Apicoplast fatty acid synthesis is essential for organelle biogenesis and parasite survival in Toxoplasma gondii
Apicoplast fatty acid synthesis is essential for organelle biogenesis and parasite survival in Toxoplasma gondii
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DOI：
10.1073/pnas.0603391103
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发表时间：
2006-08-29
影响因子：
11.1
通讯作者：
Striepen, Boris
中科院分区：
文献类型：
--
作者：
Mazumdar, Jolly;Wilson, Emma H.;Striepen, Boris
顶复合体寄生虫是许多重要的人类疾病的病因，包括疟疾和艾滋病相关的机会性感染。这些疾病的药物治疗并不令人满意，并受到耐药性的威胁。顶质体（一种类似叶绿体的细胞器）的发现为这些寄生虫提供了独特的药物靶点。顶质体定位脂肪酸合成（FAS II）途径是一种与人类类似的FAS I途径根本不同的代谢过程，它代表了这样一个靶标。然而，顶质体FAS II的具体生物学作用尚不清楚。此外，寄生虫基因组编码了额外的和潜在冗余的脂肪酸合成途径。我们构建了刚地弓形虫FAS II途径的核心成分酰基载体蛋白的条件零突变体。FAS II缺失严重影响了培养物中寄生虫的生长。我们发现FAS II是丙酮酸脱氢酶的激活所必需的，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，酰基载体蛋白敲除也会导致顶质体生物发生缺陷和细胞器的损失。最重要的是，在小鼠模型中，顶质体FAS II的体内敲除导致了致命攻击感染的治愈。总之，我们的研究证明了顶质体FAS II功能与寄生虫生存和发病之间的直接联系。我们的遗传模型还提供了一个平台来剖析顶质体与寄生虫代谢的整合，特别是它与线粒体的假设相互作用。
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.