La Trobe Institute for Molecular Science and Centre of Excellence for Coherent X-ray Science, La Trobe University, Melbourne, VIC, 3086, Australia.
J Biol Inorg Chem. 2010 Sep;15(7):1009-22. doi: 10.1007/s00775-010-0661-y. Epub 2010 Apr 29.
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.
在疟原虫生命周期的红细胞内阶段，疟原虫消化宿主红细胞血红蛋白，产生游离的亚铁原卟啉 IX（FP）。FP 结晶成血卟啉对于其解毒至关重要，也是喹啉类抗疟药物的作用靶点。为了更深入地了解血卟啉形成和喹啉作用的机制，我们研究了 FP 及其相关衍生物在 40%甲醇-水体系中的行为，研究范围涵盖了很宽的 pH 范围（2-12）和不同浓度。FP 的复杂行为可以通过引入一个 pH 依赖的二聚常数来建模，该常数反映了丙酸盐基团的电离状态对自组装水平的影响。分析表明，水合配体的 FP 自组装倾向较低，主要的自组装物种是同型二聚体的氢氧化物配体 FP 和异型二聚体的水合/氢氧化物配体 FP。后者预计是在寄生虫消化液泡的 pH 条件下主要的自组装物种。FP 的状态也影响其与氯喹的相互作用，在中性条件下具有最大亲和力，而在酸性（pH 2）和碱性（pH 12）条件下亲和力下降超过 1000 倍。氯喹-FP 配合物的一阶导数吸收光谱表明，高亲和力相互作用需要氯喹环处于中性氨基喹啉形式，而这反过来又需要配合物中的至少一种 FP 物种是水合配体。
