Red cell pyruvate kinase deficiency: from genetics to clinical manifestations

Zanella, Alberto; Bianchi, Paola

doi:10.1053/beha.1999.0057

Cited by 122 publications

(130 citation statements)

References 89 publications

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“…Constitutive hemolysis also induces an increased erythropoietic response, as is evident in this study, and P. chabaudi may have a slight preference for mature as opposed to young red cells and/or reticulocytes, resulting in a selflimiting infection. Interestingly, increased levels of 2,3-DPG (a metabolic intermediate upstream PK) that are found in PK-deficient RBCs may in turn inhibit certain metabolic pathways of the parasite, 32 and indirectly increase concentrations of oxidative species through the inhibition of G6PD, 33 creating a less hospitable environment for parasite development. Finally, because of the essential nature of PK for parasite metabolism, the deficiency of the host enzyme may hinder parasite growth at the early stages of infection.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic expression of pyruvate kinase deficiency and protection against malaria in a mouse model

Min‐Oo

Fortin

et al. 2004

Genes Immun

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The recombinant congenic mouse strains AcB55 and AcB61 are extremely resistant to malaria (Plasmodium chabaudi AS) despite the presence of susceptibility alleles at the known Char1/Char2 resistance loci. Resistance in AcB55 and AcB61 is controlled by a locus on chromosome 3 (Char4) shown to be allelic with or tightly linked to a loss-of-function mutation in pyruvate kinase (Pklr). AcB55 and AcB61 show important splenomegaly prior to infection caused by the expansion of the red pulp, and display histological signs of extramedullary erythropoiesis in the liver. Examination of splenic cell populations by flow cytometry demonstrates elevated numbers of TER119-positive erythroid precursor cells (430% of total spleen cells), while RNA expression studies show elevated expression of erythrocyte-specific transcripts such as globin, transferrin receptor, and Nramp2/Slc11a2 in the spleen of both strains. Hematological profiling in both strains is consistent with the presence of anemia as evidenced by low total erythrocyte counts, decreased hemoglobin, as well as abnormally high numbers of circulating reticulocytes (15-20%). These results strongly suggest that the mutant Pklr allele (Pklr 269A ) of AcB55/61 strains causes hemolytic anemia compensated by constitutive erythropoiesis, which in turn protects the mice against P. chabaudi infection. The possible molecular basis of the Pklr protective effect is discussed and is under current investigation in these two strains.

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Section: Discussionmentioning

confidence: 99%

Phenotypic expression of pyruvate kinase deficiency and protection against malaria in a mouse model

Min‐Oo

Fortin

et al. 2004

Genes Immun

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“…R486W (nucleotide C 1456 3 T) is among the most frequent mutations found in RPK-deficient patients (11). Characterization of this mutant reveals that such a drastic amino acid replacement results in small effects on the molecular properties.…”

Section: G332s Mutation In the A Domain Hydrophobicmentioning

confidence: 99%

“…Deficiency of human erythrocyte isozyme (RPK) is, together with glucose-6-phosphate dehydrogenase deficiency, the most common cause of nonspherocytic hemolytic anemia (11). RPK deficiency severely affects the erythrocyte metabolism, causing ATP depletion, which ultimately leads to hemolysis.…”

mentioning

confidence: 99%

Structure and Function of Human Erythrocyte Pyruvate Kinase

Valentini¹,

Chiarelli²,

Fortin³

et al. 2002

Journal of Biological Chemistry

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133

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Deficiency of human erythrocyte isozyme (RPK) is, together with glucose-6-phosphate dehydrogenase deficiency, the most common cause of the nonspherocytic hemolytic anemia. To provide a molecular framework to the disease, we have solved the 2.7 Å resolution crystal structure of human RPK in complex with fructose 1,6-bisphosphate, the allosteric activator, and phosphoglycolate, a substrate analogue, and we have functionally and structurally characterized eight mutants (G332S, G364D, T384M, D390N, R479H, R486W, R504L, and R532W) found in RPK-deficient patients. The mutations target distinct regions of RPK structure, including domain interfaces and catalytic and allosteric sites. The mutations affect to a different extent thermostability, catalytic efficiency, and regulatory properties. These studies are the first to correlate the clinical symptoms with the molecular properties of the mutant enzymes. Mutations greatly impairing thermostability and/or activity are associated with severe anemia. Some mutant proteins exhibit moderate changes in the kinetic parameters, which are sufficient to cause mild to severe anemia, underlining the crucial role of RPK for erythrocyte metabolism. Prediction of the effects of mutations is difficult because there is no relation between the nature and location of the replaced amino acid and the type of molecular perturbation. Characterization of mutant proteins may serve as a valuable tool to assist with diagnosis and genetic counseling.

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“…There have only been ∼400 documented variants since PKs first description in 1961 (Tanaka and Zerez 1990;Jacobasch and Rapoport 1996;Zanella and Bianchi 2000). PK accounts for 90% of the enzyme deficiencies found in red blood cell glycolysis (Jacobasch and Rapoport 1996).…”

Section: Pk Deficiencymentioning

confidence: 99%

“…PK exhibits 222 symmetry, and there are two states for the tetramer, the low-affinity, tight (T) conformation and the high-affinity, relaxed (R) conformation. The PEP and Mg 2+ binding sites are in the cleft between the A and B domains close to the sixth and eighth loops of the (␣␤) 8 bar- All data obtained from Solinge et al (1997); Zanella and Bianchi (2000). rel.…”

Section: Pk Deficiencymentioning

confidence: 99%

In Silico Model-Driven Assessment of the Effects of Single Nucleotide Polymorphisms (SNPs) on Human Red Blood Cell Metabolism

Jamshidi

Wiback²,

Palsson³

2002

Genome Res.

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The completion of the human genome project and the construction of single nucleotide polymorphism (SNP) maps have lead to significant efforts to find SNPs that can be linked to pathophysiology. In silico models of complete biochemical reaction networks relate a cell's individual reactions to the function of the entire network. Sequence variations can in turn be related to kinetic properties of individual enzymes, thus allowing an in silico model-driven assessment of the effects of defined SNPs on overall cellular functions. This process is applied to defined SNPs in two key enzymes of human red blood cell metabolism: glucose-6-phosphate dehydrogenase and pyruvate kinase. The results demonstrate the utility of in silico models in providing insight into differences between red cell function in patients with chronic and nonchronic anemia. In silico models of complex cellular processes are thus likely to aid in defining and understanding key SNPs in human pathophysiology.

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Red cell pyruvate kinase deficiency: from genetics to clinical manifestations

Cited by 122 publications

References 89 publications

Phenotypic expression of pyruvate kinase deficiency and protection against malaria in a mouse model

Phenotypic expression of pyruvate kinase deficiency and protection against malaria in a mouse model

Structure and Function of Human Erythrocyte Pyruvate Kinase

In Silico Model-Driven Assessment of the Effects of Single Nucleotide Polymorphisms (SNPs) on Human Red Blood Cell Metabolism

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