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PubMed1985

Enhancement of hepatocarcinogenesis by sorbitan fatty acid ester, a liver pyruvate kinase activity-reducing substance.

Effect on hepatocarcinogenesis of dietary sorbitan fatty acid ester (SorFAE), which had been known to cause decrease in pyruvate kinase (PK) activity, was studied in rats fed a diet containing 0.06% 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) for 6 weeks. The incidence of hyperplastic nodules and/or hepatocellular carcinomas in the rats fed the 3'-Me-DAB diet alone was 45.0% at the end of 51 weeks, whereas the incidence in the rats fed 3'-Me-DAB diet followed by 5 or 10% SorFAE or 0.1% phenobarbital (PB) diet were 76.2, 90.5, and 95.0%, respectively. These incidences were significantly higher compared with the group fed 3'-Me-DAB diet alone (P less than .05). No tumors were observed in rats fed 10% SorFAE diet alone. The results show that SorFAE has an enhancing effect on hepatocarcinogenesis, although the effect was weak compared to that of the effective PB dose. The results seem to confirm our assumption that a chemical that causes decrease in PK activity in rat liver might promote hepatocarcinogenesis.

Animals↗
PubMed1992

Identical point mutations of the R-type pyruvate kinase (PK) cDNA found in unrelated PK variants associated with hereditary hemolytic anemia.

We cloned and sequenced the cDNAs for R-type pyruvate kinase (R-PK) from three homozygous PK patients. A point mutation (1151ACG to ATG) identified in the R-PK cDNA of PK Nagasaki was identical with that previously identified in an unrelated family, PK Tokyo. The mutation has also been identified in the PK L gene of a Lebanese family, PK Beirut, by Neubauer et al (Blood 77:1871, 1991). These results suggest either that the point mutation is very old or that the same mutation occurs sporadically in the same hot spot in unrelated families. A point mutation, 1261CAG to AAG, was detected in both PK Fukushima and PK Maebashi; this mutation causes a single amino acid substitution, from Gln421 to Lys, in R-PK. Consequently, the hydrophobicity properties near the mutated site are drastically changed. A silent mutation (1705AGG to CGG) was also identified in those variants. The screening of these three point mutations showed only the silent mutation in a normal individual as well as in individuals with PK variants. These results indicate that the multiplicity of the mutant PK allele is smaller than expected, and that the silent mutation is a polymorphic change commonly distributed in the Japanese population.

Anemia, Hemolytic, Congenital↗
PubMed1989

Analysis by cell-free transcription of the liver-specific pyruvate kinase gene promoter.

A DNA fragment spanning nucleotides -183 to -4 with respect to the cap site of the rat L-type pyruvate kinase (L-PK) gene contains at least four binding sites for putative transcriptional factors: hepatocyte nuclear factor 1 (HNF1), liver factor A1 (LF-A1), nuclear factor 1 (NF1), and major late transcription factor (MLTF). This fragment was used to direct transcription of a reporter sequence (a G-free cassette) in cell extracts. This L-PK promoter was active in liver nuclear extracts, but not in extracts from nonhepatic tissues. A reduction of 50% of the activity was obtained with a deleted L-PK promoter containing only the HNF1-binding site. In contrast, deletion of the HNF1-binding site inactivated the promoter by more than 90%. These results were confirmed by titration experiments with synthetic oligonucleotides. Titration of HNF1 resulted in an 85% decrease of transcriptional activity, while titration of LF-A1 resulted in only a 40% decrease. The influence of NF1 and MLTF seemed to be marginal in this system. The proximal 5'-flanking sequence of the L-PK gene therefore appears to function in vitro as an efficient liver-specific promoter which requires the binding of the liver factor HNF1 and which is also stimulated by the binding of another liver-specific factor, LF-A1.

Animals↗
PubMed1990

Fractionation in two-phase systems of red cells during rat development: changes in pyruvate kinase and bisphosphoglycerate mutase activities in relation to red cell switching.

An inverse relationship between 2,3-bisphosphoglycerate levels and the ratio calculated from pyruvate kinase and bisphosphoglycerate mutase activities has been observed in red populations of rats during animal development. Counter-current distribution in aqueous two-phase systems of these cells populations shows a displacement of distribution profiles towards the high-numbered cavities of the rotor as animal ages. Heterogeneity of cells after distribution is only observed during the switching process from fetal to adult red cells taking place along the postnatal stage of development. Values for the pyruvate kinase/bisphosphoglycerate mutase ratio in these fractions suggest the separation of fetal (liver) from adult (bone marrow) red cells.

