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J Biol Chem. 2013 Dec 20;288(51):36338-50. doi: 10.1074/jbc.M113.503557. Epub 2013 Oct 25.

Kinetic flux profiling elucidates two independent acetyl-CoA biosynthetic pathways in Plasmodium falciparum.

Author information

1
From the Department of Biochemistry and Molecular Biology and Center for Infectious Disease Dynamics, Pennsylvania State University, State College, Pennsylvania 16802.

Abstract

The malaria parasite Plasmodium falciparum depends on glucose to meet its energy requirements during blood-stage development. Although glycolysis is one of the best understood pathways in the parasite, it is unclear if glucose metabolism appreciably contributes to the acetyl-CoA pools required for tricarboxylic acid metabolism (TCA) cycle and fatty acid biosynthesis. P. falciparum possesses a pyruvate dehydrogenase (PDH) complex that is localized to the apicoplast, a specialized quadruple membrane organelle, suggesting that separate acetyl-CoA pools are likely. Herein, we analyze PDH-deficient parasites using rapid stable-isotope labeling and show that PDH does not appreciably contribute to acetyl-CoA synthesis, tricarboxylic acid metabolism, or fatty acid synthesis in blood stage parasites. Rather, we find that acetyl-CoA demands are supplied through a "PDH-like" enzyme and provide evidence that the branched-chain keto acid dehydrogenase (BCKDH) complex is performing this function. We also show that acetyl-CoA synthetase can be a significant contributor to acetyl-CoA biosynthesis. Interestingly, the PDH-like pathway contributes glucose-derived acetyl-CoA to the TCA cycle in a stage-independent process, whereas anapleurotic carbon enters the TCA cycle via a stage-dependent phosphoenolpyruvate carboxylase/phosphoenolpyruvate carboxykinase process that decreases as the parasite matures. Although PDH-deficient parasites have no blood-stage growth defect, they are unable to progress beyond the oocyst phase of the parasite mosquito stage.

KEYWORDS:

Acetate; Acetyl Coenzyme A; Glycolysis; Malaria; Phosphoenolpyruvate Carboxykinase; Plasmodium; Pyruvate Dehydrogenase Complex; Tricarboxylic Acid (TCA) Cycle

PMID:
24163372
PMCID:
PMC3868748
DOI:
10.1074/jbc.M113.503557
[Indexed for MEDLINE]
Free PMC Article
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