite

show abstract

“…Suggestions that method (1) produces Fe(III)PPIX-acetate complex [49] have been disproved by a combination of elemental analysis and X-ray diffraction studies [50]. Similarly, suggestions that b-hematin is only formed during the drying process used for infrared spectroscopy [51] is discounted by X-ray diffraction and infrared spectra showing that it is present in the undried product [52].…”

Section: Abiotic Syntheses Of B-hematinmentioning

confidence: 95%

Recent advances in understanding the mechanism of hemozoin (malaria pigment) formation

Egan

2008

Journal of Inorganic Biochemistry

166

173

View full text Add to dashboard Cite

“…However, a histidine-rich protein (HRP II) has recently been localized in the digestive vacuole of malaria parasite which provides a nucleus for the polymerization of heme [16], supporting the theory that the involvement of some parasitic component is necessary for hemozom formation. Very recently, we have shown that hemozoin formation under physiological conditions cannot occur chemically in the absence of any parasite derived component [17].…”

Section: Introductionmentioning

confidence: 99%

Depolymerization of malarial hemozoin: a novel reaction initiated by blood schizontocidal antimalarials

Pandey

Tekwani

1997

FEBS Letters

Self Cite

View full text Add to dashboard Cite

Malaria parasite digests hemoglobin and utilizes the globin part for its nutritional requirements. Heme released as a byproduct of hemoglobin degradation is detoxified by polymerization into a crystalline, insoluble pigment, known as hemozoin. We have identified a novel reaction of depolymerization of hemozoin to heme. This reaction is initiated by the interaction of blood schizonticidal antimalarial drugs with the malarial hemozoin. The reaction has been confirmed, with the purified hemozoin as well as the lysate of the malaria parasite. Pigment breakdown was studied by infrared spectroscopy, thin-layer chromatography and spectrophotometric analysis. It was complete within 2 h of drug exposure, which explains the selective sensitivity of late stages (trophozoites and schizonts) of malarial parasites loaded with the hemozoin pigment to the toxic action of these drugs. It is suggested that the failure of the parasite heme detoxification system due to this reaction results in the accumulation of toxic heme, which alone, or complexed with the antimalarial leads to the death of malaria parasite.

show abstract

Formation of haemozoin/β‐haematin under physiological conditions is not spontaneous

Cited by 59 publications

References 24 publications

Artemisinin, an Endoperoxide Antimalarial, Disrupts the Hemoglobin Catabolism and Heme Detoxification Systems in Malarial Parasite

Artemisinin, an Endoperoxide Antimalarial, Disrupts the Hemoglobin Catabolism and Heme Detoxification Systems in Malarial Parasite

Recent advances in understanding the mechanism of hemozoin (malaria pigment) formation

Depolymerization of malarial hemozoin: a novel reaction initiated by blood schizontocidal antimalarials

Contact Info

Product

Resources

About