The Metabolite Repair Enzyme Phosphoglycolate Phosphatase Regulates Central Carbon Metabolism and Fosmidomycin Sensitivity in <named-content content-type="genus-species">Plasmodium falciparum</named-content>

ABSTRACT 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 pe...

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Autores principales:	Laure Dumont, Mark B. Richardson, Phillip van der Peet, Danushka S. Marapana, Tony Triglia, Matthew W. A. Dixon, Alan F. Cowman, Spencer J. Williams, Leann Tilley, Malcolm J. McConville, Simon A. Cobbold
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	CRISPR Plasmodium falciparum antimalarial fosmidomycin glycolysis isoprenoid Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0ea2ed8c7c8b4525becb3004db1c6787
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spelling	oai:doaj.org-article:0ea2ed8c7c8b4525becb3004db1c67872021-11-15T15:54:47ZThe Metabolite Repair Enzyme Phosphoglycolate Phosphatase Regulates Central Carbon Metabolism and Fosmidomycin Sensitivity in <named-content content-type="genus-species">Plasmodium falciparum</named-content>10.1128/mBio.02060-192150-7511https://doaj.org/article/0ea2ed8c7c8b4525becb3004db1c67872019-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02060-19https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE 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.Laure DumontMark B. RichardsonPhillip van der PeetDanushka S. MarapanaTony TrigliaMatthew W. A. DixonAlan F. CowmanSpencer J. WilliamsLeann TilleyMalcolm J. McConvilleSimon A. CobboldAmerican Society for MicrobiologyarticleCRISPRPlasmodium falciparumantimalarialfosmidomycinglycolysisisoprenoidMicrobiologyQR1-502ENmBio, Vol 10, Iss 6 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	CRISPR Plasmodium falciparum antimalarial fosmidomycin glycolysis isoprenoid Microbiology QR1-502
spellingShingle	CRISPR Plasmodium falciparum antimalarial fosmidomycin glycolysis isoprenoid Microbiology QR1-502 Laure Dumont Mark B. Richardson Phillip van der Peet Danushka S. Marapana Tony Triglia Matthew W. A. Dixon Alan F. Cowman Spencer J. Williams Leann Tilley Malcolm J. McConville Simon A. Cobbold The Metabolite Repair Enzyme Phosphoglycolate Phosphatase Regulates Central Carbon Metabolism and Fosmidomycin Sensitivity in <named-content content-type="genus-species">Plasmodium falciparum</named-content>
description	ABSTRACT 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. IMPORTANCE 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.
format	article
author	Laure Dumont Mark B. Richardson Phillip van der Peet Danushka S. Marapana Tony Triglia Matthew W. A. Dixon Alan F. Cowman Spencer J. Williams Leann Tilley Malcolm J. McConville Simon A. Cobbold
author_facet	Laure Dumont Mark B. Richardson Phillip van der Peet Danushka S. Marapana Tony Triglia Matthew W. A. Dixon Alan F. Cowman Spencer J. Williams Leann Tilley Malcolm J. McConville Simon A. Cobbold
author_sort	Laure Dumont
title	The Metabolite Repair Enzyme Phosphoglycolate Phosphatase Regulates Central Carbon Metabolism and Fosmidomycin Sensitivity in <named-content content-type="genus-species">Plasmodium falciparum</named-content>
title_short	The Metabolite Repair Enzyme Phosphoglycolate Phosphatase Regulates Central Carbon Metabolism and Fosmidomycin Sensitivity in <named-content content-type="genus-species">Plasmodium falciparum</named-content>
title_full	The Metabolite Repair Enzyme Phosphoglycolate Phosphatase Regulates Central Carbon Metabolism and Fosmidomycin Sensitivity in <named-content content-type="genus-species">Plasmodium falciparum</named-content>
title_fullStr	The Metabolite Repair Enzyme Phosphoglycolate Phosphatase Regulates Central Carbon Metabolism and Fosmidomycin Sensitivity in <named-content content-type="genus-species">Plasmodium falciparum</named-content>
title_full_unstemmed	The Metabolite Repair Enzyme Phosphoglycolate Phosphatase Regulates Central Carbon Metabolism and Fosmidomycin Sensitivity in <named-content content-type="genus-species">Plasmodium falciparum</named-content>
title_sort	metabolite repair enzyme phosphoglycolate phosphatase regulates central carbon metabolism and fosmidomycin sensitivity in <named-content content-type="genus-species">plasmodium falciparum</named-content>
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/0ea2ed8c7c8b4525becb3004db1c6787
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The Metabolite Repair Enzyme Phosphoglycolate Phosphatase Regulates Central Carbon Metabolism and Fosmidomycin Sensitivity in <named-content content-type="genus-species">Plasmodium falciparum</named-content>

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