Hemozoin formation in malaria: a two-step process involving histidine-rich proteins and lipids
Hemozoin formation in malaria: a two-step process involving histidine-rich proteins and lipids
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DOI：
10.1016/s0006-291x(03)01465-7
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发表时间：
2003-09-05
影响因子：
3.1
通讯作者：
Chauhan, VS
中科院分区：
文献类型：
--
作者：
Pandey, AV;Babbarwal, VK;Chauhan, VS
主要的血液阶段抗疟疾药物，如氯喹和青蒿素，主要针对疟疾寄生虫的血红素解毒过程。利用恶性疟原虫富含组氨酸的蛋白-2(Pfhrp-2)、脂类和自身催化在体外形成血虫的反应很慢，不能解释寄生虫生存所需的解毒速度。在这里，我们表明，疟疾血球蛋白的形成是一个协调的两组分过程，涉及脂质和富含组氨酸的蛋白质。在体外，Pfhrp-2的血球形成率为1-2%，脂类为0.25-0.5%。我们在12it Pfhrp-2介导的反应中在9小时后加入脂质，导致血球蛋白形成增加6倍。然而，在9之后加入Pfhrp-2的脂类介导反应，与单独使用Pfbrp-2反应相比，它只产生两倍的血球蛋白产量。与Pfbrp-2血红素结合序列相对应的合成肽，基于AHHAAD的重复序列，无论是单独还是与脂质结合，都不能在体外产生血球蛋白。这些结果表明，疟疾寄生虫中血球蛋白的形成既涉及到脂质，也涉及到支架蛋白。富含组氨酸的蛋白质可能通过与大量的血红素分子结合，促进两个血红素分子之间的铁羧酸键二聚体的形成，从而促进长链的形成，通过氢键或通过广泛的氢键网络连接在一起。(C)2003 Elsevier Inc.保留所有权利。
Major blood stage antimalarial drugs like chloroquine and artemisinin target the heme detoxification process of the malaria parasite. Hemozoin formation reactions in vitro using the Plasmodium falciparum histidine-rich protein-2 (Pfhrp-2), lipids, and autocatalysis are slow and could not explain the speed of detoxification needed for parasite survival. Here, we show that malarial hemozoin formation is a coordinated two component process involving both lipids and histidine-rich proteins. Hemozoin formation efficiency in vitro is 1-2% with Pfhrp-2 and 0.25-0.5% with lipids. We added lipids after 9 h in a 12 It Pfhrp-2 mediated reaction that resulted in sixfold increase in hemozoin formation. However, a lipid mediated reaction in which Pfhrp-2 was added after 9 It produced only twofold increase in hemozoin production compared to the reaction with Pfbrp-2 alone. Synthetic peptides corresponding to the Pfbrp-2 heme binding sequences, based on repeats of AHHAAD, neither alone nor in combination with lipids were able to generate hemozoin in vitro. These results indicate that hemozoin formation in malaria parasite involves both the lipids and the scaffolding proteins. Histidine-rich proteins might facilitate hemozoin formation by binding with a large number of heme molecules, and facilitating the dimer formation involving iron-carboxylate bond between two heme molecules, and lipids may then subsequently assist the mechanism of long chain formation, held together by hydrogen bonds or through extensive networking of hydrogen bonds. (C) 2003 Elsevier Inc. All rights reserved.