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PubMed1989

Primary structure of three peptides at the catalytic and allosteric sites of the fructose-1,6-bisphosphate-activated pyruvate kinase from Escherichia coli.

Three peptides containing 6-pyridoxyllysine have been isolated from the tryptic digest of the allosteric fructose-1,6-bisphosphate-dependent pyruvate kinase from Escherichia coli, which had been almost completely inactivated with pyridoxal 5'-phosphate. The labelled peptides have been sequenced. The comparison of their sequences with the primary structure of the cat muscle pyruvate kinase allowed to state that peptide I fits the region spanning residues 423-438 (53% identity), peptide II corresponds to residues 442-457 (44% identity) and peptide III encompasses residues 342-368 (70% identity). These findings are discussed in connection with our previous results on the involvement of the three peptides in the catalytic and regulatory properties of the enzyme (Valentini, G., Speranza, M.L., Iadarola, P., Ferri, G. & Malcovati, M. (1988) Biol. Chem. Hoppe-Seyler 369, 1219-1226) and in connection with their location in the three-dimensional structure of the cat muscle pyruvate kinase (Muirhead, H., Clayden, D.A., Lorimer, C.G., Fothergill-Gilmore, L.A., Schiltz, E. & Schmitt, W. (1986) EMBO J. 5, 475-481).

Amino Acid Sequence↗
PubMed1990

Structure and function of L-lactate dehydrogenases from thermophilic and mesophilic bacteria, X. Analysis of structural elements responsible for the differences in thermostability and activation by fructose 1,6-bisphosphate in the lactate dehydrogenases from B. stearothermophilus and B. caldolyticus by protein engineering.

The amino-acid sequences of the lactate dehydrogenases (LDH) from B. stearothermophilus and B. caldolyticus differ at only 10 positions. The properties of these enzymes however show substantial differences. The LDH from B. stearothermophilus is activated by Fru-P2 and has a higher thermostability (10 degrees C) than the enzyme from B. caldolyticus which cannot be activated by Fru-P2. To correlate these functional differences to the structural properties, we have constructed a set of hybrid- and point-mutants of the two LDHs. The amino acids at positions 207, 209B, and 209C could be identified to confer the property of activation by Fru-P2 to the enzymes. This part of the enzyme is to a large extent also responsible for the different thermostabilities of these two proteins.

Amino Acid Sequence↗
PubMed1990

Regulation of the fructose 6-phosphate/fructose 2,6-bisphosphate cycle by enzyme phosphorylation and sn-glycerol 3-phosphate.

The regulation of the Fru-6-P/Fru-2,6-P2 cycle by the cooperation of allosteric and covalent mechanisms was investigated in a reconstituted enzyme system under in vitro conditions. Phosphorylation of the bifunctional enzyme exerts a much stronger effect than sn-glycerol 3-phosphate in lowering the quasi-stationary concentration of fructose 2,6-bisphosphate and in increasing the critical concentration of the fructose phosphates, respectively. However, sn-glycerol 3-phosphate is able to strongly amplify the decrease of the quasi-stationary concentration of fructose 2,6-bisphosphate due to phosphorylation. The experiments can be described by a mathematical model involving rate equations for the dephosphorylated and the phosphorylated PFD-2 and FBPase-2. The results are compared with data from the literature obtained under in vivo conditions.

Animals↗
PubMed1991

Structure and function of L-lactate dehydrogenases from thermophilic and mesophilic bacteria, XI. Engineering thermostability and activity of lactate dehydrogenases from bacilli.

