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PubMed1985

Effects of phosphatase inhibitors on nuclease activity.

Nucleases such as DNase I, which selectively digest chromatin, are inhibited by several commonly used phosphatase inhibitors including sodium bisulfite. Two inhibitors, sodium arsenate and fructose-1,6-diphosphate, did not significantly inhibit nuclease action. Two other effective phosphatase inhibitors, p-chloromercuriphenyl sulfonate and 5,5'-dithiobis(2-nitrobenzoate), can be used during nuclei isolation and then washed out of nuclei before nuclease digestion. Using this procedure, 1mM p-chloromercuriphenyl sulfonate is as effective as 50mM bisulfite in retaining the phosphatase-sensitive mitotic phosphorylations of histones H1 and H3.

4-Chloromercuribenzenesulfonate↗
PubMed1989

On the regulatory properties of the pyruvate kinase from Trypanosoma cruzi epimastigotes.

The pyruvate kinase from Trypanosoma cruzi epimastigotes was activated by fructose 2,6-diphosphate ((A) 0.5 = 0.17 microM), through a decrease in (S) 0.5 and an increase in Vmax for both substrates. The enzyme was 50% inhibited by 0.9 mM ATP or 0.5 mM Pi in the presence of 30 mM MgCl2; these inhibitions were completely counteracted by 1.5 microM fructose 2,6-diphosphate. Both facts suggest that the effects are allosteric, and not due to chelation.

Adenosine Triphosphate↗
PubMed1979

Fructose-1,6-diphosphatase and glucose-6-phosphatase in newborn rats with intrauterine growth retardation.

The activities of two gluconeogenic enzymes, glucose-6-phosphatase and fructose-1,6-diphosphatase were examined in the normal and intrauterine growth retarded (IUGR) rat during the first 5 days of life. The fructose-1,6-diphosphatase activity, 1.54 +/- 0.10 mumol/min/g liver (means +/- SEM) in control and 1.47 +/- 0.20 in the IUGR rats, increased in both groups on days 2--4 but remained significantly lower in the IUGR rats through day 4 (4.53 +/- 0.6 mumol/min/g liver in control and 3.09 +/- 0.22 mumul/min/g liver in the IUGR rats, P less than 0.01). The glucose-6-phosphatase activity increased similarly in both groups. The weight of the IUGR rats remained lower through the third postnatal day (6.47 +/- 0.42 compared to 8.64 +/- 0.27 g in control rats). Blood glucose concentrations at birth were 117 +/- 11 mg/dl in control rats and 73 +/- 11 mg/dl in the IUGR rats (P less than 0.01). Although the glucose concentrations increased in both groups on days 2--4, the IUGR rats maintained relatively lower levels (P less than 0.01). The results indicate that IUGR fetal rats do not have augmented gluconeogenesis in spite of hypoglycemia. In addition, effective gluconeogenesis in the neonatal period appears to be delayed.

Animals↗
PubMed1986

The effect of storage on the kinetic properties of sheep hepatic pyruvate kinase.

The kinetic properties of purified sheep hepatic pyruvate kinase change upon storage. Assayed at 0.5 mM fructose-1,6-diphosphate and 2 mM ADP, saturation of fresh enzyme with phosphoenolpyruvate is hyperbolic, with KPEP = 0.1 mM (pH 7.5, and 30 degrees C). Under similar conditions enzyme stored at -20 degrees C for 1 week or more yields a nonlinear Lineweaver-Burk plot for PEP. The data may be accounted for by the appearance of two enzymic forms with identical turnover numbers, but different KPEP (0.035 +/- 0.005 and 12.4 +/- 0.6 mM). Storage also increases the concentration of fructose-1,6-diphosphate required for maximal activation from nanomolar to millimolar levels. Assayed at 2 mM ADP and 2 mM PEP, the apparent KFDP is 10 mM. Preincubation of stored enzyme with PEP in the presence of mercaptoethanol leads to significant reversion to original kinetic properties. Available data suggest that the storage-dependent change in kinetic behavior rises from changes in subunit conformation and not from dissociation into subunits.

Adenosine Diphosphate↗
PubMed1987

Regulation of hepatic gluconeogenesis and glycogenolysis by phosphorylated glycerol and glycolytic intermediates in diabetic and control Chinese hamsters.

