The proliferating cell hypothesis: a metabolic framework for Plasmodium growth and development

Salcedo-Sora, J. Enrique; Caamaño-Gutiérrez, Eva; Ward, Stephen A.; Biagini, Giancarlo A.

doi:10.1016/j.pt.2014.02.001

Cited by 56 publications

(53 citation statements)

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“…This is in line with previous studies [44] and pointed towards the rapid turnover of glycolytic end products in iRBC to downstream metabolites via the TCA cycle and/or intermediary carbon metabolism or for rapid biomass generation to help in proliferative schizogony [45]. Although pre-existing pools of glucose in the host cell can contribute to glycolysis in the parasite, the direct role of the host cell glycolytic pathway in development of intracellular parasites is unclear as the parasite glycolytic machinery is well established [46] and is supported by increased internalisation of glucose into the infected cell owing to expression of glucose transporters on the surface of the infected cell [32].…”

Section: Discussionsupporting

confidence: 92%

Stage-Specific Changes in Plasmodium Metabolism Required for Differentiation and Adaptation to Different Host and Vector Environments

et al. 2016

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Malaria parasites (Plasmodium spp.) encounter markedly different (nutritional) environments during their complex life cycles in the mosquito and human hosts. Adaptation to these different host niches is associated with a dramatic rewiring of metabolism, from a highly glycolytic metabolism in the asexual blood stages to increased dependence on tricarboxylic acid (TCA) metabolism in mosquito stages. Here we have used stable isotope labelling, targeted metabolomics and reverse genetics to map stage-specific changes in Plasmodium berghei carbon metabolism and determine the functional significance of these changes on parasite survival in the blood and mosquito stages. We show that glutamine serves as the predominant input into TCA metabolism in both asexual and sexual blood stages and is important for complete male gametogenesis. Glutamine catabolism, as well as key reactions in intermediary metabolism and CoA synthesis are also essential for ookinete to oocyst transition in the mosquito. These data extend our knowledge of Plasmodium metabolism and point towards possible targets for transmission-blocking intervention strategies. Furthermore, they highlight significant metabolic differences between Plasmodium species which are not easily anticipated based on genomics or transcriptomics studies and underline the importance of integration of metabolomics data with other platforms in order to better inform drug discovery and design.

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Section: Discussionsupporting

confidence: 92%

Stage-Specific Changes in Plasmodium Metabolism Required for Differentiation and Adaptation to Different Host and Vector Environments

et al. 2016

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“…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.…”

Section: Resultssupporting

confidence: 85%

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

Ismail

Barton

Phanchana

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The artemisinin (ART)-based antimalarials have contributed significantly to reducing global malaria deaths over the past decade, but we still do not know how they kill parasites. To gain greater insight into the potential mechanisms of ART drug action, we developed a suite of ART activity-based protein profiling probes to identify parasite protein drug targets in situ. Probes were designed to retain biological activity and alkylate the molecular target(s) of Plasmodium falciparum 3D7 parasites in situ. Proteins tagged with the ART probe can then be isolated using click chemistry before identification by liquid chromatography-MS/MS. Using these probes, we define an ART proteome that shows alkylated targets in the glycolytic, hemoglobin degradation, antioxidant defense, and protein synthesis pathways, processes essential for parasite survival. This work reveals the pleiotropic nature of the biological functions targeted by this important class of antimalarial drugs.

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“…In a manner analogous to the Warburg effect observed in highly-proliferative cancer lines and other rapidly-growing cells (e.g., yeast and bloodstream Trypanosoma spp. ), Plasmodium (in erythrocytic stages) has opted for fast generation of ATP through substrate-level phosphorylation and secretion of lactate as an end-product (aerobic fermentative glycolysis), as opposed to the 'slow but efficient' mitochondrial oxidative phosphorylation and complete oxidation [29]. Reasons for this dependence on glycolytic fermentation remain unclear -after all, blood stages of Plasmodium certainly have access to oxygen -but it may be a way of avoiding excessive reactive oxygen species (ROS) production in an environment already under considerable stress due to hemoglobin breakdown [30,31].…”

mentioning

confidence: 99%

Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

Jacot

Waller

Soldati‐Favre

et al. 2016

Trends in Parasitology

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Pages 15apicomplexan 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]. Furthermore, the pyruvate dehydrogenase complex (PDH) responsible for conversion of pyruvate into acetyl-CoA -an obligate fuel for the TCA cycle -is only present in the apicoplast [10]. Consequently, there was no obvious entry point to allow catalysis of glycolytic pyruvate by the TCA cycle [10][11][12][13][14]. Despite this, there is overwhelming evidence that apicomplexans rely on a functional and canonical TCA cycle (as reviewed [4,5,15]), and apicomplexan genome annotations indicate the presence of all enzymes of the TCA cycle. Only one clade of apicomplexans, Cryptosporidium spp., show evidence of outright loss of the TCA cycle, but these taxa retain only a highly reduced mitochondrion, the mitosome, and have also lost their apicoplast [5,8,16].This review highlights how metabolomics technologies coupled to genetic manipulation have helped in unraveling apicomplexan parasite plasticity in carbon source utilization through different life stages, revealing a complex and sometimes counter-intuitive pattern of metabolic gains, losses, and reassignments. These changes have presumably been tailored to allow these parasites to thrive within their various host niches, but may constitute some much-needed Achilles' heels in the fight against these devastating diseases. Plasmodium falciparum and the Glycolytic DeceitGlycolysis has long appeared to be the main source of ATP and NAD(P)H in the erythrocytic stages of the malaria parasites, [5,[17][18][19][20][21]. Indeed, glucose uptake in P. falciparum-infected red blood cells (RBCs) has been observed to increase 75-100-fold compared to uninfected RBC [22][23][24][25]. Up to 93% of glucose is converted directly to lactate in asexual stages [26][ 4 _ T D $ D I F F ] and is ultimately excreted into the surrounding host cell. Perturbation of glucose uptake is detrimental to parasite growth [27,28], suggesting that glycolysis is an important part of the parasite's strategy for rapid proliferation. In a manner analogous to the Warburg effect observed in highly-proliferative cancer lines and other rapidly-growing cells (e.g., yeast and bloodstream Trypanosoma spp.), Plasmodium (in erythrocytic stages) has opted for fast generation of ATP through substrate-level phosphorylation and secretion of lactate as an end-product (aerobic fermentative glycolysis), as opposed to the 'slow but efficient' mitochondrial oxidative phosphorylation and complete oxidation [29]. Reasons for this dependence on glycolytic fermentation remain unclear -after all, blood stages of Plasmodium certainly have access to oxygen -but it may be a way of avoiding excessiv...

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The proliferating cell hypothesis: a metabolic framework for Plasmodium growth and development

Abstract: HighlightsThe hypothesis offers a framework to explain the atypical features of parasite metabolism.Aerobic glycolysis is hypothesised to meet the biosynthetic demands of rapid proliferation.Differentiation may be epigenetically regulated in response to nutrient-linked metabolism.

Cited by 56 publications

References 50 publications

Stage-Specific Changes in Plasmodium Metabolism Required for Differentiation and Adaptation to Different Host and Vector Environments

Stage-Specific Changes in Plasmodium Metabolism Required for Differentiation and Adaptation to Different Host and Vector Environments

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

Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

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