Probing the metabolic network in bloodstream-form Trypanosoma brucei using untargeted metabolomics with stable isotope labelled glucose
Creek, Darren J. and Mazet, Muriel and Achcar, Fiona and Anderson, Jana and Kim, Dong Hyun and Kamour, Ruwida and Morand, Pauline and Millerioux, Yoann and Biran, Marc and Kerkhoven, Eduard J. and Chokkathukalam, Achuthanunni and Weidt, Stefan K. and Burgess, Karl E. V. and Breitling, Rainer and Watson, David G. and Bringaud, Frédéric and Barrett, Michael P. (2015) Probing the metabolic network in bloodstream-form Trypanosoma brucei using untargeted metabolomics with stable isotope labelled glucose. PLOS Pathogens, 11 (3). e1004689. ISSN 1553-7366 (https://doi.org/10.1371/journal.ppat.1004689)
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Abstract
Metabolomics coupled with heavy-atom isotope-labelled glucose has been used to probe the metabolic pathways active in cultured bloodstream form trypomastigotes of Trypanosoma brucei, a parasite responsible for human African trypanosomiasis. Glucose enters many branches of metabolism beyond glycolysis, which has been widely held to be the sole route of glucose metabolism. Whilst pyruvate is the major end-product of glucose catabolism, its transamination product, alanine, is also produced in significant quantities. The oxidative branch of the pentose phosphate pathway is operative, although the non-oxidative branch is not. Ribose 5-phosphate generated through this pathway distributes widely into nucleotide synthesis and other branches of metabolism. Acetate, derived from glucose, is found associated with a range of acetylated amino acids and, to a lesser extent, fatty acids; while labelled glycerol is found in many glycerophospholipids. Glucose also enters inositol and several sugar nucleotides that serve as precursors to macromolecule biosynthesis. Although a Krebs cycle is not operative, malate, fumarate and succinate, primarily labelled in three carbons, were present, indicating an origin from phosphoenolpyruvate via oxaloacetate. Interestingly, the enzyme responsible for conversion of phosphoenolpyruvate to oxaloacetate, phosphoenolpyruvate carboxykinase, was shown to be essential to the bloodstream form trypanosomes, as demonstrated by the lethal phenotype induced by RNAi-mediated downregulation of its expression. In addition, glucose derivatives enter pyrimidine biosynthesis via oxaloacetate as a precursor to aspartate and orotate.
ORCID iDs
Creek, Darren J., Mazet, Muriel, Achcar, Fiona, Anderson, Jana, Kim, Dong Hyun, Kamour, Ruwida, Morand, Pauline, Millerioux, Yoann, Biran, Marc, Kerkhoven, Eduard J., Chokkathukalam, Achuthanunni, Weidt, Stefan K., Burgess, Karl E. V., Breitling, Rainer, Watson, David G. ORCID: https://orcid.org/0000-0003-1094-7604, Bringaud, Frédéric and Barrett, Michael P.;-
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Item type: Article ID code: 54801 Dates: DateEvent16 March 2015Published19 January 2015AcceptedSubjects: Medicine > Pharmacy and materia medica Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
University of Strathclyde > University of StrathclydeDepositing user: Pure Administrator Date deposited: 11 Dec 2015 01:39 Last modified: 12 Dec 2024 03:41 Related URLs: URI: https://strathprints.strath.ac.uk/id/eprint/54801