An extensive comparative structural analysis of lactate dehydrogenase (LDH) sequences from thermophilic, mesophilic and psychrophilic bacilli revealed characteristic primary structural differences. These specific amino-acid substitutions were found in the entire LDH molecule. However, in certain regions of the LDH an accumulation of these exchanges could be detected. These regions seem to be particularly important for the temperature adaptation of the enzyme. The influence of one of such regions at the N-terminus on stability and activity of LDHs was analysed by the construction of hybrid mutants between LDH sequences from thermophilic, mesophilic and psychrophilic bacilli and also by site-directed mutagenesis experiments at five different positions. The substitutions of Thr-29 or Ser-39 to Ala residues in the LDH from the mesophilic B. megaterium increased the thermostability of the enzyme drastically (15 degrees C). An increase of 20 degrees C could be observed when both amino-acid substitutions were introduced. These amino-acid substitutions resulted in an increase of Km for pyruvate and led to a three-fold reduction of the activity (kcat/Km) at 40 degrees C compared with the wild type enzyme. The influence of these amino-acid substitutions was also investigated in the LDHs from thermophilic and psychrophilic bacilli. The high heat resistance of the LDH from the thermophilic B. stearothermophilus was not altered by the Ala to Thr and Ser substitutions at positions 29 and 39, respectively. This indicates a cooperatively stabilized conformation of this LDH. However, in this mutant of the B. stearothermophilus LDH the activity (kcat/Km) was increased two-fold.

Amino Acid Sequence↗
PubMed1993

Attenuation of insulin actions in primary rat hepatocyte cultures by phenylarsine oxide.

Phenylarsine oxide (PAO), a trivalent arsenical which complexes vicinal dithiols, prevented the action of insulin in primary cultured adult rat hepatocytes. Simultaneous short-term treatment of 48-h old cells with insulin and 2 microM PAO resulted in complete attenuation of the insulin-dependent increase in the level of fructose 2,6-bisphosphate and the activation of phosphofructokinase 2, pyruvate kinase, glucokinase flux and glycolysis. Basal rates of glucose transport and glycolysis were not affected. PAO also abolished stimulation of glycogen synthesis and amino-acid transport and the decrease of glycogenolysis evoked by insulin. The 20-fold activation of the insulin receptor tyrosine kinase by insulin was, however, not reduced by PAO. The data suggest that in differentiated hepatocytes insulin signal transduction involves vicinal sulhydryls located at a post-receptor step.

Amino Acids↗
PubMed1995

Bistability and damped oscillations in the fructose 6-phosphate/fructose 1,6-bisphosphate cycle in cell-free extracts from rat liver.

The dynamics of the fructose 6-phosphate/fructose 1,6-bisphosphate substrate cycle was investigated in cell-free extracts from rat liver. Under conditions of continuous substrate supply different types of stationary states and damped oscillations were observed experimentally and found to be in qualitative agreement with theoretical predictions. Changing the adenylate energy charge of the substrate supply, bistability was shown to be related to irreversible transitions between functionally different branches of stable stationary states.

Animals↗
PubMed1986

Effect of glucose on ATP dephosphorylation in rat spermatids.

Round spermatids were isolated from rat testes and the effects of different energy-yielding substrates on the cellular ATP content were estimated. The ATP content was constant and high (6-8 nmol/10(6) cells) during metabolism of exogenous lactate. During incubation for 30 min in the absence of exogenous lactate, there was a remarkably slow decline of the ATP content, indicating ATP production from other substrates. It was shown that this could reflect beta-oxidation of fatty acids, but not the mobilization of an endogenous pool of acetylcarnitine. Glucose metabolism in the absence of exogenous lactate resulted in a rapid decline of the ATP content. This effect of glucose was correlated with a high fructose 1,6-biphosphate content (6-7 nmol/10(6) cells) and could be prevented by the addition of lactate. It is suggested that metabolism of glucose (and also mannose and fructose, but not galactose) in the absence of exogenous lactate can result in ATP dephosphorylation.

Adenosine Triphosphate↗
PubMed1987

Futile substrate cycles in the glycolytic pathway of boar and rat spermatozoa and the effect of alpha-chlorohydrin.

