A profile of the joint Toxoplasma-host infection metabolome finds broad changes to metabolism and discovers a novel parasite metabolic capability

ABSTRACT: The obligate intracellular parasite Toxoplasma gondii is auxotrophic for several key metabolites and must scavenge these, and carbon sources like glucose. from the host. While the importance of metabolism to Toxoplasma infection it obvious, it is unclear how Toxoplasma infection actually changes metabolism. To address this question, we measured changes in the joint host-parasite metabolome over a time course of infection. Host and parasite transcriptomes were simultaneously generated to measure changes in expression of metabolic enzymes that might correlate with changes in metabolite abundance. Toxoplasma infection changed metabolite abundance in multiple pathways, including the tricarboxylic acid cycle, the pentose phosphate pathway, glycolysis, amino acid synthesis, and nucleotide metabolism. Our analysis indicated that changes in some pathways, such as the tricarboxylic acid cycle, were mirrored by changes in parasite transcription, while changes in others, like the pentose phosphate pathway, were paired with changes in both the host and parasite transcriptomes. Further experiments led to the discovery of a Toxoplasma enzyme, sedoheptulose bisphosphatase, which funnels carbon into the pentose phosphate pathway through an energetically driven dephosphorylation reaction. This second route for ribose synthesis resolves a possible conflict between the Toxoplasma tricarboxylic acid cycle and pentose phosphate pathway, which are both NADP+ dependent. During periods of high energetic and ribose need, the competition for NADP+ could result in lethal redox imbalances. Sedoheptulose bisphosphatase represents a novel step in Toxoplasma central carbon metabolism that allows Toxoplasma to satisfy its ribose demand without using NADP+. Sedoheptulose bisphosphatase is not present in humans, highlighting its potential as a drug target.

INSTRUMENT(S): Hybrid Quadrupole-Orbitrap high resolution mass spectrometer (Q Exactive Orbitrap; Thermo Scientific)

PROVIDER: MTBLS899 | MetaboLights | 2019-05-10

REPOSITORIES: MetaboLights