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PubMed1992

Arg-257 and Arg-307 of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase bind the C-2 phospho group of fructose-2,6-bisphosphate in the fructose-2,6-bisphosphatase domain.

Rat liver fructose-2,6-bisphosphatase, which catalyzes its reaction via a phosphoenzyme intermediate, is evolutionarily related to the phosphoglycerate mutase enzyme family (Bazan, F., Fletterick, R., and Pilkis, S.J. (1989) Proc. Natl. Acad. Sci. U.S.A. 86, 9642-9646). Arg-7 and Arg-59 of the yeast phosphoglycerate mutase have been postulated to be substrate-binding residues based on the x-ray crystal structure. The corresponding residues in rat liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, Arg-257 and Arg-307, were mutated to alanine. The Arg257Ala and Arg307Ala mutants and the wild-type enzyme were expressed in Escherichia coli and then purified to homogeneity. Both mutant enzymes had identical far and near UV circular dichroism spectra and 6-phosphofructo-2-kinase activities when compared with the wild-type enzyme. However, the Arg257Ala and Arg307Ala mutants had altered steady state fructose-2,6-bisphosphatase kinetic properties; the Km values for fructose-2,6-bisphosphate of the Arg257Ala and Arg307Ala mutants were increased by 12,500- and 760-fold, whereas the Ki values for inorganic phosphate were increased 7.4- and 147-fold, respectively, as compared with the wild-type values. However, the Ki values for the other product, fructose-6-phosphate, were unchanged for the mutant enzymes. Although both mutants exhibited parallel changes in kinetic parameters that reflect substrate/product binding, they had opposing effects on their respective maximal velocities; the maximal velocity of Arg257Ala was 11-fold higher, whereas that for Arg307Ala was 700-fold lower, than that of the wild-type enzyme. Pre-steady state kinetic studies demonstrated that the rate of phosphoenzyme formation for Arg307Ala was at least 4000-fold lower than that of the wild-type enzyme, whereas the rate for Arg257Ala was similar to the wild-type enzyme. Furthermore, consistent with the Vmax changes, the rate constant for phosphoenzyme breakdown for Arg257Ala was increased 9-fold, whereas that for Arg307Ala was decreased by a factor of 500-fold, as compared with the wild-type value. The results indicate that both Arg-257 and Arg-307 interact with the reactive C-2 phospho group of fructose 2,6-bisphosphate and that Arg-307 stabilizes this phospho group in the transition state during phosphoenzyme breakdown, whereas Arg-257 stabilizes the phospho group of the ground state phosphoenzyme intermediate.

Amino Acid Sequence↗

PubMed1994

cDNA sequences encoding human fructose 1,6-bisphosphatase from monocytes, liver and kidney: application of monocytes to molecular analysis of human fructose 1,6-bisphosphatase deficiency.

Fructose 1,6-bisphosphatase deficiency is an autosomal recessive inherited disorder of gluconeogenesis. We could isolate cDNAs encoding human fructose 1,6-bisphosphatase from normal monocytes, liver and kidney, but not from normal lymphocytes. The cDNAs contained an open reading frame coding for 338 amino acids, and their nucleotide sequences in monocytes and liver were identical. G644C645 nucleotides in this sequence were the same as those of cDNA from HL-60 cells, although our result differed from a previous report (M. El-Maghrabi et al. (1993) J. Biol. Chem. 268, 9466-9472) on an alteration to C644G645 nucleotides in human liver cDNA resulting in a change of Gly-214 to Ala-214 in the enzyme. The Gly-214 (GGC) residue was therefore conserved in the enzymes hitherto isolated from humans and other animals. Analysis of monocytes in seven patients with fructose 1,6-bisphosphatase deficiency showed a DNA fragment with apparent normal size in two sisters but no detectable DNA fragment in the other five patients. Monocytes were thus useful as an alternative source for mRNA from human liver for the molecular analysis of fructose 1,6-bisphosphatase deficiency.

