Adenosine Triphosphate Depletion of Erythrocytes Simulates the Phenotype Associated with Pyruvate Kinase Deficiency and Confers Protection against<i>Plasmodium falciparum</i>In Vitro

Ayi, Kodjo; Liles, W. Conrad; Gros, Philippe; Kain, Kevin C.

doi:10.1086/605843

Cited by 33 publications

(33 citation statements)

References 48 publications

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“…It is unlikely that full WT activity would have to be restored to see clinical benefit, because PK deficiency carriers have PK-R enzyme activity and ATP levels that are intermediate between patients with PK deficiency and WT controls and are asymptomatic. 32 Our ex vivo experiments in PK-deficient RBCs demonstrate that AG-348 increases ATP levels and PK activity and thus may help address the energy deficiency that leads to the reduced lifespan of these cells ( Figure 4D-E) or RBC precursors such as reticulocytes. Combined with the observation that glycolytic intermediates upstream of PK-R are reduced ( Figure 4C), these results suggest that AG-348 treatment can induce a metabolic state more similar to WT RBCs than to baseline.…”

Section: Discussionmentioning

confidence: 85%

AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency

Kung

Hixon

Kosinski

et al. 2017

Blood

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Section: Discussionmentioning

confidence: 85%

AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency

Kung

Hixon

Kosinski

et al. 2017

Blood

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“…Adults are not affected by bilirubinemia from red blood cell lysis because they possess a complete blood–brain barrier that prevents bilirubin access to the brain. There may be a selective advantage for heterozygotes carrying a PKR mutation as these mutations may confer some resistance to malaria [18, 19]. …”

Section: Cytosolic Pyruvate Metabolismmentioning

confidence: 99%

Regulation of pyruvate metabolism and human disease

Gray

Tompkins

Taylor

2013

Cell. Mol. Life Sci.

696

567

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Pyruvate is a keystone molecule critical for numerous aspects of eukaryotic and human metabolism. Pyruvate is the end-product of glycolysis, is derived from additional sources in the cellular cytoplasm, and is ultimately destined for transport into mitochondria as a master fuel input undergirding citric acid cycle carbon flux. In mitochondria, pyruvate drives ATP production by oxidative phosphorylation and multiple biosynthetic pathways intersecting the citric acid cycle. Mitochondrial pyruvate metabolism is regulated by many enzymes, including the recently discovered mitochondria pyruvate carrier, pyruvate dehydrogenase, and pyruvate carboxylase, to modulate overall pyruvate carbon flux. Mutations in any of the genes encoding for proteins regulating pyruvate metabolism may lead to disease. Numerous cases have been described. Aberrant pyruvate metabolism plays an especially prominent role in cancer, heart failure, and neurodegeneration. Because most major diseases involve aberrant metabolism, understanding and exploiting pyruvate carbon flux may yield novel treatments that enhance human health.

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“…3 PK-deficiency protects mice against blood-stage malaria (Plasmodium chabaudi) in vivo; 4 and studies with P. falciparum-infected erythrocytes demonstrate both homozygosity and heterozygosity for mutant PKLR alleles decrease parasite invasion and replication, and increase phagocytosis of infected cells. 5,6 These findings raise the possibility that human PKLR variants may have a protective effect if retained in malaria-pressured areas. To address this possibility, we sequenced the PKLR gene from 387 individuals, primarily those of African and Asian origin living in malaria-endemic areas (Figure 1a).…”

Section: Introductionmentioning

confidence: 99%

Genetic diversity in human erythrocyte pyruvate kinase

et al. 2011

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Previously, we have shown that pyruvate kinase, liver and red cell isoform (PKLR) deficiency protects mice in vivo against blood-stage malaria, and observed that reduced PKLR function protects human erythrocytes against Plasmodium falciparum replication ex vivo. Here, we have sequenced the human PKLR gene in 387 individuals from malaria-endemic and other regions in order to assess genetic variability in different geographical regions and ethnic groups. Rich genetic diversity was detected in PKLR, including 59 single-nucleotide polymorphisms and several loss-of-function variants (frequency 1.5%). Haplotype distribution and allele frequency varied considerably with geography. Neutrality testing suggested positive selection of the genein the sub-Saharan African and Pakistan populations. It is possible that such positive selection involves the malarial parasite.

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Adenosine Triphosphate Depletion of Erythrocytes Simulates the Phenotype Associated with Pyruvate Kinase Deficiency and Confers Protection againstPlasmodium falciparumIn Vitro

Abstract: These data suggest that reduced erythrocyte ATP levels may contribute to the protection displayed by PKD erythrocytes in vitro and may provide a model system with which to define the molecular basis of protection in inherited PKD.

Cited by 33 publications

References 48 publications

AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency

AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency

Regulation of pyruvate metabolism and human disease

Genetic diversity in human erythrocyte pyruvate kinase

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