Zinc protoporphyrin IX binds heme crystals to inhibit the process of crystallization in Plasmodium falciparum
Zinc protoporphyrin IX binds heme crystals to inhibit the process of crystallization in Plasmodium falciparum
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DOI：
10.1007/bf03402182
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发表时间：
2003-05-01
影响因子：
5.7
通讯作者：
Sullivan, DJ
中科院分区：
文献类型：
--
作者：
Iyer, JK;Shi, LR;Sullivan, DJ
红细胞内恶性疟原虫寄生虫将大部分宿主血红蛋白血红素转化为无毒的血红素晶体。红细胞锌原卟啉 IX 的浓度通常为 0.5 μM，其比例为 1:40000 血红素，在某些与疟疾疾病预防相关的贫血中可将其升高 10 倍。这项工作研究了锌原卟啉 IX 抑制血红素结晶的结合机制，类似于抗疟药喹啉。锌原卟啉 IX 既不单独形成晶体，也不在预先形成的血红素晶体上延伸。抑制浓度 (IC)(50) 为 5 μM 时，即可抑制血红素种子晶体的形成和晶体延伸。场发射透镜内扫描电子显微镜描绘了在有或没有接种预制疟原虫色素模板的情况下血红素单体聚集体向血红素晶体的转变和抑制。在体外，锌原卟啉 IX 与喹啉一样，以可饱和、特异性、pH 值和时间依赖性的方式与血红素晶体结合。饱和时的比例约为每 250 个晶体血红素 IX 锌原卟啉 IX。与喹啉不同，锌原卟啉 IX 在没有血红素的情况下可显着结合。孤立的环状和滋养体阶段寄生虫的锌原卟啉 IX 与血红素的比率升高，是红细胞胞质中的 6 至 10 倍，这也对应于从疟原虫寄生虫纯化的血红素晶体中发现的升高的比率。这项工作表明，通过贫血红细胞中升高的锌原卟啉 IX 与血红素晶体结合以抑制进一步结晶的机制来预防疟疾。在疟疾流行地区，严重缺铁性贫血应在补充铁的同时服用抗疟药。
The intraerythrocytic Plasmodium falciparum parasite converts most of host hemoglobin heme into a nontoxic heme crystal. Erythrocyte zinc protoporphyrin IX, normally present at 0.5 muM, which is a ratio of 1:40000 hemes, can elevate 10-fold in some of the anemias associated with malaria disease protection. This work examines a binding mechanism for zinc protoporphyrin IX inhibition of heme crystallization similar to the antimalarial quinolines. Zinc protoporphyrin IX neither forms crystals alone nor extends on preformed heme crystals. Inhibition of both seed heme crystal formation and crystal extension occurs with an inhibitory concentration (IC)(50) of 5 muM. Field emission in-lens scanning electron microscopy depicts the transition and inhibition of heme monomer aggregates to heme crystals with and without seeding of preformed hemozoin templates. In vitro zinc protoporphyrin IX, like the quinolines, binds to heme crystals in a saturable, specific, pH, and time-dependent manner. The ratio at saturation is approximately I zinc protoporphyrin IX per 250 hemes of the crystal. Unlike the quinolines, zinc protoporphyrin IX binds measurably in the absence of heme. Isolated ring and trophozoite stage parasites have an elevated zinc protoporphyrin IX to heme ratio 6 to 10 times that in the erythrocyte cytosol, which also corresponds to elevated ratios found in heme crystals purified from Plasmodium parasites. This work implicates protection from malaria by a mechanism where elevated zinc protoporphyrin IX in anemic erythrocytes binds to heme crystals to inhibit further crystallization. In endemic malaria areas, severe iron deficiency anemia should be treated with antimalarials along with iron replenishment.