Alanine↗

PubMed1987

Fructose-1-phosphate and fructose-1,6-bisphosphate aldolases in the small intestinal mucosa.

Reference values are presented for the activity of fructose-1-phosphate aldolase (F1PA) and fructose-1,6-bisphosphate aldolase (FBPA) in the small intestinal mucosa of 32 nonaffected children, 8 nonaffected adults and 2 children with hereditary fructose intolerance (HFI). The 96% confidence limits for F1PA in children are 1.55 to 43.0 u/g protein, completely distinct from the results of the two affected children (1.3 and less than 0.1 u/g protein). With fructose-1,6-bisphosphate as subtrate, the 96% confidence limits are 10 to 324 u/g protein and the values for the two affected children, 23.7 and 9.3 u/g. Among the nonaffected children two mucosal biopsies with F1PA activities less than 1.55 u/g were found. In one mucosal biopsy among the nonaffected children an FBPA activity less than 10 u/g was recorded. The data are interpreted as indicating that the determination of F1PA activity in intestinal mucosa is a highly sensitive test in detecting individuals with HFI. However, the specifity of the test is not absolute. Diagnosis should be based on both clinical and laboratory considerations. The determination of FBPA activity in the same biopsy specimen does not contribute substantially to the differential diagnosis.

Adult↗

PubMedDate not supplied

[Theoretical evidence for the need to suppress parasitic recirculation in the futile cycle fructose-6-P--fructose-1,6-P2].

In connection with the discussion of a possible role of the futile cycle fructose-6-P in equilibrium or formed from fructose-1,6,-P2 in the regulation of the carbohydrate energy metabolism, simple stoichiometric models of glycolysis and gluconeogenesis are examined which take account of substrate recirculation in the cycle. The recirculation is shown to involve wasteful expenditure of ATP and to divert fructose-1,6-P2 from glycolytic phosphorylation ADP and fructose-6-P from glucose or glycogen resynthesis. As a result, the glycolytic system loses its capacity to stabilize the level of ATP, while gluconeogenesis proves to be not efficient. From the analysis performed it is concluded that normal energy metabolism should involve allosteric regulatory mechanisms to suppress substrate recirculation in the cycle.

Adenosine Diphosphate↗

PubMed1978

[Postoperative fructose infusion in a case of presumed hereditary fructose intolerance (author's transl)].

Hereditary fructose intolerance (HFI) was diagnosed in a 61 year-old male patient on account of liver dysfunction followed by prolonged shock immediately after the administration of a fructose and lactose infusion postoperatively. The diagnosis of HFI was based on an increased value of fructose, hypoglycaemia, lactic acidosis and diminution of the phosphate level in combination with the typical family history. The patient's children showed a normal reaction to fructose administration. The therapy included glucose, insulin and heparin administration, balance of acidosis and partial exchange of blood, which resulted in improvement in the glucose level, coagulation factors and acidosis, but could not prevent further liver damage and uraemia with a fatal outcome.

Acidosis↗

PubMed1990

[Adults with hereditary fructose intolerance: risks of fructose infusion].

After her first grand mal seizure a 30-year-old woman was given a fructose infusion by an emergency doctor. On admission to hospital she complained of severe nausea. Ultrasonography revealed hepatosplenomegaly and the gamma-GT concentration was raised to 25 U/l. As hyperinsulinism was suspected an oral glucose tolerance test was suggested, but refused by the patient. She reported marked aversion to all sweet foods. Examination of an endoscopically obtained liver biopsy revealed clear reduction in fructoaldolase activity in liver tissue, i.e. the diagnosis of hereditary fructose intolerance. Three of the patient's siblings were also affected. The widespread use of infusion solutions containing sorbitol and fructose has twice proved acutely hazardous in this patient and is generally life-threatening for persons with an inborn error of metabolism whose pathologic status often remains undiagnosed to an adult age.