Animals↗
PubMed1999

Apoptotic changes precede mitochondrial dysfunction in red cell-type pyruvate kinase mutant mouse erythroleukemia cell lines.

Two erythroleukemia cell lines have been established from the splenic lesions of red blood cell-type pyruvate kinase (R-PK) activity-deficient mice of CBA/N origin infected with a polycythemic strain of Friend leukemia virus complex (FVp). Ten to 30% of the cells of these cell lines undergo apoptotic changes in routine passage, as shown by nuclear fragmentation, DNA laddering, DNA content (propidium iodide (PI) staining), and annexin V binding assay. In these cells, however, although adenosine 5'-triphosphate (ATP) levels were lower than in the control cells, the mitochondrial inner transmembrane potential (delta psi m), detected by rhodamine 123 (R123) and diSC3(5) staining, remained unchanged until the final stage of apoptosis. No evidence was obtained to relate this finding to R-PK mutation due to difficulty in cloning stable, conditionally inducible R-PK gene transfectants. However, low delta psi m in the apoptotic cell population of the control T3-K-1 (K-1) and T3-CI-2-0 (2-0) Friend erythroleukemia cells supports a possible relationship, as do results obtained in two Friend erythroleukemia cells recently isolated from normal CBA/N mice. These cell lines are expected to be useful for clarifying both the primary apoptotic changes independent of mitochondrial dysfunction and the PK-isozyme changes during erythrodifferentiation, for example, the decreased muscle type 2 (M2) PK level. Modification of growth signals in these cell lines may modulate differentiation and/or apoptosis and allow further elucidation of the signaling networks.

Adenosine Triphosphate↗
PubMed1973

The effects of calcium ions on the activities of trehalase, hexokinase, phosphofructokinase, fructose diphosphatase and pyruvate kinase from various muscles.

1. The effects of Ca(2+) on the activities and regulatory properties of trehalase, hexokinase, phosphofructokinase, fructose diphosphatase and pyruvate kinase from vertebrate red and white muscle and insect fibrillar and non-fibrillar muscle have been investigated. These muscles were selected because of the possible difference in the role of glycolysis in energy production in the vertebrate muscles, and the possible difference in the role of Ca(2+) in the control of contraction in the two types of insect muscle. An increase in Ca(2+) concentration from 0.001mum to 10mum did not modify the activities nor did it modify the regulatory properties of these enzymes from these various muscles. 2. Concentrations of Ca(2+) above 0.1mm inhibited the activities of hexokinase and phosphofructokinase from the different muscles. It has been suggested that this inhibition may provide the basis for a theory of regulation of glycolysis (Margreth et al., 1967). If phosphofructokinase is located within the sarcoplasmic reticulum, its activity will be inhibited when the muscle is at rest, but the release of Ca(2+) from the reticulum during contraction will lead to a stimulation of its activity and hence an increase in glycolytic flux. The distribution of hexokinase and phosphofructokinase in the various cell fractions of these muscles was very variable. In particular, both enzymes were present almost exclusively in the 100000g supernatant fraction in the extracts of insect flight muscles. Thus there is no correlation between the properties of the enzymes and their distribution in muscle. 3. It is concluded that Ca(2+) does not control the activities of the important regulatory enzymes of glycolysis in muscle. It is suggested that in some muscles the sensitivity of the control mechanism at the level of phosphofructokinase to changes in the concentration of AMP may be increased by a process known as ;substrate-cycling'.

Animals↗
PubMed1987

Reticulocyte-dependent labeling alterations of red cell membrane in pyruvate kinase deficiency anemia.

The radioactive labeling of spectrin using the pentavalent complex of molybdenum-99 was applied to the study of membrane protein in pyruvate kinase deficient red cells. Compared to the control, the labeling profile of the enzymopathic red cell membrane proteins remained generally unchanged but the molybdenum uptake was found to depend largely on the reticulocyte count. This finding may reflect changes during the cell maturation.

Anemia, Hemolytic↗
PubMed1989

Effect of zinc or copper deficiency on erythrocyte purine nucleoside phosphorylase and pyruvate kinase activity in the rat.

The effect of deficiencies of zinc or copper in the rat on the activity of purine nucleoside phosphorylase and pyruvate kinase in erythrocytes, liver and muscle was investigated. The data showed no effect of either zinc or copper deficiencies on the activity of these enzymes in the tissues tested. It is concluded that these enzymes are not useful markers for either zinc or copper deficiency.

Animals↗
PubMed1983

Change of pyruvate kinase isozymes from M2- to L-type during development of the red cell.

