The Metabolite Repair Enzyme Phosphoglycolate Phosphatase Regulates Central Carbon Metabolism and Fosmidomycin Sensitivity in Plasmodium falciparum
| العنوان: | The Metabolite Repair Enzyme Phosphoglycolate Phosphatase Regulates Central Carbon Metabolism and Fosmidomycin Sensitivity in Plasmodium falciparum |
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| المؤلفون: | Simon A. Cobbold, Phillip L. van der Peet, Spencer J. Williams, Matthew W. A. Dixon, Alan F. Cowman, Danushka S. Marapana, Leann Tilley, Mark B. Richardson, Malcolm J. McConville, Laure Dumont, Tony Triglia |
| المصدر: | mBio mBio, Vol 10, Iss 6, p e02060-19 (2019) mBio, Vol 10, Iss 6 (2019) |
| بيانات النشر: | American Society for Microbiology, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | parasitology, fosmidomycin, Metabolite, Plasmodium falciparum, Phosphatase, Drug Resistance, Pentose phosphate pathway, Microbiology, Host-Microbe Biology, Antimalarials, 03 medical and health sciences, chemistry.chemical_compound, Fosfomycin, Virology, pentose, medicine, Humans, Glycolysis, Malaria, Falciparum, 030304 developmental biology, 0303 health sciences, antimalarial, isoprenoid, Chemistry, 030302 biochemistry & molecular biology, Sugar Acids, Metabolism, glycolysis, metabolomics, QR1-502, Carbon, Phosphoric Monoester Hydrolases, Fosmidomycin, 3. Good health, Biochemistry, CRISPR, Lactates, metabolic regulation, metabolism, Flux (metabolism), Phosphoglycolate phosphatase, Research Article, medicine.drug |
| الوصف: | The malaria parasite has a voracious appetite, requiring large amounts of glucose and nutrients for its rapid growth and proliferation inside human red blood cells. The host cell is resource rich, but this is a double-edged sword; nutrient excess can lead to undesirable metabolic reactions and harmful by-products. Here, we demonstrate that the parasite possesses a metabolite repair enzyme (PGP) that suppresses harmful metabolic by-products (via substrate dephosphorylation) and allows the parasite to maintain central carbon metabolism. Loss of PGP leads to the accumulation of two damaged metabolites and causes a domino effect of metabolic dysregulation. Accumulation of one damaged metabolite inhibits an essential enzyme in the pentose phosphate pathway, leading to substrate accumulation and secondary inhibition of glycolysis. This work highlights how the parasite coordinates metabolic flux by eliminating harmful metabolic by-products to ensure rapid proliferation in its resource-rich niche. Members of the haloacid dehalogenase (HAD) family of metabolite phosphatases play an important role in regulating multiple pathways in Plasmodium falciparum central carbon metabolism. We show that the P. falciparum HAD protein, phosphoglycolate phosphatase (PGP), regulates glycolysis and pentose pathway flux in asexual blood stages via detoxifying the damaged metabolite 4-phosphoerythronate (4-PE). Disruption of the P. falciparum pgp gene caused accumulation of two previously uncharacterized metabolites, 2-phospholactate and 4-PE. 4-PE is a putative side product of the glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase, and its accumulation inhibits the pentose phosphate pathway enzyme, 6-phosphogluconate dehydrogenase (6-PGD). Inhibition of 6-PGD by 4-PE leads to an unexpected feedback response that includes increased flux into the pentose phosphate pathway as a result of partial inhibition of upper glycolysis, with concomitant increased sensitivity to antimalarials that target pathways downstream of glycolysis. These results highlight the role of metabolite detoxification in regulating central carbon metabolism and drug sensitivity of the malaria parasite. |
| تدمد: | 2150-7511 2161-2129 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::25fb1195daee95e6e0a577843cb8be1f https://doi.org/10.1128/mbio.02060-19 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....25fb1195daee95e6e0a577843cb8be1f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 21507511 21612129 |
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