Adult↗

PubMed1983

Synergistic effect of AMP and fructose 2,6-bisphosphate on the protection of fructose 1,6-bisphosphatase against inactivation by trypsin.

The rate of inactivation of chicken liver fructose 1,6-bisphosphatase by trypsin is reduced if the digestive reaction is conducted in the presence of AMP or fructose 2,6-bisphosphate. The effects of these 2 compounds are synergistic. Although fructose 1,6-bisphosphate does not protect the enzyme against tryptic inactivation, it can enhance the effect of AMP. Selective modification of the AMP allosteric site of fructose 1,6-bisphosphatase with pyridoxal-P and NaBH4 renders the enzyme more resistant to tryptic inactivation, but the modified enzyme is no longer responsive to the protective effect of AMP.

Adenosine Monophosphate↗

PubMed1992

Mineral balances in humans as affected by fructose, high fructose corn syrup and sucrose.

The utilization of selected minerals when sugars were supplemented to basal diets was investigated in two separate, laboratory-controlled human feeding studies. Fructose-fed subjects had higher fecal excretions of iron and magnesium than did subjects fed sucrose. Apparent iron, magnesium, calcium, and zinc balances tended to be less positive during the fructose feeding period as compared to balances during the sucrose feeding period. Conversely, high fructose corn syrup (HFCS) did not affect the mineral balances when compared to sucrose feeding. Subjects fed fructose experienced diarrhea which possibly decreased absorption of minerals and thus increased fecal mineral losses. No such adverse effects were noticed when HFCS was fed.

Absorption↗

PubMed1983

Cyclic AMP and fructose-2,6-bisphosphate stimulated in vitro phosphorylation of yeast fructose-1,6-bisphosphatase.

Phosphorylation of purified yeast fructose-1,6-bisphosphatase was studied using purified preparations from yeast of two different cyclic AMP-independent protein kinases and a cyclic AMP-dependent protein kinase. Incorporation of 32P into fructose-1,6-bisphosphatase could be demonstrated only with the cyclic AMP-dependent protein kinase. Phosphorylation of fructose-1,6-bisphosphatase was stimulated by 3 microM fructose-2,6-bisphosphate and inhibited by 1 mM 5'-AMP.

Cyclic AMP↗

PubMed1984

Effects of ethanol, fructose, and ethanol plus fructose infusions on plasma glucose concentration and glucose turnover in monkeys (Macaca fascicularis) as measured by [6-3H]glucose.

Six adult, female, cynomolgus monkeys were fasted for 64 hr and then continuously infused with [6-3H]glucose to determine the rates of glucose turnover and clearance while they were also being infused with ethanol (110 mumol/min/kg), 1,3-butanediol (110 mumol/min/kg), fructose (30 mumol/min/kg) or ethanol plus fructose (110 and 30 mumol/min/kg) respectively. Both ethanol and 1,3-butanediol infusions decreased the glucose turnover rate (the steady-state input-output rate from the plasma glucose pool) and the plasma glucose concentration by halving the glucose production rate. In contrast, fructose infusions increased the glucose turnover rate and glucose concentration by increasing the glucose production rate by 20%. The plasma clearance rate of glucose was lowest when the animals were infused with ethanol plus fructose; this suggests that acetate from ethanol oxidation may have a glucose-sparing effect if normoglycemia is maintained.

Animals↗

PubMed1977

[The fructose induces "glycogenosis". III. Histochemical and morphometrical studies of glycogen metabolism in mouse liver after fructose overload (author's transl)].

