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Solution behavior of hematin under acidic conditions and implications for its interactions with chloroquine

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Abstract

During the intraerythrocytic stage of its lifecycle, the malaria parasite digests host erythrocyte hemoglobin, producing free ferriprotoporhyrin IX (FP). Crystallization of FP into hemozoin is essential for its detoxification and is the target of quinoline antimalarials. To gain further insight into the mechanism of hemozoin formation and quinoline action we have studied the behavior of FP and related derivatives in 40% methanol in water at different concentrations across a broad pH range (2–12). The complex behavior of FP can be modeled by incorporating a pH-dependent dimerization constant that reflects the influence of the ionization state of the propionate groups on the level of self-association. The analysis reveals that aqua-ligated FP has a low propensity to self-associate and that the predominant self-associated species are homodimeric hydroxide-ligated FP and heterodimeric aqua/hydroxide-ligated FP. The latter is predicted to be the main self-associated species at the pH of the parasite digestive vacuole. The state of FP also affects its interaction with chloroquine, with maximum affinity under neutral conditions and a more than 1,000-fold decrease in affinity under acidic (pH 2) and basic (pH 12) conditions. First-derivative absorption spectra of the chloroquine–FP complex indicate that the high-affinity interaction requires the chloroquine ring in its neutral aminoquinoline form and this in turn requires at least one of the FP species in the complex to be aqua-ligated.

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Abbreviations

CQ:

Chloroquine

deuteroFP:

Iron(III) deuteroprotoporphyrin IX chloride

DV:

Digestive vacuole

FP:

Ferriprotoporphyrin IX

FPdme:

Iron(III) dimethylester protoporphyrin IX chloride

mesoFP:

Iron(III) mesoprotoporphyrin IX chloride

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Acknowledgments

This work was supported by the Australian Research Council and the National Health and Medical Research Council, Australia.

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Authors and Affiliations

  1. La Trobe Institute for Molecular Science and Centre of Excellence for Coherent X-ray Science, La Trobe University, Melbourne, VIC, 3086, Australia

    Maria P. Crespo, Leann Tilley & Nectarios Klonis

Authors
  1. Maria P. Crespo
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  2. Leann Tilley
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  3. Nectarios Klonis
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Correspondence to Nectarios Klonis.

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Crespo, M.P., Tilley, L. & Klonis, N. Solution behavior of hematin under acidic conditions and implications for its interactions with chloroquine. J Biol Inorg Chem 15, 1009–1022 (2010). https://doi.org/10.1007/s00775-010-0661-y

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