Central carbon metabolism of Plasmodium parasites

Abstract

The central role of metabolic perturbation to the pathology of malaria, the promise of antimetabolites as antimalarial drugs and a basic scientific interest in understanding this fascinating example of highly divergent microbial metabolism has spurred a major and concerted research effort towards elucidating the metabolic network of the Plasmodium parasites. Central carbon metabolism, broadly comprising the flow of carbon from nutrients into biomass, has been a particular focus due to clear and early indications that it plays an essential role in this network. Decades of painstaking efforts have significantly clarified our understanding of these pathways of carbon flux, and this foundational knowledge, coupled with the advent of advanced analytical technologies, have set the stage for the development of a holistic, network-level model of plasmodial carbon metabolism. In this review we summarize the current state of knowledge regarding central carbon metabolism and suggest future avenues of research. We focus primarily on the blood stages of Plasmodium falciparum, the most lethal of the human malaria parasites, but also integrate results from simian, avian and rodent models of malaria that were a major focus of early investigations into plasmodial metabolism.

Artemisinin activity-based probes identify multiple molecular targets within the asexual stage of the malaria parasites Plasmodium falciparum 3D7

“…In support of this observation, studies in Schistosoma japonicum-infected mice exposed to artemether also showed an effect of drug treatment on important glycolytic enzymes in the parasite (39,40). In general, these findings are consistent with the vital and essential role that glycolytic enzymes play in supporting rapid growth and proliferation, similar to that seen in other rapidly proliferating cells, such as cancer cells (41,42). The high glycolytic flux of intraerythrocytic developmental cycle maintains rate-limiting glycolytic intermediates to support other pathways (e.g., nucleotide and lipid biosynthesis) (Fig.…”

Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

“…apicomplexan mitochondrion in energy generation has remained unclear, given the glucosereplete intracellular nature of the environmental niches of these parasites and the apparent reduction of mitochondrial metabolic pathways [4][5][6][7]. For example, apicomplexan mitochondria lack 'type I' NADH dehydrogenase (NDH, complex I of the ETC) and many apparently lack the enzymes and transporters required for fatty acid b-oxidation [8,9].…”

Isoprenoid Biosynthesis in Plasmodium falciparum

“…In the inner mitochondrial membrane, the electron transport chain uses high-energy electrons to harness energy in the form of ATP. In the mitochondria of asexual Plasmodium parasites, however, the electron transport chain is not a primary source of ATP and the parasite instead relies on glycolysis for most of its ATP production (107). Indeed, little of the parasitic glucose supply is completely oxidized, and glucose is instead excreted as lactic acid (108,109).…”