INTRODUCTION: After feeding fructose for 7 days rat liver cells show an accumulation of glycogen, a high activity of glucose-6-phosphatase combined with a SER- and RER-reduction. This result was reviewed by mouse liver cells using histochemical and morphometrical methods. MATERIAL AND METHODS: 60% fructose in drinking water was given mice as only nutritional source. Controls had free access to Altromin-R-standard diet and drinking water. Glycogen and glycogen metabolizing enzymes are demonstrated in the course of an 1-14 days fructose diet. After a 7 days diet liver tissue was analysed morphometrically. RESULTS AND DISCUSSION: Feeding of fructose leads to a high glycogen content, combined with a high activity of glycogen-phosphorylase and glucose-6-phosphatase in the liver parenchyma of mouse. Glycogen-synthetase activity falls to a low level. The SER and RER and the peroxisomes are reduced. The single volume of the hepatic nucleus is decreased and the hepatocellular chondrioma is transformed in a smaller number of larger mitochondria. Compared with the rate the analysed organelles and enzymes of mouse liver show only slight quantitative differences. The increase of glucose-6-phosphatase and simultaneous reduction of endoplasmic reticulum-membranes is illustrated by the dynamic structure of endoplasmic reticulum-membranes, which adapt to metabolic changes. The variable turnover of different parts of endoplasmic reticulum-membranes seems to be very important.

Animals↗

PubMed2000

Synthesis and evaluation of fructose analogues as inhibitors of the D-fructose transporter GLUT5.

We have examined the specificity and binding-site spatial requirements of the fructose transporter GLUT5. Interaction with a series of fructofuranosides and fructopyranosides suggests that both furanose and pyranose ring forms of D-fructose combine with GLUT5. The epimers of D-fructose all have low affinity for GLUT5 suggesting that the transporter requires all hydroxyls to be in the fructo-configuration. Similarly there is poor tolerance of all allyl derivatives of D-fructose except 6-O-allyl-D-fructofuranose. Therefore, the C-6 position offers the most suitable position for development of affinity probes and labels for exploring GLUT5 biochemistry.

Animals↗

PubMed1981

Inhibition of fructose-1,6-bisphosphatase by fructose 2,6-biphosphate.

Fructose 2,6-bisphosphate, a known powerful stimulator of phosphofructokinase [Van Schaftingen, E., Hue, L. & Hers, H.-G. (1980) Biochem. J. 192, 897-901] was found to inhibit, at micromolar concentrations, liver and muscle fructose-1,6-biphosphate (D-fructose-1,6-bisphosphate 1-phosphohydrolase, EC 3.1.3.11). The main characteristics of this inhibition are that (i) it is much stronger at low than at high substrate concentrations, (ii) it changes the substrate saturation curve from almost hyperbolic to sigmoidal, and (iii) it is synergistic with the inhibition by AMP. This inhibition may play an important role in the stimulation of gluconeogenesis by glucagon, because this hormone is known to decrease the concentration of fructose 2,6-bisphosphate in the liver [Van Schaftingen, E., Hue, L. & Hers, H.-G. (1980) Biochem. J. 192, 887-895].

Adenosine Monophosphate↗

PubMed1992

Crystal structure of the neutral form of fructose 1,6-bisphosphatase complexed with regulatory inhibitor fructose 2,6-bisphosphate at 2.6-A resolution.

The three-dimensional structure of the complex between fructose 1,6-bisphosphatase (EC 3.1.3.11) and the physiological inhibitor beta-D-fructose 2,6-bisphosphate (Fru-2,6-P2), an analogue of the substrate (fructose 1,6-bisphosphate), has been refined at 2.6-A resolution to a residual error (R) factor of 0.171. The rms deviations are 0.012 A and 2.88 degrees from ideal geometries of bond lengths and angles, respectively. The Fru-2,6-P2 occupies the active sites of both polypeptides C1 and C2 in the crystallographic asymmetric unit in the space group P3(2)21. The furanose and 6-phosphate of Fru-2,6-P2 are located at the fructose 6-phosphate site established earlier, and the 2-phosphate binds to the OH of Ser-124, the NH3+ of Lys-274, and the backbone NH of Gly-122 and Ser-123. Backbone displacements of 1 A occur for residues from Asp-121 to Asn-125. Model building of substrate alpha-D-Fru-1,6-P2 based on the binding structure of Fru-2,6-P2 in the active site shows interactions of the 1-phosphate with the backbone NH of Ser-123 and Ser-124. In the AMP sites, density peaks attributed to Fru-2,6-P2 are seen in C1 (and C4) but not in C2 (and C3). This minor binding of Fru-2,6-P2 to AMP sites partially explains the synergistic interaction between AMP and Fru-2,6-P2 and the protection of the AMP site from acetylation in the presence of Fru-2,6-P2. In the synergistic interaction between AMP and Fru-2,6-P2, inhibition of catalytic metal binding by the presence of Fru-2,6-P2 at the active site, and propagation of structural changes over some 28 A along beta-strand B3 from residues 121 to 125 in the active site to Lys-112 and Tyr-113 in the AMP site, as well as movement of helices across the interdimeric interfaces, may affect AMP binding and the subsequent R-to-T transition. In addition, occupancy of Fru-2,6-P2 at the AMP sites of C1 and C4 may favor binding of AMP to the remaining unoccupied AMP sites and thus promote the accompanying quaternary conformational changes.

