Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.9 (glucose-6-phosphatase)
3,081 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The relevance of our present findings should not rest on the possible role of mannose as an important teratogen in man. Excessive exposure to mannose during pregnancy via dietary intake seems unlikely since mannose is absorbed poorly from the gastrointestinal tract and intestinal hydrolysis of mannosidic linkages may be minimal. Moreover, although some plasma mannose may be generated continuously from endogenous sources via the cleavage of mannose-6-phosphate by hepatic glucose-6-phosphatase or mannosidic linkages by other hydrolases, our ongoing surveys have not uncovered any specimens of plasma or amniotic fluid containing mannose in amounts which could compete effectively with prevailing levels of glucose. Although we are continuing to monitor clinical samples for unusual mannose levels, we believe that the major significance of our experiences with this hexose pertains to its applications as a physiological tool for evaluating the metabolic determinants of early organogenesis. Within the above context, our findings must be viewed in relation to the known features of energy metabolism in the embryo during the interval that we have studied (Fig. 9). The classic studies of Shepherd and colleagues, similar findings by others, and more recent experiments in our own laboratory have indicated that glycolysis constitutes the chief energy source for the post-implantation embryo prior to the establishment of the yolk sac circulation on day 10 1/2. Almost all of the assimilated glucose goes to lactic acid, mitochondrial electron transfer is poorly developed, and oxidative metabolism via the Krebs' cycle is minimal. Meaningful Krebs' cycle activity does not become operative until day 10 1/2 and full expression is not found until the establishment of the allantoic circulation on day 11 (Fig. 9). The present experiences with mannose provide the first documentation of how precariously development is balanced during that transitory 9 1/2-10 1/2 day phase of organogenesis when glycolysis predominates. We have shown that even minor perturbations of glycolytic flux during that interval can result in major dysmorphogenic sequelae. Thus, the proposition by Kalter and Warkany that "any meaningful attempt to reduce infant mortality further will have to address the still unresolved causes of congenital malformations" prompts our speculation that major congenital lesions may result from relatively minor disturbances in glycolysis occurring prior to oxidative maturation in the embryo unit. Such effects on glycolysis during this vulnerable phase of embryogenesis could provide a common basis for the teratogenic actions of many unrelated and as yet unidentified agents.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The honeybee syndrome: teratogenic effects of mannose during organogenesis in rat embryo culture. 667 63

Glucosamine, a potent inhibitor of glucokinase (hexokinase IV or D), was used to estimate the contribution of this enzyme to glucose phosphorylation in freshly isolated rat hepatocytes and its sensitivity to fructose 6-phosphate in situ. Experiments with radiolabelled glucosamine indicated that this amino sugar, at concentrations of 5 or 40 mM, readily penetrated hepatocytes to reach in 1 min a total (i.e., glucosamine+metabolites) intracellular concentration equal to 0.8-1.2-fold its extracellular concentration. In marked contrast, N-acetylglucosamine barely penetrated the cells. The detritiation of [2-3H]glucose, used to estimate glucose phosphorylation in intact cells, was inhibited by glucosamine much more potently than by N-acetylglucosamine, half-maximal effects being reached at about 2.5 and 30 mM respectively. Extrapolation of the data indicated that about 12% of the detritiation was resistant to glucosamine. Dihydroxyacetone (10 mM), lactate (10 mM) + pyruvate (1 mM), and glucagon (1 microM) increased up to 8-fold the concentration of hexose 6-phosphates (glucose 6-phosphate+fructose 6-phosphate) and, against expectations, modestly decreased the detritiation rate measured in the absence of glucosamine. In the presence of 40 mM glucosamine, these agents increased the detritiation rate, which then positively correlated with the concentration of hexose 6-phosphates. This hexose 6-phosphates-dependent detritiation was sensitive to inhibition by vanadate, and was also catalysed by gel-filtered cell-free extracts, as well as by liver microsomes in the presence of phosphoglucoisomerase; it can be explained by an exchange reaction catalysed by glucose-6-phosphatase. When this exchange reaction is taken into account, it appears that the rate of glucose detritiation attributable to glucokinase decreases when the concentration of hexose 6-phosphates increases. This is in agreement with the known effect of fructose 6-phosphate to potentiate the inhibition of glucokinase by its regulatory protein.
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PMID:Glucosamine-sensitive and -insensitive detritiation of [2-3H]glucose in isolated rat hepatocytes: a study of the contributions of glucokinase and glucose-6-phosphatase. 775 69