In boar spermatozoa incubated with 0.1 mM-glucose about 20 nmol glucose were converted to lactate and CO2 and the rate of futile substrate cycling between glucose and glucose 6-phosphate was about 6 nmol/10(8) spermatozoa/30 min. Futile cycling was increased in the presence of 0.05 or 1 mM-alpha-chlorohydrin but not to an extent sufficient to account for the rapid decline in ATP concentration observed under these conditions. These estimates include a substantial rate of fructose formation from fructose phosphates. The addition of 10 mM-L-lactate plus 1 mM-pyruvate protected the spermatozoa against the effect of alpha-chlorohydrin and glucose on the ATP concentration but increased futile substrate cycling. Substrate cycling between fructose 6-phosphate and fructose 1,6-bisphosphate could not be measured in boar spermatozoa but in rat spermatozoa its rate (nmol/10(8) spermatozoa/30 min) was about 10 under control condition and about 25 in the presence of 1 mM-alpha-chlorohydrin. This increase was insufficient to account for the decline in ATP concentration. In both species futile substrate cycling consumed a significant proportion of the ATP synthesis during lactate production but only about 5% of that produced in the oxidation of glucose to acetyl carnitine and CO2.

Adenosine Triphosphate↗
PubMed1992

Metabolism of glycerol by mature boar spermatozoa.

Mature boar spermatozoa oxidized glycerol to carbon dioxide in the absence of any detectable activity of glycerol kinase. With triosephosphate isomerase and glyceraldehyde-3-phosphate dehydrogenase inhibited by the presence of 3-chloro-1-hydroxypropanone (CHOP), dihydroxyacetone phosphate accumulated in incubates when glycerol-3-phosphate was the substrate, but not when it was glycerol. Both dihydroxyacetone and glyceraldehyde could be used as substrates; in the presence of CHOP, dihydroxyacetone phosphate and fructose-1,6-bisphosphate accumulated when dihydroxyacetone was the substrate, but not when it was glyceraldehyde. The metabolic pathways glycerol----glyceraldehyde----glyceraldehyde 3-phosphate and dihydroxyacetone----dihydroxyacetone phosphate have been shown to operate in these cells.

Animals↗
PubMed2006

Fructose-1,6-bisphosphate supports cerebral energy metabolism in pigs after ischemic brain injury caused by experimental particle embolization.

BACKGROUND: Fructose-1,6-bisphosphate (FDP) is a high-energy intermediate that enhances glycolysis, preserves cellular adenosine triphosphate stores, and prevents the increase of intracellular calcium in ischemic tissue. Since it has been shown to provide metabolic support to the brain during ischemia, we planned this study to evaluate whether FDP is neuroprotective in the setting of combining hypothermic circulatory arrest (HCA) and irreversible embolic brain ischemic injury. METHODS: Twenty pigs were randomly assigned to receive 2 intravenous infusions of either FDP (500 mg/kg) or saline. The first infusion was given just before a 25-minute period of HCA and the second infusion immediately after HCA. Immediately before HCA, the descending aorta was clamped and 200 mg of albumin-coated polystyrene microspheres (250-750 mm in diameter) were injected into the isolated aortic arch in both study groups. RESULTS: There were no significant differences between the study groups in terms of neurological outcome. Brain lactate/pyruvate ratio was significantly lower (P = .015) and brain pyruvate levels (P = .013) were significantly higher in the FDP group compared with controls. Brain lactate levels were significantly higher 8 hours after HCA (P = .049). CONCLUSION: The administration of FDP before and immediately after HCA combined with embolic brain ischemic injury was associated with significantly lower brain lactate/pyruvate ratio and significantly higher levels of brain pyruvate, as well as lower lactate levels 8 hours after HCA. FDP seems to protect the brain by supporting energy metabolism. The neurological outcome was not improved, most likely resulting from the irreversible nature of the microsphere occlusion.

Animals↗
PubMed2005

Effects of fructose-1,6-diphosphate on concentration of calcium and activities of sarcoplosnic Ca2+-ATPase in cardiomyocytes of Adriamycin-treated rats.

