scholarly journals Pyruvate Kinase (PK) Deficiency Hereditary Nonspherocytic Hemolytic Anemia

Blood ◽  
1962 ◽  
Vol 19 (3) ◽  
pp. 267-295 ◽  
Author(s):  
KOUICHI R. TANAKA ◽  
WILLIAM N. VALENTINE ◽  
SHIRO MIWA
Keyword(s):  
Pyruvate Kinase ◽  
Hemolytic Anemia ◽  
Glycolytic Enzyme ◽  
Enzyme Deficiency ◽  
Exact Nature ◽  
Symptomatic Disease ◽  
Genetically Determined ◽  
Recessive Transmission ◽  
Enzymatic Defect

Abstract 1. The erythrocytes of seven patients conforming to the criteria of Type II congenital nonspherocytic hemolytic anemia have been demonstrated to have a specific deficiency in the glycolytic enzyme pyruvate kinase. Other glycolytic enzymes, glucose-6-phosphate and 6-phosphogluconic dehydrogenases, and certain non-glycolytic erythrocyte enzymes are normally active. The leukocytes of these patients possess normal pyruvate kinase activity. 2. Although no inhibitors were detected, the exact nature of the enzymatic defect remains to be elucidated. 3. Family studies provide strong evidence for a genetically determined disorder and are consistent with an autosomal recessive transmission of the defect. A partial enzyme deficiency, not reflected in clinical disease, is present in heterozygotes. The symptomatic disease, though variable in severity, appears to be due to homozygosity for the defect. 4. It is suggested that the enzyme deficiency is pathogenetically related to the premature demise of the red cells in vivo. 5. The name "pyruvate kinase (PK) deficiency hereditary nonspherocytic hemolytic anemia" is proposed for these patients.

scholarly journals Eradication of ENO1-deleted Glioblastoma through Collateral Lethality

2018 ◽  
Author(s):  
Yu-Hsi Lin ◽  
Nikunj Satani ◽  
Naima Hammoudi ◽  
Jeffrey J. Ackroyd ◽  
Sunada Khadka ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Cancer Metabolism ◽  
Potent Inhibitor ◽  
Glioma Cells ◽  
Glycolytic Enzyme ◽  
Precision Oncology ◽  
Pharmacokinetic Properties ◽  
Inhibition Of Glycolysis ◽  
Nm Range

ABSTRACTInhibiting glycolysis remains an aspirational approach for the treatment of cancer. We recently demonstrated that SF2312, a natural product phosphonate antibiotic, is a potent inhibitor of the glycolytic enzyme Enolase with potential utility for the collateral lethality-based treatment of Enolase-deficient glioblastoma (GBM). However, phosphonates are anionic at physiological pH, limiting cell and tissue permeability. Here, we show that addition of pivaloyloxymethyl (POM) groups to SF2312 (POMSF) dramatically increases potency, leading to inhibition of glycolysis and killing of ENO1-deleted glioma cells in the low nM range. But the utility of POMSF in vivo is dose-limited by severe hemolytic anemia. A derivative, POMHEX, shows equipotency to POMSF without inducing hemolytic anemia. POMHEX can eradicate intracranial orthotopic ENO1-deleted tumors, despite sub-optimal pharmacokinetic properties. Taken together, our data provide in vivo proof-of-principal for collateral lethality in precision oncology and showcase POMHEX as a useful molecule for the study of glycolysis in cancer metabolism.

scholarly journals Molecular defect of a phosphoglycerate kinase variant (PGK-Matsue) associated with hemolytic anemia: Leu----Pro substitution caused by T/A- ---C/G transition in exon 3

Blood ◽  
1991 ◽  
Vol 77 (6) ◽  
pp. 1348-1352
Author(s):  
M Maeda ◽  
A Yoshida
Keyword(s):  
Hemolytic Anemia ◽  
Blot Hybridization ◽  
Phosphoglycerate Kinase ◽  
Southern Blot Hybridization ◽  
Enzyme Deficiency ◽  
Nucleotide Sequencing ◽  
Molecular Defect ◽  
Coding Regions ◽  
Variant Gene

We have identified the mutation in a phosphoglycerate kinase variant (PGK-Matsue) associated with severe enzyme deficiency, congenital nonspherocytic hemolytic anemia, and mental disorders. The mRNA coding for PGK was reverse transcribed and amplified by the polymerase chain reaction. Nucleotide sequencing of the variant cDNA showed a point mutation, a T/A----C/G transition in exon 3 of the variant gene. No other mutation was found in all coding regions of PGK-Matsue. The nucleotide change created an additional NciI cleavage site in the variant gene; thus, the NciI fragment types detected by Southern blot hybridization differ in the variant DNA and normal DNA. The mutation should cause Leu----Pro substitution at the 88th position from the NH2- terminal Ser of PGK. Because the Leu----Pro substitution is expected to induce serious perturbation and instability in the protein structure, the severe enzyme deficiency is mainly caused by more rapid in vivo denaturation and degradation of the variant enzyme.

