Plasmodium Para-Aminobenzoate Synthesis and Salvage Resolve Avoidance of Folate Competition and Adaptation to Host Diet
Plasmodium Para-Aminobenzoate Synthesis and Salvage Resolve Avoidance of Folate Competition and Adaptation to Host Diet
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DOI：
10.1016/j.celrep.2018.12.062
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发表时间：
2019-01-08
期刊：
影响因子：
8.8
通讯作者：
Matuschewski, Kai
中科院分区：
文献类型：
--
作者：
Matz, Joachim Michael;Watanabe, Mutsumi;Matuschewski, Kai
叶酸代谢对于DNA合成至关重要，并且是快速生长的细胞群体（包括肿瘤和疟疾寄生虫）中经过验证的药物靶标。基因组数据表明，疟原虫保留了从头产生叶酸的能力。然而，疟疾寄生虫摄取和生物合成叶酸的代谢可塑性仍然没有得到解决。在这里，我们证明了疟原虫使用一个aminodeoxychorismate合成酶和aminodeoxychorismate裂解酶，以促进中央叶酸前体对氨基苯甲酸（pABA）在细胞质中的生物合成。我们表明，寄生虫依赖于从头叶酸合成只有当哺乳动物宿主的饮食摄入的pABA是有限的，只有pABA，而不是完全形成的叶酸，有效地采取。这种适应，很容易调整感染高度可变的pABA水平在哺乳动物的饮食，是特定的血液阶段，并可能已经演变为避免叶酸之间的竞争寄生虫和它的主机。
Folate metabolism is essential for DNA synthesis and a validated drug target in fast-growing cell populations, including tumors and malaria parasites. Genome data suggest that Plasmodium has retained its capacity to generate folates de novo. However, the metabolic plasticity of folate uptake and biosynthesis by the malaria parasite remains unresolved. Here, we demonstrate that Plasmodium uses an aminodeoxychorismate synthase and an aminodeoxychorismate lyase to promote the biogenesis of the central folate precursor para-aminobenzoate (pABA) in the cytoplasm. We show that the parasite depends on de novo folate synthesis only when dietary intake of pABA by the mammalian host is restricted and that only pABA, rather than fully formed folate, is taken up efficiently. This adaptation, which readily adjusts infection to highly variable pABA levels in the mammalian diet, is specific to blood stages and may have evolved to avoid folate competition between the parasite and its host.