The relationship between erythroid cell maturation and the change of pyruvate kinase (PK) isozymes was studied using fluorescent antibody techniques. The fluorescence of M2-type PK was strongest in the proerythroblast stage, and then steeply declined with red cell maturation so that only weak fluorescence was seen in orthochromatic erythroblasts. On the other hand, the fluorescence of L-type PK was seen throughout the maturation of the erythroblasts, with stronger fluorescence in the basophilic or polychromatic erythroblasts than in proerythroblasts.

Bone Marrow↗
PubMed1983

A study of the properties of pyruvate kinase isolated from a mutant of Neurospora crassa: a comparison with the parental enzyme.

1. A mutant of Neurospora crassa has been isolated whose pyruvate kinase is twice as active as the wild type enzyme. 2. The purified mutant and the wild type enzymes exhibit similar immunological properties, pI values (6.4) and Arrhenius activation energy (11.2 kcal/mol). 3. Both the enzymes show hyperbolic saturation kinetics with ADP and sigmoidal kinetics with PEP. 4. The mutant enzyme displays a higher affinity for PEP and a greater extent of cooperativity in binding than the wild type. 5. Conformational alterations in the mutant enzyme are inferred on the basis of electrophoretic analyses and denaturation by urea, SDS and heat.

Hot Temperature↗
PubMed1979

Effects of sustained oxygen depletion on tissue pyruvate kinase activities in the freshwater turtle, Pseudemys scripta elegans.

1. The effect of sustained (48 hr) oxygen depletion on tissue (brain, heart, skeletal muscle) pyruvate kinase (PyKi) activities was examined in the pond turtle (Pseudemys scripta elegans). 2. PyKi activities in skeletal muscle are significantly increased (from 322 +/- 84 to 450 +/- 95) following 48 hr of tissue hypoxia. PyKi activities in brain may already be elevated under ambient conditions but do not change following prolonged submersion (334 +/- 75 vs 325 +/- 77). Cardiac muscle PyKi is actually decreased (from 135 +/- 35 to 94 +/- 18) under anaerobic conditions. 3. The data suggest that prolonged O2 depletion may increase PyKi biosynthesis in turtle skeletal muscle (subserving enhanced glycolysis), but also demonstrate that factors other than oxygen availability are involved in the regulation of tissue PyKi activities in intact vertebrates.

Animals↗
PubMedDate not supplied

Aspirin shares a short-term effect, inhibition of pyruvate kinase activity with tumor-promoting agents, but fails to promote rat liver carcinogenesis.

Since aspirin was found to cause a persistent decrease in pyruvate kinase activity, which is a prominent characteristic of the hepatic promoters, the effect of aspirin on hepatic tumorigenesis in the rat has been studied. Male Wistar rats were initiated with a diet containing 0.06% 3'-methyl-4-dimethylamino-azobenzene for 4 weeks. They were divided into 3 groups and each group was fed one of the following diets containing either 0, 0.5 or 1% aspirin. At the end of a 58-week experimental period, no differences were observed in the incidence of hepatic lesions and hepatocellular carcinomas among the groups. Thus, it was concluded that aspirin does not promote nor inhibit the postinitiation step of hepatic tumorigenesis in the rat.

Animals↗
PubMed1986

Preleukemia manifested by hemolytic anemia with pyruvate-kinase deficiency.

A 27-year-old patient manifested severe hemolytic anemia during a preleukemia phase. Low levels of adenosine triphosphate and decreased activity of pyruvate kinase were found. Acute myeloblastic leukemia developed in this patient 20 months later. The case suggests that acquired enzyme deficiency may play a role in the development of anemia in the preleukemic state.

Adult↗
PubMed1990

Fructose-1,6-bisphosphate-activated pyruvate kinase from Escherichia coli. Nature of bonds involved in the allosteric mechanism.

The allosteric properties of the fructose-1,6-bis-phosphate-activated pyruvate kinase from Escherichia coli were examined in the presence of a number of fructose bisphosphate analogues, as well as of increased ionic strength (NaCl) and of the hydrogen-bond-breaking agent, formamide. Fructose 2,6-bisphosphate, ribulose 1,5-bisphosphate and 5-phosphorylribose 1-pyrophosphate gave allosteric activation (additive to that of fructose 1,6-bisphosphate). Formamide always decreased Vmax, but left unchanged the Km for phosphoenolpyruvate, while it decreased the concentration of fructose bisphosphate required to give half-maximal activity (K0.5). NaCl increased the K0.5 for both phosphoenolpyruvate and fructose bisphosphate, leaving Vmax unchanged. These results are consistent with ionic binding of fructose bisphosphate through phosphates and with a critical role of hydrogen bonds in stabilizing both the inactive and the active enzyme conformers.