Amino Acid Sequence↗

PubMed1993

Fructose and behavior: does fructose influence food intake and macronutrient selection?

Fructose, as compared with other sugars, may have a suppressant effect on subsequent food intake and may result in a different selection of macronutrients. The research investigating these effects and the possible underlying mechanisms of action is reviewed. These mechanisms include fructose's effects on the rate of gastric emptying, concentrations of plasma glucose and insulin, and hepatic metabolism. The research is not conclusive. Questions that remain to be examined more thoroughly are the time course of fructose's effects on food intake and macronutrient selection in the short-term, and effects of long-term administration of fructose on these appetitive processes.

Dietary Carbohydrates↗

PubMed1980

Resolution of the phosphoenolpyruvate: fructose phosphotransferase system of Escherichia coli into two components: enzyme IIfructose and fructose-induced HPr-like protein (FPr).

A protein that substitutes for histidine-containing protein (HPr) in the phosphoenolpyruvate, fructose phosphotransferase system has been found in Escherichia coli grown on fructose. The impure preparation of the fructose-induced HPr-like protein (FPr) appears to be an extrinsic membrane protein which differs from HPr on the basis of its apparent molecular weight (45 000 vs. 9600, respectively), its affinity for DEAE-cellulose and its ability to promote sugar phosphorylation which is specific for fructose, rather than for glucose.

Bacterial Proteins↗

PubMed1985

[Fructose utilization by hepatocytes isolated from fed obese fa/fa Zucker rats. Metabolic fate of fructose in the absence of the modulator].

The utilization of fructose by isolated hepatocytes was investigated in fed obese Zucker fa/fa rats compared with their lean littermates (Fa/?) and Sprague-Dawley rats. Hepatocytes were incubated during 3 h using U14C fructose (20 mM). Our results show: a significant increase of fructose consumption, glucose, lactate and pyruvate production and faster turnover of glycogen by fa/fa rats. In these animals, synthesis of acylglycerol was also significantly enhanced. Our results suggest that fructose in fa/fa rats was used preferentially as precursor for lipid synthesis not only by the liver but also by the adipose tissue after a prior transformation into glucose by hepatocytes. All these abnormalities result in an accumulation of acylglycerols maintaining an obesity state in fa/fa rats.

Animals↗

PubMedDate not supplied

Urinary fructose excretion in health after fructose test.

Urinary excretion of fructose during three hours following the ingestion of 100 g of hydrolysed sucrose (in 200 ml) was studied in 85 normal men. This solution was better tolerated than a solution of 50 g of pure fructose and gave higher urinary excretion of fructose than with 100 g of unhydrolysed sucrose. The mean fructose excretion was 54.0 mg (S.D. 40.6 MG). The majority of subjects (63) excreted between 1 and 75 mg and the highest value was 187mg. This suggests a relatively inexpensive method for assessing the existence of porta-systemic shunts beyond normal.

Adolescent↗