Metabolic fate of fumarate, a side product of the purine salvage pathway in the intraerythrocytic stages of Plasmodium falciparum

Abstract

In aerobic respiration, the tricarboxylic acid (TCA) 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 TCA cycle and depends exclusively on glycolysis for ATP production. However, all the constituent enzymes of the TCA cycle are annotated in the genome of P. falciparum implicating that the pathway might be having important, yet unidentified biosynthetic function(s). Here we show that fumarate, a side product of the purine salvage pathway and a metabolic intermediate of the TCA cycle is not a metabolic waste but converted to aspartate through malate and oxaloacetate. P. falciparum infected erythrocytes and free parasites incorporated 14C-2,3-fumarate into the nucleic acid and protein fractions. 13C-NMR of parasites incubated with 13C-2,3-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 to be an electron transport chain dependent process. This study therefore, provides biosynthetic function for fumarate hydratase, malate quinone oxidoreductase and aspartate aminotransferase of P. falciparum.