Journal article
Branched tricarboxylic acid metabolism in Plasmodium falciparum
Nature, v 466(7307), pp 774-778
05 Aug 2010
PMID: 20686576
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
A central hub of carbon metabolism is the tricarboxylic acid cycle, 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.
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Details
- Title
- Branched tricarboxylic acid metabolism in Plasmodium falciparum
- Creators
- Manuel Llinás - Department of Molecular Biology and Lewis-Sigler Institute for Integrative Genomics, Princeton UniversityJoshua D Rabinowitz - Department of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Princeton UniversityMichael W Mather - Center for Molecular Parasitology, Drexel University College of MedicineJoanne M Morrisey - Center for Molecular Parasitology, Drexel University College of MedicineAkhil B Vaidya - Center for Molecular Parasitology, Drexel University College of MedicineBenjamin A Garcia - Department of Molecular Biology, Princeton UniversityKellen L Olszewski - Department of Molecular Biology and Lewis-Sigler Institute for Integrative Genomics, Princeton University
- Publication Details
- Nature, v 466(7307), pp 774-778
- Publisher
- Springer Nature
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000286385600060
- Scopus ID
- 2-s2.0-79955660777
- Other Identifier
- 991014877683704721
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- Web of Science research areas
- Biochemistry & Molecular Biology