Metabolic regulation of gluconeogenesis and glycogenolysis by two phosphorylated derivatives of glycerol, G3P, and DHAP, and by F2,6BP, was assessed in vitro in liver homogenates obtained from Chinese hamsters (C. griseus) of two types: diabetic animals from sublines with consistent glycosuria and hyperglycemia, and normoglycemic controls. Only FBPase was sensitive to inhibition by the phosphorylated metabolites. G3P was weakly inhibitory of FBPase. Addition of 7 X 10(-3) M DHAP halved FBPase activity in the diabetic hamsters and 4 X 10(-3) M DHAP produced the same effect in the controls. The other gluconeogenic enzymes and phosphorylase a were only negligibly inhibited. In contrast, F2,6BP inhibited FBPase at concentrations in the micromolar range. Liver homogenates from diabetic hamsters appeared significantly more sensitive to F2,6BP inhibition of FBPase than those from controls at concentrations 0.6 X 10(-6) M and higher. These data indicate that in well-fed hamsters phosphorylated glycerol derivatives are unlikely to regulate hepatic gluconeogenesis at physiologic concentrations. However, the effects of F2,6BP on gluconeogenesis and glycolysis may be linked to those mediated by insulin. Thus, the deficiency of insulin, elevated end-organ insulin resistance, the alteration in the glucagon-insulin interaction, or a combination of these possible causes can be involved in an abnormal regulation of glycolysis and gluconeogenesis at the FBPase step, associated with changes in F2,6BP concentration.

Animals↗
PubMed1991

Effect of TPA on fructose 2,6-bisphosphate levels and protein kinase C activity in B-chronic lymphocytic leukemia (B-CLL).

Normal B lymphocytes and peripheral mononuclear blood cells from B-chronic lymphocytic leukemia (B-CLL) patients were incubated in the presence of the tumor promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). In normal B lymphocytes and lymphocytes from five patients with B-CLL, TPA stimulation increased lymphocyte fructose 2,6-bisphosphate (fructose 2,6-P2) content and activity of 6-phosphofructo 2-kinase (PFK-2), which is the enzyme that catalyzes the synthesis of fructose 2,6-P2. This effect was evident after 6 h and maximal after 12-24 h of TPA exposure. In three patients, lymphocytes seemed to be refractory to TPA stimulation in the conditions described here. Lymphocyte stimulation by TPA was associated with the translocation of protein kinase C (PKC) from the soluble to the particulate membrane fraction, except in B-CLL lymphocytes refractory to the TPA effect. These results give further support to the existence within B-CLL of subsets of cells which are refractory to the stimulation by TPA and demonstrate that the tumor promoter TPA induces important metabolic changes in lymphocytes of some patients with B-CLL.

B-Lymphocytes↗
PubMed2006

Roles for fructose-2,6-bisphosphate in the control of fuel metabolism: beyond its allosteric effects on glycolytic and gluconeogenic enzymes.

Fructose-2,6-bisphosphate (F26P2) was identified as a regulator of glucose metabolism over 25 years ago. A truly bifunctional enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (6PFK2/FBP2), with two active sites synthesizes F26P2 from fructose-6-phosphate (F6P) and ATP or degrades F26P2 to F6P and Pi. In the classic view, F26P2 regulates glucose metabolism by allosteric effects on 6-phosphofructo-1-kinase (6PFK1, activation) and fructose-1,6-bisphosphatase (FBPase, inhibition). When levels of F26P2 are high, glycolysis is enhanced and gluconeogenesis is inhibited. In this regard, altering levels of F26P2 via 6PFK2/FBP2 overexpression has been used for metabolic modulation, and has been shown capable of restoring euglycemia in rodent models of diabetes. Recently, a number of novel observations have suggested that F26P2 has much broader effects on the enzymes of glucose metabolism. This is evidenced by the effects of F26P2 on the gene expression of two key glucose metabolic enzymes, glucokinase (GK) and glucose-6-phosphatase (G6Pase). When levels of F26P2 are elevated in the liver, the gene expression and protein amount of GK is increased whereas G6Pase is decreased. These coordinated changes in GK and G6Pase protein illustrate how F26P2 regulates glucose metabolism. F26P2 also affects the gene expression of enzymes related to lipid metabolism. When F26P2 levels are elevated in liver, the expression of two key lipogenic enzymes, acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FAS) is reduced, contributing to a unique coordinated decrease in lipogenesis. When combined, F26P2 effects on glucose and lipid metabolism provide cooperative regulation of fuel metabolism. The regulatory roles for F26P2 have also expanded to transcription factors, as well as certain key proteins (enzymes) of signaling and/or energy sensoring. Although some effects may be secondary to changes in metabolite levels, high levels of F26P2 have been shown to regulate protein amount and/or phosphorylation state of hepatic nuclear factor 1-alpha (HNF1alpha), carbohydrate response element binding protein (ChREBP), peroxisome proliferators-activated receptor alpha (PPARalpha), and peroxisome proliferators-activated receptor gamma co-activator 1beta (PGC1beta), as well as Akt and AMP-activated protein kinase (AMPK). Importantly, changes in these transcription factors, signaling proteins, and sensor proteins are produced in a way that appropriately coordinates whole body fuel metabolism.

