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.

Fig 1

An integrated map of carbon flow through the metabolic network of Plasmodium falciparum. Arrows show the proposed direction of flux through the corresponding enzymatic reaction as suggested by experimental evidence; note that this is only intended to indicate net flux, and that the reaction in question might be reversible. Cofactors (ATP, NADH, etc.) are not shown for the sake of clarity. Text in circles represent major biomass components; the circled question mark indicates uncertainty about the existence of the enzyme transaldolase. Abbreviations: Glc, glucose; G6P, glucose-6-phosphate; F6P, fructose-6-phosphate; F1,6BP, fructose-1,6-bisphosphate; DHAP, dihydroxyacetone phosphate; GADP, glyceraldehyde-3-phosphate; 1,3BPG, 1,3-bisphosphoglycerate; 3PG, 3-phosphoglycerate; 2PG, 2-phosphoglycerate; PEP, phosphoenolpyruvate; Pyr, pyruvate; Lac, lactate; Ac-CoA, acetyl-CoA; Ac-R, either acetate or acetyl-CoA; GlycP, glycerol-3-phosphate; Glyc, glycerol; Man6P, mannose-6-phosphate; Man1P, mannose-1-phosphate; GDP-Man, GDP-mannose; GlcN6P, glucosamine-6-phosphate; GlcNAc6P, N-acetyl-glucosamine-6-phosphate; GlcNAc1P, N-acetylglucosamine-1-phosphate; UDP-GlcNAc, UDP-N-acetyl-glucosamine; 6PGL, 6-phosphoglucono-δ-lactone; 6PGa, 6-phosphogluconate; Ru5P, ribulose-5-phosphate; R5P, ribose-5-phosphate; X5P, xylulose-5-phosphate; S7P, sedoheptulose-7-phosphate; E4P, erythrose-4-phosphate; Asp, aspartate; Gln, glutamine; Glu, glutamate; 2OG, 2-oxoglutarate; ICT, isocitrate; Cit, citrate; OAA, oxaloacetate; Mal, malate; Suc-CoA, succinyl-CoA; Suc, succinate; Fum, fumarate; GPI, glycophosphatidylinositol.