Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 46, Pages 17718-17723Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0806664105
Keywords
glycosome; PEX14; regulation of glycolysis; systems biology; Trypanosoma brucei
Categories
Funding
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek-vernieuwingsimpuls
- National Institutes of Health [R01 A122635]
- Fonds de la Recherche Scientifique medicale [2.4652.06]
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Biotechnology and Biological Sciences Research Council
- European Union-Framework Programme 7-Biosym
- Nucsys
- Biotechnology and Biological Sciences Research Council [BB/C008219/1] Funding Source: researchfish
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ATP generation by both glycolysis and glycerol catabolism is autocatalytic, because the first kinases of these pathways are fuelled by ATP produced downstream. Previous modeling studies predicted that either feedback inhibition or compartmentation of glycolysis can protect cells from accumulation of intermediates. The deadly parasite Trypanosoma brucei lacks feedback regulation of early steps in glycolysis yet sequesters the relevant enzymes within organelles called glycosomes, leading to the proposal that compartmentation prevents toxic accumulation of intermediates. Here, we show that glucose 6-phosphate indeed accumulates upon glucose addition to PEX14 deficient trypanosomes, which are impaired in glycosomal protein import. With glycerol catabolism, both in silico and in vivo, loss of glycosomal compartmentation led to dramatic increases of glycerol 3-phosphate upon addition of glycerol. As predicted by the model, depletion of glycerol kinase rescued PEX14-deficient cells of glycerol toxicity. This provides the first experimental support for our hypothesis that pathway compartmentation is an alternative to allosteric regulation.
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