INHIBITION BY CHLOROQUINE OF A NOVEL HEME POLYMERASE ENZYME-ACTIVITY IN MALARIA TROPHOZOITES
INHIBITION BY CHLOROQUINE OF A NOVEL HEME POLYMERASE ENZYME-ACTIVITY IN MALARIA TROPHOZOITES
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DOI：
10.1038/355167a0
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发表时间：
1992-01-09
期刊：
影响因子：
64.8
通讯作者：
CERAMI, A
中科院分区：
文献类型：
--
作者：
SLATER, AFG;CERAMI, A
在过去的20年里，人类疟疾的发病率有所增加；目前估计有2.7亿人感染了这种寄生虫1。这一增长的一个重要贡献是出现了对含有喹啉的抗疟疾药物，如氯喹和奎宁2具有抗药性的疟疾生物。这些药物在红细胞内阶段疟疾寄生虫3-5的酸性食物液泡中积累，尽管它们在这个细胞器中的具体毒性机制尚不确定。食物液泡的主要功能是对摄入的红细胞血红蛋白6，7进行蛋白质分解，为生长中的寄生虫提供必需的氨基酸。血红蛋白在食物液泡中的分解释放出血红素，如果溶解，它会破坏生物膜8，并抑制各种酶9-10。这种寄生虫没有降解或排泄血红素，而是通过将其融入一种名为血球蛋白或疟疾色素11的不溶结晶物质中，进化出了一种新的解毒途径。这些晶体在寄生虫的食物液泡中形成，同时伴随着血红蛋白的降解，它们会一直留在那里，直到受感染的红细胞破裂。血球蛋白的结构包括连接在一个血红素的中心铁离子和另一个12的羧酸基侧基氧之间的HAEM的聚合物。在生理条件12-14下，这种结构不是由游离的血红素或血红蛋白自发形成的，其形成的生物化学尚不清楚。本文报道了恶性疟原虫滋养体提取物中一种血红素聚合酶活性的鉴定和性质，并表明该酶可被含有喹啉的药物如氯喹和奎宁所抑制。这为这些药物具有高度阶段特异性的抗疟疾特性提供了可能的解释。
THE incidence of human malaria has increased during the past 20 years; 270 million people are now estimated to be infected with the parasite 1. An important contribution to this increase has been the appearance of malaria organisms resistant to quinoline-containing antimalarials such as chloroquine and quinine 2. These drugs accumulate in the acid food vacuoles of the intraerythrocytic-stage malaria parasite 3-5, although the mechanism of their specific toxicity in this organelle is uncertain. The primary function of the food vacuole is the proteolysis of ingested red cell haemoglobin 6,7 to provide the growing parasite with essential amino acids. Haemoglobin breakdown in the food vacuole releases haem, which if soluble can damage biological membranes 8 and inhibit a variety of enzymes 9-10. Rather than degrading or excreting the haem, the parasite has evolved a novel pathway for its detoxification by incorporating it into an insoluble crystalline material called haemozoin or malaria pigment 11. These crystals form in the food vacuole of the parasite concomitant with haemoglobin degradation, where they remain until the infected red cell bursts. The structure of haemozoin comprises a polymer of haems linked between the central ferric ion of one haem and a carboxylate side-group oxygen of another 12. This structure does not form spontaneously from either free haem or haemoglobin under physiological conditions 12-14, and the biochemistry of its formation is unclear. Here we report the identification and characterization of a haem polymerase enzyme activity from extracts of Plasmodium falciparum trophozoites, and show that this enzyme is inhibited by quinoline-containing drugs such as chloroquine and quinine. This provides a possible explanation for the highly stage-specific anti-malarial properties of these drugs.