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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Apicoplast fatty acid synthesis is essential for organelle biogenesis and parasite survival in Toxoplasma gondii
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Apicoplast fatty acid synthesis is essential for organelle biogenesis and parasite survival in Toxoplasma gondii

机译：黏质塑料脂肪酸合成对于弓形虫的细胞器生物发生和寄生虫生存至关重要

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摘要

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.
机译：蚜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。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（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。一种与人中类似的FASⅠ途径根本不同的代谢过程，即是原生质体局部脂肪酸合成（FASⅡ）途径，就是一个这样的目标。但是，apicoplast FASⅡ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。我们构建了一个条件性的空缺突变体，即酰基弓形虫FASⅡ途径的重要组成部分-酰基载体蛋白。 FASⅡ的丧失严重损害了培养物中的寄生虫生长。我们表明，FASⅡ是激活丙酮酸脱氢酶所必需的，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 FASⅡ可导致致命性攻击感染的治愈。总之，我们的研究表明了apicoplast FASⅡ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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