2015
DOI: 10.1371/journal.pcbi.1004261
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Metabolic Needs and Capabilities of Toxoplasma gondii through Combined Computational and Experimental Analysis

Abstract: Toxoplasma gondii is a human pathogen prevalent worldwide that poses a challenging and unmet need for novel treatment of toxoplasmosis. Using a semi-automated reconstruction algorithm, we reconstructed a genome-scale metabolic model, ToxoNet1. The reconstruction process and flux-balance analysis of the model offer a systematic overview of the metabolic capabilities of this parasite. Using ToxoNet1 we have identified significant gaps in the current knowledge of Toxoplasma metabolic pathways and have clarified i… Show more

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Cited by 96 publications
(140 citation statements)
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“…For example, based on recent findings [25], the pyruvate dehydrogenase activity of the mitochondrial BCKDH complex was included in iPfa, whereas it was absent in the previous GEMs of the malaria parasite, iTH366 [5], PlasmoNet [6] and their modifications [7, 8] (see S1 Methods for more details). The coverage of metabolic enzymes (Fig 1A) is consistent with the ones reported in iTH366 and in the model of the related apicomplexan parasite Toxoplasma gondii , ToxoNet1 [3]. In contrast to the earlier GEMs of P .…”
Section: Resultssupporting
confidence: 87%
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“…For example, based on recent findings [25], the pyruvate dehydrogenase activity of the mitochondrial BCKDH complex was included in iPfa, whereas it was absent in the previous GEMs of the malaria parasite, iTH366 [5], PlasmoNet [6] and their modifications [7, 8] (see S1 Methods for more details). The coverage of metabolic enzymes (Fig 1A) is consistent with the ones reported in iTH366 and in the model of the related apicomplexan parasite Toxoplasma gondii , ToxoNet1 [3]. In contrast to the earlier GEMs of P .…”
Section: Resultssupporting
confidence: 87%
“…Orphan reactions in iPfa render feasible 24 of the 73 total metabolic tasks. Metabolic tasks are defined here as the production of biomass building blocks [3, 24]. The identified orphan reactions and alternatives might serve as a reference for further biochemical characterization of non-annotated genes in Plasmodium species (S1 Table).…”
Section: Resultsmentioning
confidence: 99%
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“…In T. gondii, acetyl-CoA for fatty acid synthesis can be derived via multiple sources, including pyruvate dehydrogenase located in the apicoplast (3), branched-chain ␣-keto acid dehydrogenase in the mitochondrion (8), and ATP-citrate lyase and acetylCoA synthetase in the cytosol ((36), this work). The latter two proteins are genetically redundant and synthetically lethal for the parasite (36), and therefore appear to be functionally redundant with each other. Although the role of citrate for fatty acid synthesis remains to be explored, acetate is efficiently utilized by elongase (and FAS1?)…”
Section: Discussionmentioning
confidence: 99%
“…Indeed, computational and experimental studies show that T. gondii ACL is essential when accompanied by deletion of the other source of cytosolic acetyl-CoA, acetyl-CoA synthase (ACS) [83]. It follows that reduced levels of mitochondrial [BCKDH E1/ knockout (KO)] or cytoplasmic (ACL-ACS double KO) acetyl-CoA may have implications for the activities and balance of fatty acid biosynthesis and/or acetylation [84][85][86][87][88].…”
Section: Mitochondrial Metabolism Across the Alveolatamentioning
confidence: 99%