Six Previously Undescribed Pyruvate Kinase Mutations Causing Enzyme Deficiency

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 647-652
Author(s):  
Anna Demina ◽  
Kottayil I. Varughese ◽  
José Barbot ◽  
Linda Forman ◽  
Ernest Beutler
Keyword(s):  
Amino Acid ◽  
Binding Site ◽  
Pyruvate Kinase ◽  
Hemolytic Anemia ◽  
Enzyme Deficiency ◽  
Sufficient Data ◽  
Common Cause ◽  
Pyruvate Kinase Deficiency ◽  
Substrate Binding Site ◽  
Local Perturbations

Erythrocyte pyruvate kinase deficiency is the most common cause of hereditary nonspherocytic hemolytic anemia. We present 6 previously undescribed mutations of the PKLR gene associated with enzyme deficiency located at cDNA nt 476 G→T (159Gly→Val), 884 C→T (295Ala→Val), 943 G→A (315Glu→Lys), 1022 G→A (341Gly→Asp), 1511 G→T (504Arg→Leu), and 1528 C→T (510Arg→Ter). Two of these mutations are near the substrate binding site: the 315Glu→Lys (943A) mutation may be involved in Mg2+ binding and159Gly→Val (476T) mutation has a possible effect on ADP binding. Four of six mutations produce deduced changes in the shape of the molecule. Two of these mutations,504Arg→Leu (1511T) and510Arg→Ter (1528T), are located at the interface of domains A and C. One of them (510Arg→Ter) is a deletion of the C-terminal residues affecting the integrity of the protein. The 504Arg→Leu mutation eliminates a stabilizing interaction between domains A and C. Changes in amino acid 341(nt 1022) from Gly to Asp cause local perturbations. The mutation295Ala→Val (884T) might affect the way pyruvate kinase interacts with other molecules. We review previously described mutations and conclude that there is not yet sufficient data to allow us to draw conclusions regarding genotype/phenotype relationship.

scholarly journals Molecular defect of a phosphoglycerate kinase variant (PGK-Matsue) associated with hemolytic anemia: Leu----Pro substitution caused by T/A- ---C/G transition in exon 3

Blood ◽  
1991 ◽  
Vol 77 (6) ◽  
pp. 1348-1352 ◽  
Author(s):  
M Maeda ◽  
A Yoshida
Keyword(s):  
Hemolytic Anemia ◽  
Blot Hybridization ◽  
Phosphoglycerate Kinase ◽  
Southern Blot Hybridization ◽  
Enzyme Deficiency ◽  
Nucleotide Sequencing ◽  
Molecular Defect ◽  
Coding Regions ◽  
Variant Gene

Abstract We have identified the mutation in a phosphoglycerate kinase variant (PGK-Matsue) associated with severe enzyme deficiency, congenital nonspherocytic hemolytic anemia, and mental disorders. The mRNA coding for PGK was reverse transcribed and amplified by the polymerase chain reaction. Nucleotide sequencing of the variant cDNA showed a point mutation, a T/A----C/G transition in exon 3 of the variant gene. No other mutation was found in all coding regions of PGK-Matsue. The nucleotide change created an additional NciI cleavage site in the variant gene; thus, the NciI fragment types detected by Southern blot hybridization differ in the variant DNA and normal DNA. The mutation should cause Leu----Pro substitution at the 88th position from the NH2- terminal Ser of PGK. Because the Leu----Pro substitution is expected to induce serious perturbation and instability in the protein structure, the severe enzyme deficiency is mainly caused by more rapid in vivo denaturation and degradation of the variant enzyme.

Six Previously Undescribed Pyruvate Kinase Mutations Causing Enzyme Deficiency

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 647-652 ◽  
Author(s):  
Anna Demina ◽  
Kottayil I. Varughese ◽  
José Barbot ◽  
Linda Forman ◽  
Ernest Beutler
Keyword(s):  
Amino Acid ◽  
Binding Site ◽  
Pyruvate Kinase ◽  
Hemolytic Anemia ◽  
Enzyme Deficiency ◽  
Sufficient Data ◽  
Common Cause ◽  
Pyruvate Kinase Deficiency ◽  
Substrate Binding Site ◽  
Local Perturbations

