Apicomplexan parasites are the cause of numerous important human diseases including malaria and AIDS-associated opportunistic infections. Drug treatment for these diseases is not satisfactory and is threatened by resistance. The discovery of the apicoplast, a chloroplast-like organelle, presents drug targets unique to these parasites. The apicoplast-localized fatty acid synthesis (FAS II) pathway, a metabolic process fundamentally divergent from the analogous FAS I pathway in humans, represents one such target. However, the specific biological roles of apicoplast FAS II remain elusive. Furthermore, the parasite genome encodes additional and potentially redundant pathways for the synthesis of fatty acids. We have constructed a conditional null mutant of acyl carrier protein, a central component of the FAS II pathway in Toxoplasma gondii. Loss of FAS II severely compromises parasite growth in culture. We show FAS II to be required for the activation of pyruvate dehydrogenase, an important source of the metabolic precursor acetyl-CoA. Interestingly, acyl carrier protein knockout also leads to defects in apicoplast biogenesis and a consequent loss of the organelle. Most importantly, in vivo knockdown of apicoplast FAS II in a mouse model results in cure from a lethal challenge infection. In conclusion, our study demonstrates a direct link between apicoplast FAS II functions and parasite survival and pathogenesis. Our genetic model also offers a platform to dissect the integration of the apicoplast into parasite metabolism, especially its postulated interaction with the mitochondrion.

译文

顶杆虫寄生虫是导致许多重要人类疾病的原因,包括疟疾和艾滋病相关的机会性感染。对这些疾病的药物治疗并不令人满意,并且受到耐药性的威胁。 apicoplast(一种叶绿体样细胞器)的发现提出了这些寄生虫特有的药物靶标。脂蛋白定位的脂肪酸合成(FAS II)途径(一种与人的类似FAS I途径基本不同的代谢过程)代表了这样一个目标。但是,apicoplast FAS II的具体生物学作用仍然难以捉摸。此外,寄生虫基因组编码用于脂肪酸合成的其他途径和潜在的冗余途径。我们已经构建了一个有条件的空缺突变体的酰基载体蛋白,这是弓形虫中FAS II途径的重要组成部分。 FAS II的丧失严重损害了培养物中寄生虫的生长。我们显示FAS II是激活丙酮酸脱氢酶所需的,丙酮酸脱氢酶是代谢前体乙酰辅酶A的重要来源。有趣的是,酰基载体蛋白的敲除也导致了无顶质生物发生中的缺陷和随之而来的细胞器的损失。最重要的是,在小鼠模型中体内敲除apicoplast FAS II可导致致命性攻击感染的治愈。总之,我们的研究表明了apicoplast FAS II功能与寄生虫生存和发病机制之间的直接联系。我们的遗传模型还提供了一个平台,可用于分析apicoplast整合到寄生虫代谢中,尤其是其与线粒体相互作用的假设。

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