Branched tricarboxylic acid metabolism in Plasmodium falciparum

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Abstract
The tricarboxylic acid (TCA) cycle is a central hub of carbon metabolism, connecting glycolysis, gluconeogenesis, respiration, amino-acid synthesis and other biosynthetic pathways. TCA metabolism in the malaria parasite Plasmodium falciparum is now shown to be largely disconnected from glycolysis, and is organized along fundamentally different lines. In the parasite, glutamine and glutamate are the principal carbon sources for TCA metabolism in a pathway that is branched rather than cyclic. Glucose-derived carbon is virtually absent from the pathway. The results provide a mechanistic explanation for many long-standing observations regarding basic central carbon metabolism in Plasmodium spp., and suggest new targets for antimalarial therapeutic intervention. A central hub of carbon metabolism is the tricarboxylic acid (TCA) cycle, which serves to connect the processes of glycolysis, gluconeogenesis, respiration, amino acid synthesis and other biosynthetic pathways. These authors show that TCA metabolism in the human malaria parasite Plasmodium falciparum is largely disconnected from glycolysis and is organized along a fundamentally different architecture — not cyclic, but branched — from the canonical textbook pathway. A central hub of carbon metabolism is the tricarboxylic acid cycle1, which serves to connect the processes of glycolysis, gluconeogenesis, respiration, amino acid synthesis and other biosynthetic pathways. The protozoan intracellular malaria parasites (Plasmodium spp.), however, have long been suspected of possessing a significantly streamlined carbon metabolic network in which tricarboxylic acid metabolism plays a minor role2. Blood-stage Plasmodium parasites rely almost entirely on glucose fermentation for energy and consume minimal amounts of oxygen3, yet the parasite genome encodes all of the enzymes necessary for a complete tricarboxylic acid cycle4. Here, by tracing 13C-labelled compounds using mass spectrometry5 we show that tricarboxylic acid metabolism in the human malaria parasite Plasmodium falciparum is largely disconnected from glycolysis and is organized along a fundamentally different architecture from the canonical textbook pathway. We find that this pathway is not cyclic, but rather is a branched structure in which the major carbon sources are the amino acids glutamate and glutamine. As a consequence of this branched architecture, several reactions must run in the reverse of the standard direction, thereby generating two-carbon units in the form of acetyl-coenzyme A. We further show that glutamine-derived acetyl-coenzyme A is used for histone acetylation, whereas glucose-derived acetyl-coenzyme A is used to acetylate amino sugars. Thus, the parasite has evolved two independent production mechanisms for acetyl-coenzyme A with different biological functions. These results significantly clarify our understanding of the Plasmodium metabolic network and highlight the ability of altered variants of central carbon metabolism to arise in response to unique environments.