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Mapping the metabolism of five amino acids in bloodstream form Trypanosoma brucei using U-13C-labelled substrates and LC–MS

ABSTRACT: The metabolism of the parasite Trypanosoma brucei has been the focus of numerous studies since the 1940s. Recently it was shown, using metabolomics coupled with heavy-atom isotope labelled glucose, that the metabolism of the bloodstream form parasite is more complex than previously thought. The present study also raised a number of questions regarding the origin of several metabolites, for example succinate, only a proportion of which derives from glucose. In order to answer some of these questions and explore the metabolism of bloodstream form T. brucei in more depth we followed the fate of five heavy labelled amino acids – glutamine, proline, methionine, cysteine and arginine – using an LC–MS based metabolomics approach. We found that some of these amino acids have roles beyond those previously thought and we have tentatively identified some unexpected metabolites which need to be confirmed and their function determined.

INSTRUMENT(S): Exactive (Thermo Scientific)

SUBMITTER: Fiona Achcar

PROVIDER: MTBLS624 | MetaboLights | 2019-06-24

REPOSITORIES: MetaboLights

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Mapping the metabolism of five amino acids in bloodstream form Trypanosoma brucei using U-13C-labelled substrates and LC-MS.

Johnston Katharina K Kim Dong-Hyun DH Kerkhoven Eduard J EJ Burchmore Richard R Barrett Michael P MP Achcar Fiona F

Bioscience reports 20190517 5

The metabolism of the parasite Trypanosoma brucei has been the focus of numerous studies since the 1940s. Recently it was shown, using metabolomics coupled with heavy-atom isotope labelled glucose, that the metabolism of the bloodstream form parasite is more complex than previously thought. The present study also raised a number of questions regarding the origin of several metabolites, for example succinate, only a proportion of which derives from glucose. In order to answer some of these ...[more]

PMID: 31028136

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Project description:Animal African Trypanosomiasis (AAT) is a debilitating livestock disease prevalent across sub-Saharan Africa, a main cause of which is the protozoan parasite Trypanosoma congolense. In comparison to the well-studied T. brucei, there is a major paucity of knowledge regarding the biology of T. congolense. Here, we use a combination of omics technologies and novel genetic tools to characterise core metabolism in T. congolense mammalian-infective bloodstream-form parasites, and test whether metabolic differences compared to T. brucei impact upon sensitivity to metabolic inhibition. Like the bloodstream stage of T. brucei, glycolysis plays a major part in T. congolense energy metabolism. However, the rate of glucose uptake is significantly lower in bloodstream stage T. congolense, with cells remaining viable when cultured in concentrations as low as 2 mM. Instead of pyruvate, the primary glycolytic endpoints are succinate, malate and acetate. Transcriptomics analysis showed higher levels of transcripts associated with the mitochondrial pyruvate dehydrogenase complex, acetate generation, and the glycosomal succinate shunt in T. congolense, compared to T. brucei. Stable-isotope labelling of glucose enabled the comparison of carbon usage between T. brucei and T. congolense, highlighting differences in nucleotide and saturated fatty acid metabolism. To validate the metabolic similarities and differences, both species were treated with metabolic inhibitors, confirming that electron transport chain activity is not essential in T. congolense. However, the parasite exhibits increased sensitivity to inhibition of mitochondrial pyruvate import, compared to T. brucei. Strikingly, T. congolense exhibited significant resistance to inhibitors of fatty acid synthesis, including a 780-fold higher EC50 for the lipase and fatty acid synthase inhibitor Orlistat, compared to T. brucei. These data highlight that bloodstream form T. congolense diverges from T. brucei in key areas of metabolism, with several features that are intermediate between bloodstream- and insect-stage T. brucei. These results have implications for drug development, mechanisms of drug resistance and host-pathogen interactions.

			Action	DRS
	MTBLS624	Other
	FILES	Other
	a_MTBLS624_NEG_arg_RNAi_MS.txt	Txt
	a_MTBLS624_NEG_label_MS.txt	Txt
	a_MTBLS624_POS_arg_RNAi_MS.txt	Txt

Dataset Information

Mapping the metabolism of five amino acids in bloodstream form Trypanosoma brucei using U-13C-labelled substrates and LC–MS

Dataset's files

Publications

Mapping the metabolism of five amino acids in bloodstream form <i>Trypanosoma brucei</i> using U-<sup>13</sup>C-labelled substrates and LC-MS.

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