Abstract Erythrocyte pyruvate kinase deficiency is the most common cause of hereditary nonspherocytic hemolytic anemia. We present 6 previously undescribed mutations of the PKLR gene associated with enzyme deficiency located at cDNA nt 476 G→T (159Gly→Val), 884 C→T (295Ala→Val), 943 G→A (315Glu→Lys), 1022 G→A (341Gly→Asp), 1511 G→T (504Arg→Leu), and 1528 C→T (510Arg→Ter). Two of these mutations are near the substrate binding site: the 315Glu→Lys (943A) mutation may be involved in Mg2+ binding and159Gly→Val (476T) mutation has a possible effect on ADP binding. Four of six mutations produce deduced changes in the shape of the molecule. Two of these mutations,504Arg→Leu (1511T) and510Arg→Ter (1528T), are located at the interface of domains A and C. One of them (510Arg→Ter) is a deletion of the C-terminal residues affecting the integrity of the protein. The 504Arg→Leu mutation eliminates a stabilizing interaction between domains A and C. Changes in amino acid 341(nt 1022) from Gly to Asp cause local perturbations. The mutation295Ala→Val (884T) might affect the way pyruvate kinase interacts with other molecules. We review previously described mutations and conclude that there is not yet sufficient data to allow us to draw conclusions regarding genotype/phenotype relationship.

scholarly journals Hereditary Hemolytic Anemia Associated with Glucosephosphate Isomerase (GPI) Deficiency— a New Enzyme Defect of Human Erythrocytes

Blood ◽  
1968 ◽  
Vol 32 (2) ◽  
pp. 236-249 ◽  
Author(s):  
MARJORIE A. BAUGHAN ◽  
WILLIAM N. VALENTINE ◽  
DONALD E. PAGLIA ◽  
PETER O. WAYS ◽  
ERNEST R. SIMONS ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Autosomal Recessive ◽  
Clinical Evidence ◽  
Glycolytic Enzyme ◽  
Enzyme Deficiency ◽  
Second Step ◽  
Glucosephosphate Isomerase ◽  
Enzyme Defect ◽  
Mode Of Inheritance ◽  
Congenital Hemolytic Anemia

Abstract A new congenital hemolytic anemia not characterized by spherocytosis has been defined as due to a deficiency in another glycolytic enzyme, glucosephosphate isomerase, the catalyst specific for the second step of the Embden-Meyerhof glycolytic pathway. The leukocytes and the plasma are involved as well as the erythrocytes, but there is no clinical evidence of dysfunction other than the hemolytic anemia. Family studies are consistent with an autosomal-recessive mode of inheritance with the asymptomatic heterozygotes demonstrating an intermediate enzyme deficiency, and the symptomatic homozygote, the propositus, demonstrating a marked enzyme deficiency.

120-LB: Small Molecule Activator of Pyruvate Kinase Regulates In Vivo Glucose Homeostasis

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 120-LB
Author(s):  
ABUDUKADIER ABULIZI ◽  
REBECCA L. CARDONE ◽  
STEPHAN SIEBEL ◽  
CHARLES KUNG ◽  
RICHARD KIBBEY
Keyword(s):  
Pyruvate Kinase ◽  
Small Molecule ◽  
Glucose Homeostasis

FcγRIII (CD16)-Deficient Mice Show IgG Isotype-Dependent Protection to Experimental Autoimmune Hemolytic Anemia

Blood ◽  
1998 ◽  
Vol 92 (11) ◽  
pp. 3997-4002 ◽  
Author(s):  
Dirk Meyer ◽  
Carsten Schiller ◽  
Jürgen Westermann ◽  
Shozo Izui ◽  
Wouter L. W. Hazenbos ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Knock Out ◽  
Effector Cells ◽  
Igg Isotypes ◽  
Knock Out Mice ◽  
Deficient Mice ◽  
Experimental Autoimmune

Abstract In autoimmune hemolytic anemia (AIHA), there is accumulating evidence for an involvement of FcγR expressed by phagocytic effector cells, but demonstration of a causal relationship between individual FcγRs and IgG isotypes for disease development is lacking. Although the relevance of IgG isotypes to human AIHA is limited, we could show a clear IgG isotype dependency in murine AIHA using pathogenic IgG1 (105-2H) and IgG2a (34-3C) autoreactive anti–red blood cell antibodies in mice defective for FcγRIII, and comparing the clinical outcome to those in wild-type mice. FcγRIII-deficient mice were completely resistent to the pathogenic effects of 105-2H monoclonal antibody, as shown by a lack of IgG1-mediated erythrophagocytosis in vitro and in vivo. In addition, the IgG2a response by 34-3C induced a less severe but persistent AIHA in FcγRIII knock-out mice, as documented by a decrease in hematocrit. Blocking studies indicated that the residual anemic phenotype induced by 34-3C in the absence of FcγRIII reflects an activation of FcγRI that is normally coexpressed with FcγRIII on macrophages. Together these results show that the pathogenesis of AIHA through IgG1-dependent erythrophagocytosis is exclusively mediated by FcγRIII and further suggest that FcγRI, in addition to FcγRIII, contributes to this autoimmune disease when other IgG isotypes such as IgG2a are involved.