OBJECTIVE: To observe the effects of fructose-1,6-diphosphate (FDP) on serum levels of cardiac troponin I (cTnI) and creatine kinase-MB (CK-MB), as well as the concentration of calcium in cardiomyocytes (Myo[Ca(2+)]) and activity of sarcoplosnic Ca(2+)-ATPase (SRCa(2+)-ATPase) in Adriamycin (ADR)-treated rats. METHODS: Rats were intraperitoneally injected with ADR (2.5 mg/kg every other day for 6 times) and then with different dosages of FDP (every other day for twenty-one times). Bi-antibodies sandwich Enzyme linked immune absorption assay (ELISA) was performed to detect serum level of cTnI. CK-MB was detected by monoclonal antibody, Myo[Ca(2+)] was detected by fluorescent spectrophotometry and the activity of SRCa(2+)-ATPase was detected by inorganic phosphate method. RESULTS: FDP (300, 600, 1200 mg/kg) significantly reduced the serum levels of cTnI and CK-MB, while at the same time decreased calcium concentration and increased SRCa(2+)-ATPase activity in cardiomyocytes of ADR-treated rats (P<0.01). CONCLUSIONS: FDP might alleviate the cardiotoxic effects induced by ADR through decreasing calcium level as well as increasing SRCa(2+)-ATPase activity in cardiomyocytes.

Animals↗
PubMed1985

Lactic acid and steroid production by intact mouse adrenal glands and cell suspensions: effects of nucleotide derivatives and substrates.

The effects of the dibutyryl derivatives of cyclic GMP and cyclic AMP on lactic acid and steroid production were compared in intact mouse adrenal glands at concentrations of 0.5-1 mmol/l and in mouse adrenal cell suspensions at concentrations of 0.01-1 mmol/l. The dibutyryl derivative of cyclic GMP had little or no effect on lactic acid production in either tissue preparation. It caused a slight stimulation of corticosteroid output in intact glands at a concentration of 1 mmol/l, amounting to one-tenth of the response observed with 1 mM-dibutyryl cyclic AMP. Dose-dependent increases in lactic acid and steroid production were obtained with dibutyryl cyclic AMP in cell suspensions. AMP and GMP increased lactic acid but not steroid production. All the substrates tested (glucose, glucose-6-phosphate, fructose, fructose-6-phosphate, fructose-1,6-diphosphate, 10 mmol/l; pyruvate and glycerol, 20 mmol/l) stimulated basal glycolysis in intact glands and cell suspensions and none affected basal steroid production significantly. By far the greatest increase in lactic acid production was noted with fructose-1,6-diphosphate. However, only glucose and, in unsectioned glands, pyruvate exerted a potentiating effect on the glycolytic response to ACTH. Glucose potentiated the steroidogenic response to ACTH also, but only in intact glands. The relative ineffectiveness of dibutyryl cyclic GMP is in accord with the species-dependent differing responses to the free form of the cyclic nucleotides noted in mouse and rat adrenal glands. The substrate requirements are in keeping with a rate-limiting role of phosphofructokinase and an action of ACTH at some site between the entry of glucose into the cell and the formation of fructose-1,6-diphosphate.

Adrenal Glands↗
PubMed1992

Effects of in-vivo administration of insulin-like growth factor-I on the rate of glucose utilization in the soleus muscle of the rat.

This study investigated the effects of insulin-like growth factor-I (IGF-I) administered to rats in vivo on the soleus muscle isolated from these rats. In order to study the interactions between IGF-I and insulin, the soleus muscles were incubated in the presence of various concentrations of insulin. IGF-I (190-200 micrograms) was given twice daily; the rats were killed 1 h after one injection of IGF-I (acute administration) or after treatment with IGF-I for 10 days (prolonged administration). The level of IGF-I in plasma was increased by approximately 100% after acute administration and by around 30% after 10 days of treatment with IGF-I. Acute administration of IGF-I to the rats increased the flux of glucose to hexose monophosphate and the rates of lactate formation and glycogen synthesis in the soleus muscles; however, the responsiveness of these muscles to insulin was lost: the increase in the rate of glucose utilization by IGF-I at physiological concentrations of insulin (10 or 100 mU/l) was similar to that observed at maximal concentrations of insulin (1000 mU/l). Similar results were obtained after prolonged treatment of the rats with IGF-I; however, the increase in the rate of glucose utilization was less pronounced than when IGF-I was given acutely and the muscles were still capable of responding to insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2001

Regulation of glucogenesis by thyroid hormones in fetal sheep during late gestation.