We wished to determine whether the elevated glucose cycling (GC) between glucose and glucose-6-phosphate (G<-->G6P) in diabetes can be reversed with acute insulin treatment. In six insulin-deprived, anesthetized, depancreatized dogs, insulin was infused for 6-9 h at a starting dose of 45-150 pmol.kg-1.min-1 to normalize plasma glucose from 23.9 +/- 1.4 to 5.0 +/- 0.4 mmol/l and gradually decreased to and maintained at a basal rate (1.7 +/- 1.0 pmol.kg-1.min-1) during the last 3 h. GC, measured with [2-3H]- and [6-3H]glucose, fell markedly from 15.3 +/- 2.7 and normalized at 1.3 +/- 0.6 mumol.kg-1.min-1 (P < 0.001). This occurred because total hepatic glucose output fell much more (from 41.2 +/- 3.1 to 11.6 +/- 1.2) than did glucose production (from 25.9 +/- 1.9 to 10.3 +/- 1.0 mumol.kg-1.min-1) (both P < 0.01). Freeze-clamped liver biopsies were taken at timed intervals for measurements of hepatic enzymes and substrates. The elevated hepatic hexose-6-phosphate levels decreased with insulin infusion (151 +/- 24 vs. 71 +/- 13 nmol/g, P < 0.01). Maximal activities of glucose-6-phosphatase (G6Pase) (from 17.6 +/- 0.8 to 19.6 +/- 2.6 U/g) and glucokinase (from 1.1 +/- 0.2 to 1.0 +/- 0.2 U/g) did not change. Insulin infusion resulted in a threefold increase (P < 0.05) in the activity of glycogen synthase (active form), but had no effect on hepatic glycogen content.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Importance of substrate changes in the decrease of hepatic glucose cycling during insulin infusion and declining glycemia in the depancreatized dog. 792 1

Lung surfactant was isolated from human amniotic fluid collected at term and studied with reference to the material isolated from human and rabbit lung lavage. The isolated material showed 58 per cent lipid by dry weight, 29 per cent protein and relatively smaller amounts of nucleic acids, sialic acid and hexose. Phosphatidyl choline was the predominant phospholipid species and accounted for 46 per cent of the total lipid by weight, followed by phosphatidyl glycerol (7%) and phosphatidyl ethanolamine (5%). Cholesterol was the major neutral lipid fraction present (10%) and was almost entirely in the free form. Other lipid fractions present in minor quantity were triglycerides, esterified cholesterol, phosphatidyl serine, phosphatidyl inositol and sphingomyelin. The material contained a very high degree of alkaline phosphatase activity, while other enzymes such as acid phosphatase, glucose-6-phosphatase, ATPases, 5'-nucleotidase and beta-N-acetyl glucosaminidase were also present.
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PMID:Isolation & chemical composition of lung surfactant from human amniotic fluid. 800 43

We have studied the rapid kinetics of glucose-6-phosphatase (Glc6Pase) toward glucose 6-phosphate (Glc6P) and mannose 6-phosphate (Man6P) in intact and detergent-treated microsomes, using a radiometric assay based on the use of [U(-)14C]hexose 6-phosphates. We show that a hysteretic transition of Glc6Pase from a rapid hydrolytic form to slower kinetic form within the intact membrane occurs for both substrates with the same relaxation time. During the hysteretic transition, preceding the steady-state rate of hydrolysis, Glc6Pase is able to hydrolyze both Glc6P and Man6P at very similar rates. Only Glc6P is significantly hydrolyzed at steady state. Moreover, the initial rates of hydrolysis of both Glc6P and Man6P in intact microsomes are higher than the respective rates of hydrolysis after detergent treatment of the membrane at high substrate concentrations (10 and 20 microM), while these rates are not different at lower substrate concentrations. These data show that the marked specificity of Glc6Pase at steady state in the membrane is acquired owing to a hysteretic transition induced by the hydrolytic phenomenon, independently of the nature of the prior phosphate donor. The role of the membrane in this phenomenon is crucial, since the transition does not occur in its absence.
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PMID:Glucose 6-phosphate and mannose 6-phosphate are equally and more actively hydrolyzed by glucose 6-phosphatase during hysteretic transition within intact microsomal membrane than after detergent treatment. 861 Oct 29

N-Bromoacetylethanolamine phosphate (BAEP) has been used previously as an affinity label to study the hexose phosphate binding sites of fructose-6-P, 2-kinase:fructose-2, 6-bisphosphatase (Sakakibara et al. (1984) J. Biol. Chem. 259, 14023-14028). We have employed this compound to probe components of the glucose-6-phosphatase system using a combination of time-dependent and immediate inhibition kinetic techniques. Inhibition of D-glucose-6-phosphate (G6P) phosphohydrolase activity of native microsomes was irreversible and time- and inhibitor-concentration-dependent. Only a partial time-dependent, irreversible inhibition of the PPi phosphohydrolase activity of native microsomes was observed. BAEP inhibited PPi:glucose phosphotransferase activity of native microsomes in a concentration-dependent, irreversible manner which was more extensive than that seen with PPi phosphohydrolase, but less extensive than was observed with G6P phosphohydrolase. Disruption of microsomal integrity by detergent-treatment either prior to incubation with BAEP or subsequent to preliminary incubation with BAEP but prior to assay for activity abolished the time-dependent inhibition. These irreversible, time- and concentration-dependent inhibitory actions of BAEP thus are manifest at a site or sites where the intact membrane-bound enzyme first makes contact with substrates G6P and PPi. An additional site of inhibition by BAEP, through relatively weak, reversible competitive inhibition at the active catalytic site, is indicated by classical steady-state kinetic analysis. The irreversible, time- and concentration-dependent inhibitions by BAEP seen with G6P and PPi as substrates strongly suggest the potential utility of radio-labeled BAEP as an affinity label for the identification and ultimate isolation and study of uncharacterized auxiliary components of the glucose-6-phosphatase system.
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PMID:Inhibition of the glucose-6-phosphatase system by N-bromoacetylethanolamine phosphate, a potential affinity label for auxiliary proteins. 891 28