scholarly journals Kinetic and regulatory properties of cytosolic pyruvate kinase from germinating castor oil seeds

1991 ◽  
Vol 279 (2) ◽  
pp. 495-501 ◽  
Author(s):  
F E Podestá ◽  
W C Plaxton
Keyword(s):  
Pyruvate Kinase ◽  
Castor Oil ◽  
Mixed Type ◽  
Competitive Inhibition ◽  
Ricinus Communis ◽  
Cytosolic Ph ◽  
Oil Seeds ◽  
Saturation Kinetics ◽  
Regulatory Properties

The kinetic and regulatory properties of cytosolic pyruvate kinase (PKc) isolated from endosperm of germinating castor oil seeds (Ricinus communis L.) have been studied. Optimal efficiency in substrate utilization (in terms of Vmax/Km for phosphoenolpyruvate or ADP) occurred between pH 6.7 and 7.4. Enzyme activity was absolutely dependent on the presence of a bivalent and a univalent metal cation, with Mg2+ and K+ fulfilling this requirement. Mg2+ binding showed positive and negative co-operativity at pH 6.5 (h = 1.6) and pH 7.2 (h = 0.69) respectively. Hyperbolic saturation kinetics were observed with phosphoenolpyruvate (PEP) and K+, whereas ADP acted as a mixed-type inhibitor over 1 mM. Glycerol (10%, v/v) increased the S0.5(ADP) 2.3-fold and altered the pattern of nucleotide binding from hyperbolic (h = 1.0) to sigmoidal (h = 1.79) without modifying PEP saturation kinetics. No activators were identified. ATP, AMP, isocitrate, 2-oxoglutarate, malate, 2-phosphoglycerate, 2,3-bisphosphoglycerate, 3-phosphoglycerate, glycerol 3-phosphate and phosphoglycolate were the most effective inhibitors. These metabolites yielded additive inhibition when tested in pairs. ATP and 3-phosphoglycerate were mixed-type inhibitors with respect to PEP, whereas competitive inhibition was observed for other inhibitors. Inhibition by malate, 2-oxoglutarate, phosphorylated triose sugars or phosphoglycolate was far more pronounced at pH 7.2 than at pH 6.5. Although 32P-labelling studies revealed that extensive phosphorylation in vivo of soluble endosperm proteins occurred between days 3 and 5 of seed germination, no alteration in the 32P-labelling pattern of 5-day-germinated endosperm was observed after 30 min of anaerobiosis. Moreover, no evidence was obtained that PKc was a phosphoprotein in aerobic or anoxic endosperms. It is proposed that endosperm PKc activity of germinating castor seeds is enhanced after anaerobiosis through concerted decreases in ATP levels, cytosolic pH and concentrations of several key inhibitors.

scholarly journals Changes in activities and isozyme patterns of glycolytic enzymes during erythroid differentiation in vitro

Blood ◽  
1984 ◽  
Vol 64 (3) ◽  
pp. 607-613 ◽  
Author(s):  
W Nijhof ◽  
PK Wierenga ◽  
GE Staal ◽  
G Jansen
Keyword(s):  
Pyruvate Kinase ◽  
Gradient Centrifugation ◽  
Recovery Period ◽  
Erythroid Differentiation ◽  
Glycolytic Enzyme ◽  
Minor Amount ◽  
Type I ◽  
In Vitro Differentiation ◽  
Percoll Density Gradient Centrifugation

Late committed progenitor cells of erythropoiesis, CFU-E (colony- forming unit--erythroid), were isolated from mouse spleens to near homogeneity by a three-step enrichment procedure. The procedure included a four-day pretreatment of bled mice with the antibiotic thiamphenicol, a recovery period of 3 1/2 days, followed by centrifugal elutriation and Percoll density gradient centrifugation of the spleen cells. This practically pure CFU-E population was used to study some aspects of erythroid differentiation in vitro. Colony growth, as well as morphology and glycolytic enzyme activities of cells isolated at selected times of the 48-hour culture period, were determined. Marked declining activities of several enzymes, including hexokinase, phosphofructokinase, aldolase, enolase, pyruvate kinase, and glucose-6- phosphate dehydrogenase, were observed during in vitro differentiation. The activity of diphosphoglycerate mutase was almost absent in the CFU- E, but progressively increased during differentiation. The isozyme distribution of aldolase and enolase did not change during CFU-E in vitro differentiation into the reticulocyte. Hexokinase (HK) in the CFU- E contained mainly a double-banded type I isozyme, in addition to a minor amount of HK II. During differentiation, a shift was noticed within the double-banded HK I region, whereas HK ii disappeared after one cell division. Pyruvate kinase in the CFU-E was characterized by the presence of both the K-type and the L-type isozyme and hybrids of these isozyme types. During in vitro differentiation, the production of the K-type isozyme rapidly stops in favor of the L type.

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