Dataset Information

Pantothenate biosynthesis is critical for chronic infection by the neurotropic parasite Toxoplasma gondii

ABSTRACT: Coenzyme A (CoA) is an essential molecule acting in metabolism, post-translational modification, and regulation of gene expression. While all organisms synthesize CoA, many, including humans, are unable to produce its precursor, pantothenate. Intriguingly, like most plants, fungi and bacteria, parasites of the coccidian subgroup of Apicomplexa, including the human pathogen Toxoplasma gondii, possess all the enzymes required for de novo synthesis of pantothenate. Here, the importance of CoA and pantothenate biosynthesis for the acute and chronic stages of T. gondii infection is dissected through genetic, biochemical and metabolomic approaches, revealing that CoA synthesis is essential for T. gondii tachyzoites, due to the parasite's inability to salvage CoA or intermediates of the pathway. In contrast, pantothenate synthesis is only partially active in T. gondii tachyzoites, making the parasite reliant on its uptake. However, pantothenate synthesis is crucial for the establishment of chronic infection, offering a promising target for intervention against the persistent stage of T. gondii.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Gas Chromatography MS - positive, Liquid Chromatography MS - negative - hilic

SUBMITTER: Joachim Kloehn

PROVIDER: MTBLS2501 | MetaboLights | 2022-03-21

REPOSITORIES: MetaboLights

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Pantothenate biosynthesis is critical for chronic infection by the neurotropic parasite Toxoplasma gondii.

Lunghi Matteo M Kloehn Joachim J Krishnan Aarti A Varesio Emmanuel E Vadas Oscar O Soldati-Favre Dominique D

Nature communications 20220117 1

Coenzyme A (CoA) is an essential molecule acting in metabolism, post-translational modification, and regulation of gene expression. While all organisms synthesize CoA, many, including humans, are unable to produce its precursor, pantothenate. Intriguingly, like most plants, fungi and bacteria, parasites of the coccidian subgroup of Apicomplexa, including the human pathogen Toxoplasma gondii, possess all the enzymes required for de novo synthesis of pantothenate. Here, the importance of CoA and p ...[more]

PMID: 35039477

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Project description:Tymoshenko2015 - Genome scale metabolic model - ToxoNet1 This model is described in the article: Metabolic Needs and Capabilities of Toxoplasma gondii through Combined Computational and Experimental Analysis. Tymoshenko S, Oppenheim RD, Agren R, Nielsen J, Soldati-Favre D, Hatzimanikatis V. PLoS Comput. Biol. 2015 May; 11(5): e1004261 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 its minimal nutritional requirements for replication. By probing the model via metabolic tasks, we have further defined sets of alternative precursors necessary for parasite growth. Within a human host cell environment, ToxoNet1 predicts a minimal set of 53 enzyme-coding genes and 76 reactions to be essential for parasite replication. Double-gene-essentiality analysis identified 20 pairs of genes for which simultaneous deletion is deleterious. To validate several predictions of ToxoNet1 we have performed experimental analyses of cytosolic acetyl-CoA biosynthesis. ATP-citrate lyase and acetyl-CoA synthase were localised and their corresponding genes disrupted, establishing that each of these enzymes is dispensable for the growth of T. gondii, however together they make a synthetic lethal pair. This model is hosted on BioModels Database and identified by: MODEL1504280000. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Dataset Information

Pantothenate biosynthesis is critical for chronic infection by the neurotropic parasite Toxoplasma gondii

Publications

Pantothenate biosynthesis is critical for chronic infection by the neurotropic parasite Toxoplasma gondii.

Similar Datasets

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