Functional genomics of Plasmodium falciparum using metabolic modelling and analysis

Tymoshenko, Stepan; Oppenheim, Rebecca; Soldati‐Favre, Dominique; Hatzimanikatis, Vassily

doi:10.1093/bfgp/elt017

Cited by 17 publications

(10 citation statements)

References 83 publications

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“…Several P. falciparum reconstructions have been generated since the publication of iTH366, including those highlighting unique developmental stages within the blood-stage asexual cycle by integrating stage-specific expression [ 70 ], de novo reconstructions to implement novel modeling approaches [ 71 ], integrated host and pathogen networks [ 72 ], and those exploring the other life stages of the parasite [ 73 , 74 ]. iPfal17 represents the most comprehensive and validated metabolic reconstruction of the asexual blood-stage malaria parasite, P. falciparum , to date.…”

Section: Discussionmentioning

confidence: 99%

Novel Plasmodium falciparum metabolic network reconstruction identifies shifts associated with clinical antimalarial resistance

2017

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BackgroundMalaria remains a major public health burden and resistance has emerged to every antimalarial on the market, including the frontline drug, artemisinin. Our limited understanding of Plasmodium biology hinders the elucidation of resistance mechanisms. In this regard, systems biology approaches can facilitate the integration of existing experimental knowledge and further understanding of these mechanisms.ResultsHere, we developed a novel genome-scale metabolic network reconstruction, iPfal17, of the asexual blood-stage P. falciparum parasite to expand our understanding of metabolic changes that support resistance. We identified 11 metabolic tasks to evaluate iPfal17 performance. Flux balance analysis and simulation of gene knockouts and enzyme inhibition predict candidate drug targets unique to resistant parasites. Moreover, integration of clinical parasite transcriptomes into the iPfal17 reconstruction reveals patterns associated with antimalarial resistance. These results predict that artemisinin sensitive and resistant parasites differentially utilize scavenging and biosynthetic pathways for multiple essential metabolites, including folate and polyamines. Our findings are consistent with experimental literature, while generating novel hypotheses about artemisinin resistance and parasite biology. We detect evidence that resistant parasites maintain greater metabolic flexibility, perhaps representing an incomplete transition to the metabolic state most appropriate for nutrient-rich blood.ConclusionUsing this systems biology approach, we identify metabolic shifts that arise with or in support of the resistant phenotype. This perspective allows us to more productively analyze and interpret clinical expression data for the identification of candidate drug targets for the treatment of resistant parasites.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-3905-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Novel Plasmodium falciparum metabolic network reconstruction identifies shifts associated with clinical antimalarial resistance

2017

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“…For the predictions with TFA and metabolomics data integrated, an accuracy score of 59% is obtained based on the data available for P . falciparum in the literature (references reported in S2 Table and previous reviews [64]). Overall in the literature, we found information about the essential function of 71 genes out of the total 325 genes in iPfa.…”

Section: Methodsmentioning

confidence: 99%

Bioenergetics-based modeling of Plasmodium falciparum metabolism reveals its essential genes, nutritional requirements, and thermodynamic bottlenecks

et al. 2017

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Novel antimalarial therapies are urgently needed for the fight against drug-resistant parasites. The metabolism of malaria parasites in infected cells is an attractive source of drug targets but is rather complex. Computational methods can handle this complexity and allow integrative analyses of cell metabolism. In this study, we present a genome-scale metabolic model (iPfa) of the deadliest malaria parasite, Plasmodium falciparum, and its thermodynamics-based flux analysis (TFA). Using previous absolute concentration data of the intraerythrocytic parasite, we applied TFA to iPfa and predicted up to 63 essential genes and 26 essential pairs of genes. Of the 63 genes, 35 have been experimentally validated and reported in the literature, and 28 have not been experimentally tested and include previously hypothesized or novel predictions of essential metabolic capabilities. Without metabolomics data, four of the genes would have been incorrectly predicted to be non-essential. TFA also indicated that substrate channeling should exist in two metabolic pathways to ensure the thermodynamic feasibility of the flux. Finally, analysis of the metabolic capabilities of P. falciparum led to the identification of both the minimal nutritional requirements and the genes that can become indispensable upon substrate inaccessibility. This model provides novel insight into the metabolic needs and capabilities of the malaria parasite and highlights metabolites and pathways that should be measured and characterized to identify potential thermodynamic bottlenecks and substrate channeling. The hypotheses presented seek to guide experimental studies to facilitate a better understanding of the parasite metabolism and the identification of targets for more efficient intervention.

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“…The two previous metabolic reconstructions (13,15) identified several essential metabolic functions and differences within the clonal strains of T. gondii that display distinct virulence profiles. Within the apicomplexans, the most studied and comprehensive metabolic reconstructions were generated for P. falciparum and the rodent malaria parasite, Plasmodium berghei (14,16,31). Constant modeling efforts with the incorporation of physiological parameters, such as metabolomics and fluxomics, continue to expand our knowledge of the metabolic versatility of the apicomplexans.…”

mentioning

confidence: 99%

“…Constant modeling efforts with the incorporation of physiological parameters, such as metabolomics and fluxomics, continue to expand our knowledge of the metabolic versatility of the apicomplexans. Although challenging, future models should consider the kinetic properties of reactions, allowing the simulation of altered enzymatic activities in both the host and parasite (31). Ideally, as complementary constituents of an iterative process, both computational and experimental efforts will ultimately lead to the identification of potential drug targets, mechanisms of drug action and complex host-pathogen interactions.…”

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confidence: 99%

Vitamin and cofactor acquisition in apicomplexans: Synthesis versus salvage

Krishnan¹,

Kloehn²,

Lunghi³

et al. 2019

J. Biol. Chem.

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The Apicomplexa phylum comprises diverse parasitic organisms that have evolved from a free-living ancestor. These obligate intracellular parasites exhibit versatile metabolic capabilities reflecting their capacity to survive and grow in different hosts and varying niches. Determined by nutrient availability, they either use their biosynthesis machineries or largely depend on their host for metabolite acquisition. Because vitamins cannot be synthesized by the mammalian host, the enzymes required for their synthesis in apicomplexan parasites represent a large repertoire of potential therapeutic targets. Here, we review recent advances in metabolic reconstruction and functional studies coupled to metabolomics that unravel the interplay between biosynthesis and salvage of vitamins and cofactors in apicomplexans. A particular emphasis is placed on Toxoplasma gondii, during both its acute and latent stages of infection.

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Functional genomics of Plasmodium falciparum using metabolic modelling and analysis

Cited by 17 publications

References 83 publications

Novel Plasmodium falciparum metabolic network reconstruction identifies shifts associated with clinical antimalarial resistance

Novel Plasmodium falciparum metabolic network reconstruction identifies shifts associated with clinical antimalarial resistance

Bioenergetics-based modeling of Plasmodium falciparum metabolism reveals its essential genes, nutritional requirements, and thermodynamic bottlenecks

Vitamin and cofactor acquisition in apicomplexans: Synthesis versus salvage

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