An inherited molecular lesion of erythrocyte pyruvate kinase

Paglia, Donald E.; Valentine, William N.; Baughan, Marjorie A.; Miller, Denis R.; Reed, Claude F.; McIntyre, O. Ross

doi:10.1172/jci105883

Cited by 276 publications

(223 citation statements)

References 20 publications

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“…This effect, which is presumably a consequence of a specific structural alteration in the enzyme protein, is apparently sufficient to account for the metabolic disturbances seen in the condition. A catalytically abnormal enzyme has also been demonstrated in some but not in other cases of pyruvic kinase deficiency causing haemolytic anaemia (Boivin and Galand, 1967;Paglia et al, 1968). Several other examples of the same type of phenomenon have also been found in other metabolic disorders.…”

Section: Main Possibilitiesmentioning

confidence: 94%

Genetical theory and the "inborn errors of metabolism".

Harris¹

1970

BMJ

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Section: Main Possibilitiesmentioning

confidence: 94%

Genetical theory and the "inborn errors of metabolism".

Harris¹

1970

BMJ

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“…Hereditary nonspherocytic hemolytic anemia caused by a deficiency of erythrocyte PK activity was first reported in 1961 (7), and since then, >300 PK cases have been reported (8,9). Enzymatic characterization of variant enzymes revealed that a deficiency of PK activity was from the production of a structurally aberrant enzyme (10,11). To clarify the molecular defects of PK variants, we have previously isolated cDNA clones for human L-type PK (12).…”

mentioning

confidence: 99%

cDNA cloning of human R-type pyruvate kinase and identification of a single amino acid substitution (Thr384----Met) affecting enzymatic stability in a pyruvate kinase variant (PK Tokyo) associated with hereditary hemolytic anemia.

Kanno¹,

Fujii²,

Hirono³

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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ABSTRACTcDNA clones for human R-type pyruvate kinase (PK) were isolated from a human reticulocyte cDNA library, constructed by PCR with a single gene-spedflc primer. The full-length cDNA was 2060 base pairs long, and the cDNA encoded 574 amino adds, the same number as that by rat R-type PK. Compared with human L-type PK, R-type PK was 31 amino acids longer at the amino terminus. We also cloned and characterized R-type PK cDNA clones from patients with hereditary hemolytic anemia from a PK deficiency, PK Tokyo. A single nucleotide substitution (ACG to ATG) was found at nucleotide 1151 of the coding sequence of the R-type PK, which caused an amino acid substitution, Thr3N -Met. Dot blot hybridization of PCR-ampifled genomic DNA from patients and their parents by allele-specific oligonucleotide probes showed that the patients were homozygous for this nucleotide change and that the parents, who were second cousins, were heterozygous. To confirm that the nucleotide change was responsible for the variant phenotype, we expressed the L-type PK with the single amino acid change in Escherichia coil and characterized the enzyme. The variant PK was thermolabile and moved slowly in the polyacrylamide gel buffered in 10 mM Tris-HCI, pH 8.3; these characteristics were fully compatible with data obtained from the patient's PK. From these results, we concluded that enzymatic stability of the variant was affected by the point mutation of the PK-encoding gene.

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“…Heterogeneity of pyruvate kinase defects repeatedly has been report ed. In most cases, the deficiency appears to be purely quantitative, but a qualitative pyruvate kinase defect characterized by a lowered affinity for phosphoenolpyruvate has been described unequivocally [5,26,33]. From the 13 deficient patients whose pyruvate kinase kinetic character istics were studied in our laboratory, only one (Her.)…”

Section: Pyruvate Kinase Deficiencymentioning

confidence: 99%

Metabolie Regulation in Enzyme-Deficient Red Cells

Ha¹,

Jp²,

Garreau³

et al. 1974

Enzyme

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Measurement of intracellular metabolites and glycolytic activities in enzyme-deficient red cells has proved to be a valuable approach to studying the mechanism of hemolysis and metabolic regulations. Glycolytic intermediates, nucleotides, glucose consumption, and lactate formation were measured in phosphohexose isomerase, phosphoglycerate kinase, diphosphoglycerate mutase, and pyruvate kinase deficiencies. Pyruvate kinase deficiency was the only defect which was found to impair glycolytic activity, since there is no metabolic bypass at this level. Pyruvate kinase and phosphoglycerate kinase deficiencies may produce hemolysis through a decreased ADP phosphorylation to ATP. Defects of phosphoglycerate kinase and diphosphoglycerate mutase modify 2,3-diphosphoglycerate levels, but self-regulating mechanism limit these variations which alter the oxygen affinity of hemoglobin. The mechanism of hemolysis has not been explained definitely in diphosphoglycerate mutase and phosphohexose isomerase deficiencies; however, in the latter case it has been tentatively postulated that the compensatory bypass through the pentose-phosphate pathway may decrease progressively in aging cells and thus shorten their lifespan.

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An inherited molecular lesion of erythrocyte pyruvate kinase

Cited by 276 publications

References 20 publications

Genetical theory and the "inborn errors of metabolism".

Genetical theory and the "inborn errors of metabolism".

cDNA cloning of human R-type pyruvate kinase and identification of a single amino acid substitution (Thr384----Met) affecting enzymatic stability in a pyruvate kinase variant (PK Tokyo) associated with hereditary hemolytic anemia.

Metabolie Regulation in Enzyme-Deficient Red Cells

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