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A basic research on anti-oxidant system of Plasmodium falciparum for its suitability as targets for anti-malarial chemotherapy: In special relation to the parasite peroxiredoxins as the drug targets.

关于恶性疟原虫抗氧化系统作为抗疟疾化疗靶点的适用性的基础研究：与作为药物靶点的寄生虫过氧化还原蛋白的特殊关系。

基本信息

批准号：
13670260
负责人：
KAWAZU Shin-ichiro
金额：
$ 2.62万
依托单位：
Research Institute, International Medical Center of Japan
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670260/
关键词：
antioxidant peroxiredoxin malaria Plasmodium

项目摘要

We demonstrated that the 2-Cys peroxiredoxin (2-Cys Prx) from the human malaria parasite P. falciparum can act as a terminal peroxidase of the parasite thioredoxin system. The 2-Cys Prx-null parasite line was more sensitive to superoxide and nitric oxide than wildtype. These findings suggest that the 2-Cys Prx protects the parasite cells from oxidative and nitrosative stresses. A constitutive expression of the 2-Cys Px mRNA, which was depicted by real-time quantitative reverse transcriptase PCR in the intraerythrocytic stage, indicated its fundamental roles in the parasite's antioxidat defense mechanism. The 2-Cys Px protein showed similar expression profile in the intraerythrocytic stage of rodent malaria parasite, P. yoelii. In addition, this Prx protein was expressed in the insect stage (zygote, ookinete and sporozoite) of the rodent malaria parasite.In contrast, the parasite's 1-Cys Prx mRNA showed a stage-specific expression at the late trophozoite. The trophozoite-specific expression of the Prx protein during the intraerythrocytic and insect stages was confirmed in the rodent malaria parasite. The 1-Cys Prx-overexpressing parasite was less susceptible to chloroquine, which increases heme burden to the parasite cell. The recombinant 1-Cys Prx protein can deal with reactive oxygen species (ROS), emerged from glutathione-induced heme degradation in vitro. An elevated expression of the Prx protein seen in the trophozoite, the stage with active hemoglobin metabolism, suggests an association of this Prx with heme-derived ROS.Further studies to elucidate such roles of Prx proteins in the malaria parasite may pave the way to utilize the proteins as an alternative targets for the malaria chemotherapy.

我们证明，2-半胱氨酸过氧化物酶（2-Cys Prx）从人类疟原虫恶性疟原虫可以作为一个终端过氧化物酶的寄生虫硫氧还蛋白系统。2-Cys Prx无效寄生虫系比野生型对超氧化物和一氧化氮更敏感。这些发现表明2-Cys Prx保护寄生虫细胞免受氧化和亚硝化应激。实时荧光定量RT-PCR显示2-Cys Px mRNA在红细胞内的组成型表达，表明其在疟原虫抗氧化防御机制中起重要作用。2-Cys Px蛋白在啮齿类疟原虫约氏疟原虫的红细胞内阶段显示出相似的表达谱。此外，Prx蛋白在啮齿类疟原虫的受精卵、动合子和子孢子中均有表达，而1-Cys Prx mRNA在滋养体晚期有阶段特异性表达。Prx蛋白在红细胞内和昆虫阶段的滋养体特异性表达在啮齿类疟原虫中得到证实。1-Cys Prx过表达的寄生虫对氯喹不太敏感，氯喹会增加寄生虫细胞的血红素负担。重组1-Cys Prx蛋白在体外可处理谷胱甘肽诱导的血红素降解产生的活性氧。一个升高的表达的Prx蛋白质的滋养体，阶段与血红蛋白代谢活跃，这表明一个协会的Prx与血红素衍生的ROS。进一步的研究，以阐明这种作用的Prx蛋白质在疟疾寄生虫可能铺平了道路，利用蛋白质作为疟疾化疗的替代目标。