Metabolic Fate of Fumarate, a Side Product of the Purine Salvage Pathway in the Intraerythrocytic Stages of Plasmodium falciparum
Metabolic Fate of Fumarate, a Side Product of the Purine Salvage Pathway in the Intraerythrocytic Stages of Plasmodium falciparum
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DOI：
10.1074/jbc.m110.173328
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发表时间：
2011-03-18
影响因子：
4.8
通讯作者：
Balaram, Hemalatha
中科院分区：
文献类型：
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作者：
Bulusu, Vinay;Jayaraman, Vijay;Balaram, Hemalatha
在有氧呼吸中，三羧酸循环是碳水化合物、蛋白质和脂质完全氧化为二氧化碳和水的关键。恶性疟原虫是人类疟疾的病原体，缺乏常规的三羧酸循环，仅依赖于糖酵解产生ATP。然而，三羧酸循环的所有组成酶都在恶性疟原虫的基因组中被注释，这意味着该途径可能具有重要但尚未确定的生物合成功能。在这里，我们表明，富马酸，嘌呤补救途径的副产品和三羧酸循环的代谢中间体，不是代谢废物，而是通过苹果酸和草酰乙酸转化为天冬氨酸。恶性疟原虫感染的红细胞和游离寄生虫将[2，3-C-14]富马酸盐掺入核酸和蛋白质组分中。用[2，3-C-13]富马酸盐孵育的寄生虫的C-13 NMR显示形成苹果酸盐、丙酮酸盐、乳酸盐和天冬氨酸盐，但不形成柠檬酸盐或琥珀酸盐。此外，用阿托伐醌处理游离寄生虫可抑制富马酸向天冬氨酸的转化，从而表明该途径为电子传递链依赖性过程。因此，本研究提供了一个生物合成功能的延胡索酸水合酶，苹果酸醌氧化还原酶，天冬氨酸转氨酶的恶性疟原虫。
In aerobic respiration, the tricarboxylic acid cycle is pivotal to the complete oxidation of carbohydrates, proteins, and lipids to carbon dioxide and water. Plasmodium falciparum, the causative agent of human malaria, lacks a conventional tricarboxylic acid cycle and depends exclusively on glycolysis for ATP production. However, all of the constituent enzymes of the tricarboxylic acid cycle are annotated in the genome of P. falciparum, which implies that the pathway might have important, yet unidentified biosynthetic functions. Here we show that fumarate, a side product of the purine salvage pathway and a metabolic intermediate of the tricarboxylic acid cycle, is not a metabolic waste but is converted to aspartate through malate and oxaloacetate. P. falciparum-infected erythrocytes and free parasites incorporated [2,3-C-14] fumarate into the nucleic acid and protein fractions. C-13 NMR of parasites incubated with [2,3-C-13] fumarate showed the formation of malate, pyruvate, lactate, and aspartate but not citrate or succinate. Further, treatment of free parasites with atovaquone inhibited the conversion of fumarate to aspartate, thereby indicating this pathway as an electron transport chain-dependent process. This study, therefore, provides a biosynthetic function for fumarate hydratase, malate quinone oxidoreductase, and aspartate aminotransferase of P. falciparum.