The effects of thyroid hormone deficiency in utero on the fetal glucogenic capacity were investigated by measuring glucose production and hepatic levels of glycogen and gluconeogenic enzymes in normal sheep fetuses in the fed and fasted states during late gestation and in those made thyroid hormone deficient by fetal thyroidectomy (TX). In the fed state, fetal TX had no effect on glucose uptake, utilisation or production by the fetus. It also had no apparent effect on the glycogen content or activities of the key gluconeogenic enzymes in the fetal liver. In addition, fetal plasma concentrations of insulin, cortisol, adrenaline or noradrenaline were unaffected by fetal TX in the fed state. In contrast, the rates of fetal O(2) consumption and CO(2) production per kilogram fetal bodyweight were significantly lower in TX than in intact fetuses in the fed state (P<0.05). TX prevented fetal glucose production in response to maternal fasting for 48 h. It also abolished the normal decreases in the fetal glucose carbon oxidation fraction, the rate of CO(2) production from glucose carbon and in the fraction of the umbilical O(2) uptake used for glucose carbon oxidation that occur during fasting in intact fetuses. At the end of the fast, plasma noradrenaline concentrations and hepatic levels of glycogen, glucose 6-phosphatase, fructose diphosphatase and alanine aminotransferase were significantly lower in TX than in intact fetuses. These observations show that thyroid hormones are essential for glucogenesis in the sheep fetus during late gestation and suggest that these hormones act both on the hepatic glucogenic pathways and on the mechanisms activating glucogenesis in utero.

Alanine Transaminase↗
PubMed1996

Hereditary deficiency of lactate dehydrogenase H-subunit.

We report herein the fifth family of hereditary deficiency of lactate dehydrogenase (LDH) H-subunit with an autosomal recessive inheritance including two cases of complete deficiency. Their LDH activities were low both in the serum and in the red blood cells (RBC). Electrophoretic analysis revealed that the patients with the complete deficiency had only the LDH5 isozyme. The complete deficiency was associated with marked elevation of fructose-1, 6-diphosphate (FDP) and dihydroxyacetonephosphate (DHAP) and a less marked rise in glyceraldehyde-3-phosphate (GA3P) among glycolytic intermediates in the RBC. Furthermore, hemolysis was observed in the present cases, but this finding was not included in the other reports.

Consanguinity↗
PubMed1981

Effect of diabetes, insulin, starvation, and refeeding on the level of rat hepatic fructose 2,6-bisphosphate.

The influence of alloxan diabetes and starvation for 72 h on the level of rat hepatic fructose 2,6-biphosphate was investigated. Both diabetes and starvation decreased the level to 10% of the value found in livers of normal, fed rats (10 nmol/g liver). The activity of the enzyme responsible for the synthesis of fructose 2,6-bisphosphate, 6-phosphofructo 2-kinase, was also decreased in livers of diabetic rats. Insulin administration for 24 h to diabetic rats restored the level of fructose 2,6-bisphosphate to normal. Refeeding a high carbohydrate diet for 24 h to starved rats resulted in fructose, 2,6-biphosphate levels that were 2.5-fold higher than that in livers of fed rats. The level of fructose 2,6-bisphosphate in diabetes and starvation, and after refeeding correlates as well with the rate of glycolysis and gluconeogenesis in these states and thereby provides further support for its role in regulating hepatic carbohydrate metabolism.

Animals↗