Allosteric Regulation↗
PubMedDate not supplied

TUM2-PK (pyruvate kinase type tumor M2), CA19-9 and CEA in patients with benign, malignant and metastasizing pancreatic lesions.

The diagnostic value of the tumor marker pyruvate kinase type tumor M2 was evaluated in patients with benign, malignant and metastasizing pancreatic lesions and compared to the reference markers CA19-9 and CEA. This prospective study comprised 166 individuals; 66 patients had various pancreatic pathologies (38 histologically proven pancreatic cancer, 28 benign pancreatic lesions such as pseudotumorous pancreatitis, pseudocysts or pancreatic (cyst)adenoma) and 100 healthy blood donors served as controls. With a cut-off value of 28 U/ml (corresponding to a specificity of 90%) the sensitivity of TUM2-PK for pancreatic cancer (as related to the control group) was 79% (CA19-9: 65%, CEA: 22%). There was a good correlation between the TUM2-PK levels and tumor metastasis (p < 0.001 for no versus distant metastasis, p = n.s. for CA19-9 and CEA). However, TUM2-PK was also elevated in 64.3% of the patients with benign pancreatic pathologies. In our study TUM2-PK had good diagnostic qualities for pancreatic cancer and also showed better correlation to metastasis than CA 19-9 and CEA.

Biomarkers, Tumor↗
PubMed1994

L- and M2-pyruvate kinase expression in renal cell carcinomas and their metastases.

Using immunohistochemical and enzyme biochemical methods we investigated the expression of L- and M2-pyruvate kinase (PK) in normal renal tissue, renal cell carcinomas (RCCs; of clear cell, chromophilic cell and mixed cell type) and RCC metastases. L-PK was expressed in the proximal tubules of normal renal tissue and, to a variable extent, in 23/25 primary RCCs, in 1 RCC recurrence and in 10 RCC metastases. Staining intensity and percentage of stained tissue did not correlate with tumour grade. One renal oncocytoma and all extrarenal malignancies examined lacked L-PK immunoreactivity. M2-PK was mainly expressed in the distal tubules of the normal kidney and was found in all renal tumours as well as extrarenal malignancies. Quantitative biochemical investigations yielded a two- to seventeen-fold increase in PK activity in RCCs compared to the normal renal cortex taken from the same patient, whereas fructose-1,6-bisphosphatase and cytosolic glycerol-3-phosphate dehydrogenase activity was dramatically lower in RCCs. Otherwise, the activity of all other enzymes investigated (glucose-6-phosphate dehydrogenase, enolase and lactate dehydrogenase) was not significantly changed in the RCCs. The immunocytochemical results suggest that L-PK is a useful marker for RCC and its metastases, if acetone-fixed tissue is available. The quantitative changes of the concentration of PK and other enzymes in RCCs when compared with normal renal tissue probably reflect metabolic alterations related to tumour growth.

Carcinoma, Renal Cell↗
PubMed1990

Electron paramagnetic resonance studies of the coordination schemes and site selectivities for divalent metal ions in complexes with pyruvate kinase.

Electron paramagnetic resonance (EPR) spectroscopy has been used to investigate the properties of the binuclear divalent metal center at the active site of pyruvate kinase. The preferred binding sites for different types of divalent cation in complexes of the enzyme with ATP and oxalate were determined in hybrid metal complexes with Mn(II). Superhyperfine coupling between the unpaired electron spin of Mn(II) and the nuclear spin of 17O in isotopically enriched forms of oxalate and ATP was used to determine the position of Mn(II) at the binuclear metal center. When Mn(II) is present in combination with Zn(II), Ni(II), or Co(II), Mn(II) binds predominantly at the site defined by ligands from the protein, oxalate, and the gamma-phosphate of ATP. In contrast, EPR data of samples with mixtures of Mn(II)/Ca(II) or Mn(II)/Cd(II) reveal signals of two distinct hybrid-metal complexes. In one species, Mn(II) binds at the oxalate/gamma-phosphate site, and Ca(II) or Cd(II) binds at the ATP site. In the other species, the positions of Mn(II) and the second metal ion are reversed. The results indicate that, in enzymic complexes with ATP and oxalate, the relative size of the cation is a major factor controlling site selectivity. Metal ions that have ionic radii smaller than Mn(II) bind preferentially at the site occupied by ATP whereas metal ions that have ionic radii larger than Mn(II) bind preferentially at the site occupied by oxalate. EPR data of one of the hybrid complexes formed by Cd(II) and Mn(II) show that an alpha,beta,gamma-tridentate species of MnIIATP binds to the enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