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Branched tricarboxylic acid metabolism in Plasmodium falciparum

A Retraction to this article was published on 24 April 2013

A Corrigendum to this article was published on 19 January 2011

Abstract

A central hub of carbon metabolism is the tricarboxylic acid cycle1, which serves to connect the processes of glycolysis, gluconeogenesis, respiration, amino acid synthesis and other biosynthetic pathways. The protozoan intracellular malaria parasites (Plasmodium spp.), however, have long been suspected of possessing a significantly streamlined carbon metabolic network in which tricarboxylic acid metabolism plays a minor role2. Blood-stage Plasmodium parasites rely almost entirely on glucose fermentation for energy and consume minimal amounts of oxygen3, yet the parasite genome encodes all of the enzymes necessary for a complete tricarboxylic acid cycle4. Here, by tracing 13C-labelled compounds using mass spectrometry5 we show that tricarboxylic acid metabolism in the human malaria parasite Plasmodium falciparum is largely disconnected from glycolysis and is organized along a fundamentally different architecture from the canonical textbook pathway. We find that this pathway is not cyclic, but rather is a branched structure in which the major carbon sources are the amino acids glutamate and glutamine. As a consequence of this branched architecture, several reactions must run in the reverse of the standard direction, thereby generating two-carbon units in the form of acetyl-coenzyme A. We further show that glutamine-derived acetyl-coenzyme A is used for histone acetylation, whereas glucose-derived acetyl-coenzyme A is used to acetylate amino sugars. Thus, the parasite has evolved two independent production mechanisms for acetyl-coenzyme A with different biological functions. These results significantly clarify our understanding of the Plasmodium metabolic network and highlight the ability of altered variants of central carbon metabolism to arise in response to unique environments.

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Figure 1: Glutamine drives reverse flux through the TCA cycle.
Figure 2: Acetyl groups deriving from glucose and glutamine are functionally distinct.
Figure 3: Malate excretion by P. falciparum -infected red blood cell cultures.
Figure 4: An integrated model for central carbon metabolism in P. falciparum.

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Acknowledgements

We thank G. McFadden and I. Sherman for discussions and scrutiny of the manuscript; B. Bennett, T. Campbell, E. De Silva, J. O’Hara, and H. Painter for reading of the manuscript; I. Ying for assistance with histone extraction; T. Spurck and C. Tonkin for the modified erythrocyte immobilization procedure for microscopy; M. Clasquin and W. Lu for developing the LC–MS methodology; E. Melamud for LC–MS data extraction and analysis; and J. Groves and H. Cooper for GC–MS analysis. M.L. is funded by the Burroughs Wellcome Fund and an NIH Director’s New Innovators award (1DP2OD001315-01). J.D.R. is funded by a Beckman Young Investigators award, an NSF CAREER award and NIH R01 AI078063. M.L and J.D.R. receive support from the Center for Quantitative Biology (P50 GM071508). B.A.G. receives support from NSF grant CBET-0941143. K.L.O. is funded by an NSF Graduate Research Fellowship. J.M.M., M.W.M. and A.B.V. are supported by grant AI028398 from NIAID, NIH.

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Contributions

K.L.O. cultured the parasites, and collected and analysed all LC–MS and GC–MS data; B.A.G. performed mass spectrometric analysis of histones. M.W.M. and J.M.M. carried out IDH localization studies. M.W.M. purified mitochondria and K.L.O. did biochemical assays. K.L.O., M.L., J.D.R., M.W.M., A.B.V. and B.A.G. designed the study; J.D.R. provided the metabolomic technology. M.L. and K.L.O. wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Manuel Llinás.

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The authors declare no competing financial interests.

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This file contains Supplementary Figures 1-8 with legends, a Supplementary Discussion and References. Supplementary Fig. 3 was corrected on 20 January 2011. (PDF 4015 kb)

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Olszewski, K., Mather, M., Morrisey, J. et al. Branched tricarboxylic acid metabolism in Plasmodium falciparum. Nature 466, 774–778 (2010). https://doi.org/10.1038/nature09301

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