Solution behavior of hematin under acidic conditions and implications for its interactions with chloroquine |
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Authors: | Maria P Crespo Leann Tilley Nectarios Klonis |
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Institution: | (1) La Trobe Institute for Molecular Science and Centre of Excellence for Coherent X-ray Science, La Trobe University, Melbourne, VIC, 3086, Australia; |
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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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