Allosteric Regulation↗
PubMed2006

Purification and kinetic properties of 6-phosphofructo-1-kinase from gilthead sea bream muscle.

The kinetic properties of 6-phosphofructo-1-kinase (PFK) from skeletal muscle (PFKM) of gilthead sea bream (Sparus aurata) were studied, after 10,900-fold purification to homogeneity. The native enzyme had an apparent molecular mass of 662 kDa and is composed of 81 kDa subunits, suggesting a homooctameric structure. At physiological pH, S. aurata PFKM exhibited sigmoidal kinetics for the substrates, fructose-6-phosphate (fru-6-P) and ATP. Fructose-2,6-bisphosphate (fru-2,6-P(2)) converted the saturation curves for fru-6-P to hyperbolic, activated PFKM synergistically with other positive effectors of the enzyme such as AMP and ADP, and counteracted ATP and citrate inhibition. The fish enzyme showed differences regarding other animal PFKs: it is active as a homooctamer, and fru-2,6-P(2) and pH affected affinity for ATP. By monitoring incorporation of (32)P from ATP, we show that fish PFKM is a substrate for the cAMP-dependent protein kinase. The mechanism involved in PFKM activation by phosphorylation contrasts with previous observations in other species: it increased V(max) and did not affect affinity for fru-6-P. Unlike the mammalian muscle enzyme, our findings support that phosphorylation of PFKM may exert a major role during starvation in fish muscle.

Adenosine Triphosphate↗
PubMed2006

Stereoselectivity of fructose-1,6-bisphosphate aldolase in Thermus caldophilus.

It was recently established that fructose-1,6-bisphosphate (FBP) aldolase (FBA) and tagatose-1,6-bisphosphate (TBP) aldolase (TBA), two class II aldolases, are highly specific for the diastereoselective synthesis of FBP and TBP from glyceraldehyde-3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP), respectively. In this paper, we report on a FBA from the thermophile Thermus caldophilus GK24 (Tca) that produces both FBP and TBP from C(3) substrates. Moreover, the FBP:TBP ratio could be adjusted by manipulating the concentrations of G3P and DHAP. This is the first native FBA known to show dual diastereoselectivity among the FBAs and TBAs characterized thus far. To explain the behavior of this enzyme, the X-ray crystal structure of the Tca FBA in complex with DHAP was determined at 2.2A resolution. It appears that as a result of alteration of five G3P binding residues, the substrate binding cavity of Tca FBA has a greater volume than those in the Escherichia coli FBA-phosphoglycolohydroxamate (PGH) and TBA-PGH complexes. We suggest that this steric difference underlies the difference in the diastereoselectivities of these class II aldolases.

Binding Sites↗
PubMed2004

Neuroprotection by fructose-1,6-bisphosphate involves ROS alterations via p38 MAPK/ERK.

Fructose-1,6-bisphosphate (FBP) is a glucose metabolism intermediate that shows a neuroprotective action in animal models of ischemia and other injuries. The intracellular mechanism of FBP on neuroprotection has not been previously defined. Here, we examined whether FBP has a neuroprotective effect against excitotoxicity, and whether it affects the production of reactive oxygen species (ROS), which are involved in the MAPK pathway in cortical neurons. FBP prevented neuronal death in a dose-dependent manner following 24 h of treatment with the excitotoxin, NMDA. After 8 h of NMDA treatment, we observed FBP-induced inhibition of the production of intracellular ROS, and at the earlier time FBP suppressed NMDA-induced p-p38 and p-ERK expression. In addition, MAPK inhibitors reduced NMDA-induced excitotoxicity and also ROS production. Taken together, our results suggest that the neuroprotective effects of FBP could be explained by down-regulation of free radical production through the p38MAPK/ERK pathway.

Animals↗