Branched tricarboxylic acid metabolism in Plasmodium falciparum

Kellen L. Olszewski, Michael W. Mather, Joanne M. Morrisey, Benjamin A. Garcia, Akhil B. Vaidya, Joshua D. Rabinowitz, Manuel Llinás

Research output: Contribution to journalArticle

97 Citations (Scopus)

Abstract

A central hub of carbon metabolism is the tricarboxylic acid cycle 1, 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 role. Blood-stage Plasmodium parasites rely almost entirely on glucose fermentation for energy and consume minimal amounts of oxygen, yet the parasite genome encodes all of the enzymes necessary for a complete tricarboxylic acid cycle. Here, by tracing 13C-labelled compounds using mass spectrometry 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.

Original languageEnglish (US)
Pages (from-to)774-778
Number of pages5
JournalNature
Volume466
Issue number7307
DOIs
StatePublished - Aug 5 2010

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Tricarboxylic Acids
Plasmodium falciparum
Acetyl Coenzyme A
Parasites
Carbon
Citric Acid Cycle
Plasmodium
Glycolysis
Metabolic Networks and Pathways
Glutamine
Plasmodium malariae
Amino Sugars
Amino Acids
Glucose
Gluconeogenesis
Textbooks
Falciparum Malaria
Biosynthetic Pathways
Acetylation
Histones

All Science Journal Classification (ASJC) codes

  • General

Cite this

Olszewski, K. L., Mather, M. W., Morrisey, J. M., Garcia, B. A., Vaidya, A. B., Rabinowitz, J. D., & Llinás, M. (2010). Branched tricarboxylic acid metabolism in Plasmodium falciparum. Nature, 466(7307), 774-778. https://doi.org/10.1038/nature09301
Olszewski, Kellen L. ; Mather, Michael W. ; Morrisey, Joanne M. ; Garcia, Benjamin A. ; Vaidya, Akhil B. ; Rabinowitz, Joshua D. ; Llinás, Manuel. / Branched tricarboxylic acid metabolism in Plasmodium falciparum. In: Nature. 2010 ; Vol. 466, No. 7307. pp. 774-778.
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Olszewski, KL, Mather, MW, Morrisey, JM, Garcia, BA, Vaidya, AB, Rabinowitz, JD & Llinás, M 2010, 'Branched tricarboxylic acid metabolism in Plasmodium falciparum', Nature, vol. 466, no. 7307, pp. 774-778. https://doi.org/10.1038/nature09301

Branched tricarboxylic acid metabolism in Plasmodium falciparum. / Olszewski, Kellen L.; Mather, Michael W.; Morrisey, Joanne M.; Garcia, Benjamin A.; Vaidya, Akhil B.; Rabinowitz, Joshua D.; Llinás, Manuel.

In: Nature, Vol. 466, No. 7307, 05.08.2010, p. 774-778.

Research output: Contribution to journalArticle

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Olszewski KL, Mather MW, Morrisey JM, Garcia BA, Vaidya AB, Rabinowitz JD et al. Branched tricarboxylic acid metabolism in Plasmodium falciparum. Nature. 2010 Aug 5;466(7307):774-778. https://doi.org/10.1038/nature09301