Dept. of Chemical Research Support, Weizmann Institute of Science, Rehovot, 7610001, Israel.
Center of Cellular and Molecular Biology of Diseases, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), City of Knowledge, 0843 (Republic of, Panama.
ChemMedChem. 2021 May 18;16(10):1515-1532. doi: 10.1002/cmdc.202000895. Epub 2021 Mar 19.
The biogenic formation of hemozoin crystals, a crucial process in heme detoxification by the malaria parasite, is reviewed as an antimalarial drug target. We first focus on the in-vivo formation of hemozoin. A model is presented, based on native-contrast 3D imaging obtained by X-ray and electron microscopy, that hemozoin nucleates at the inner membrane leaflet of the parasitic digestive vacuole, and grows in the adjacent aqueous medium. Having observed quantities of hemoglobin and hemozoin in the digestive vacuole, we present a model that heme liberation from hemoglobin and hemozoin formation is an assembly-line process. The crystallization is preceded by reaction between heme monomers yielding hematin dimers involving fewer types of isomers than in synthetic hemozoin; this is indicative of protein-induced dimerization. Models of antimalarial drugs binding onto hemozoin surfaces are reviewed. This is followed by a description of bromoquine, a chloroquine drug analogue, capping a significant fraction of hemozoin surfaces within the digestive vacuole and accumulation of the drug, presumably a bromoquine-hematin complex, at the vacuole's membrane.
疟原虫通过生物合成形成亚铁血红素晶体，这是血红素解毒的关键过程，该过程被视为抗疟药物靶点。我们首先关注亚铁血红素在体内的形成。本文基于 X 射线和电子显微镜获得的原生对比 3D 成像，提出了一个模型，即亚铁血红素在寄生虫消化泡的内膜小叶上成核，并在相邻的水介质中生长。由于在消化泡中观察到了大量的血红蛋白和亚铁血红素，我们提出了一个模型，即血红蛋白和亚铁血红素的形成是一个装配线过程。在结晶之前，血红素单体之间发生反应，生成涉及较少异构体类型的血晶素二聚体，这表明存在蛋白诱导的二聚化。本文还综述了抗疟药物与亚铁血红素表面结合的模型。接下来描述了溴喹啉，一种氯喹药物类似物，它占据了消化泡内亚铁血红素表面的很大一部分，并且药物（推测是溴喹啉-血晶素复合物）在泡膜处积累。
