The fatty acid biosynthesis enzyme FabI plays a key role in the development of liver-stage malarial parasites.
The fatty acid biosynthesis enzyme FabI plays a key role in the development of liver-stage malarial parasites.
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DOI：
10.1016/j.chom.2008.11.001
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发表时间：
2008-12-11
影响因子：
30.3
通讯作者：
Fidock DA
中科院分区：
文献类型：
--
作者：
Yu M;Kumar TR;Nkrumah LJ;Coppi A;Retzlaff S;Li CD;Kelly BJ;Moura PA;Lakshmanan V;Freundlich JS;Valderramos JC;Vilcheze C;Siedner M;Tsai JH;Falkard B;Sidhu AB;Purcell LA;Gratraud P;Kremer L;Waters AP;Schiehser G;Jacobus DP;Janse CJ;Ager A;Jacobs WR Jr;Sacchettini JC;Heussler V;Sinnis P;Fidock DA
脂肪酸生物合成已被视为恶性疟原虫无性血期感染的重要生物学功能和治疗靶点。与哺乳动物 I 型过程不同，这种顶端质体驻留的 II 型途径包括 FabI。在这里，我们报告了合成化学和转染研究，得出的结论是疟原虫 FabI 不是细菌 FabI 抑制剂三氯生的抗疟活性目标。恶性疟原虫或啮齿动物寄生虫伯氏疟原虫中 fabI 的破坏不会阻碍血液阶段的生长。相比之下，蚊子来源的 fabI 缺陷的伯氏疟原虫子孢子对小鼠的感染性明显较低，并且通常无法在体外完成肝脏阶段的发育。其特征是无法形成通常引发血液阶段感染的肝内粒体。这些数据阐明了肝脏阶段和血液阶段寄生虫对宿主脂肪酸与从头合成脂肪酸的需求之间的关键差异，并为特定阶段的抗疟干预措施创造了新的前景。
Fatty acid biosynthesis has been viewed as an important biological function of and therapeutic target for Plasmodium falciparum asexual blood stage infection. This apicoplast-resident type II pathway, distinct from the mammalian type I process, includes FabI. Here, we report synthetic chemistry and transfection studies concluding that Plasmodium FabI is not the target of the antimalarial activity of the bacterial FabI inhibitor triclosan. Disruption of fabI in P. falciparum or the rodent parasite P. berghei does not impede blood stage growth. In contrast, mosquito-derived fabI-deficient P. berghei sporozoites are markedly less infective for mice and typically fail to complete liver stage development in vitro. This is characterized by an inability to form intra-hepatic merosomes that normally initiate blood stage infections. These data illuminate key differences between liver and blood stage parasites in their requirements for host versus de novo synthesized fatty acids, and create new prospects for stage-specific antimalarial interventions.