Department of Biological Sciences, Clemson University, Clemson, South Carolina, United States of America.
Department of Chemistry, Clemson University, Clemson, South Carolina, United States of America.
PLoS Pathog. 2020 May 14;16(5):e1008499. doi: 10.1371/journal.ppat.1008499. eCollection 2020 May.
Heme, an iron-containing organic ring, is essential for virtually all living organisms by serving as a prosthetic group in proteins that function in diverse cellular activities ranging from diatomic gas transport and sensing, to mitochondrial respiration, to detoxification. Cellular heme levels in microbial pathogens can be a composite of endogenous de novo synthesis or exogenous uptake of heme or heme synthesis intermediates. Intracellular pathogenic microbes switch routes for heme supply when heme availability fluctuates in their replicative environment throughout infection. Here, we show that Toxoplasma gondii, an obligate intracellular human pathogen, encodes a functional heme biosynthesis pathway. A chloroplast-derived organelle, termed apicoplast, is involved in heme production. Genetic and chemical manipulation revealed that de novo heme production is essential for T. gondii intracellular growth and pathogenesis. Surprisingly, the herbicide oxadiazon significantly impaired Toxoplasma growth, consistent with phylogenetic analyses that show T. gondii protoporphyrinogen oxidase is more closely related to plants than mammals. This inhibition can be enhanced by 15- to 25-fold with two oxadiazon derivatives, lending therapeutic proof that Toxoplasma heme biosynthesis is a druggable target. As T. gondii has been used to model other apicomplexan parasites, our study underscores the utility of targeting heme biosynthesis in other pathogenic apicomplexans, such as Plasmodium spp., Cystoisospora, Eimeria, Neospora, and Sarcocystis.
血红素是一种含铁的有机环，作为参与各种细胞活动的蛋白质中的辅基，对几乎所有的生物体都是必不可少的，这些细胞活动的范围从双原子气体的运输和感应，到线粒体呼吸，再到解毒。微生物病原体中的细胞血红素水平可以是内源性从头合成或外源性摄取血红素或血红素合成中间体的组合。当感染过程中其复制环境中的血红素可用性发生波动时，细胞内病原体微生物会切换供血红素的途径。在这里，我们表明，刚地弓形虫，一种必需的细胞内人类病原体，编码了一个功能性的血红素生物合成途径。一个被称为类质体的由叶绿体衍生而来的细胞器，参与血红素的生产。遗传和化学操作表明，从头合成血红素对于刚地弓形虫的细胞内生长和发病机制是必不可少的。令人惊讶的是，除草剂恶嗪草酮显著损害了弓形虫的生长，与系统发育分析一致，该分析表明刚地弓形虫原卟啉原氧化酶与植物的关系比与哺乳动物的关系更密切。这种抑制作用可以用两种恶嗪草酮衍生物增强 15-25 倍，这为刚地弓形虫血红素生物合成是一个可用药的靶点提供了治疗证据。由于刚地弓形虫已被用于模拟其他顶复门寄生虫，我们的研究强调了靶向血红素生物合成在其他致病顶复门寄生虫中的应用，如疟原虫、等孢球虫、艾美耳球虫、新孢子虫和肉孢子虫。