Glucose-6-phosphate transport was investigated in rat or human liver microsomal vesicles using rapid filtration and light-scattering methods. Upon addition of glucose-6-phosphate, rat liver microsomes accumulated the radioactive tracer, reaching a steady-state level of uptake. In this phase, the majority of the accumulated tracer was glucose, but a significant intraluminal glucose-6-phosphate pool could also be observed. The extent of the intravesicular glucose pool was proportional with glucose-6-phosphatase activity. The relative size of the intravesicular glucose-6-phosphate pool (irrespective of the concentration of the extravesicular concentration of added glucose-6-phosphate) expressed as the apparent intravesicular space of the hexose phosphate was inversely dependent on glucose-6-phosphatase activity. The increase of hydrolysis by elevating the extravesicular glucose-6-phosphate concentration or temperature resulted in lower apparent intravesicular glucose-6-phosphate spaces and, thus, in a higher transmembrane gradient of glucose-6-phosphate concentrations. In contrast, inhibition of glucose-6-phosphate hydrolysis by vanadate, inactivation of glucose-6-phosphatase by acidic pH, or genetically determined low or absent glucose-6-phosphatase activity in human hepatic microsomes of patients suffering from glycogen storage disease type 1a led to relatively high intravesicular glucose-6-phosphate levels. Glucose-6-phosphate transport investigated by light-scattering technique resulted in similar traces in control and vanadate-treated rat microsomes as well as in microsomes from human patients with glycogen storage disease type 1a. It is concluded that liver microsomes take up glucose-6-phosphate, constituting a pool directly accessible to intraluminal glucose-6-phosphatase activity. In addition, normal glucose-6-phosphate uptake can take place in the absence of the glucose-6-phosphatase enzyme protein, confirming the existence of separate transport proteins.
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PMID:Demonstration of a metabolically active glucose-6-phosphate pool in the lumen of liver microsomal vesicles. 915 6

In rats injected with bacterial lipopolysaccharide (LPS; 5 gamma mg/g body weight [BWT]), the toxin provokes death within 24 h in 23% of the animals and, in surviving rats, causes a decrease in BWT, hyperlactacidemia, hyperlipacidemia, and hyperketonemia, as well as depletion of both liver and muscle glycogen content. In the liver, LPS severely lowers the ATP and total adenine nucleotide content, ATP/ADP ratio, and adenylate charge. In hepatocytes from LPS-injected rats, the oxidation of D-glucose is first increased 2 h after administration of the toxin, despite close-to-normal phosphorylation of the hexose. In hepatocytes prepared from rats killed 24 h after injection of LPS, the phosphorylation of D-glucose, its incorporation into glycogen, and its oxidation are all severely impaired. This sequence of changes, which coincides with a decreased ratio between pyruvate and lactate production from exogenous D-glucose, is comparable to that found with agents that uncouple oxidative phosphorylation. The injection of LPS also alters the metabolic response of hepatocytes to the dimethyl ester of succinic acid (SAD), in terms, for instance, of the sparing action of the ester upon both the production of 14CO2 by hepatocytes prelabeled with L-[U-14C] glutamine and the output of NH4+, and its inhibitory action on glycogenolysis and futile cycling in the reactions catalyzed by glucokinase and glucose-6-phosphatase. Nevertheless, the infusion of SAD protects the rats against the deleterious effect of LPS upon such variables as the plasma concentration of free fatty acids and beta-hydroxybutyrate, the liver ATP content, and the oxidation of D-glucose, as well as the pyruvate/lactate ratio, in hepatocytes prepared from the LPS-injected rats. The infusion of SAD also virtually suppresses lethality in the LPS-injected animals. It is proposed, therefore, that the infusion of succinic acid esters may represent a novel therapeutic approach in endotoxemia and multiple-organ failure.
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PMID:Protective effects of succinic acid dimethyl ester infusion in experimental endotoxemia. 917 84

Methods have been developed for producing functional, transporting monolayers of avian proximal tubule (PT) cells. A highly homogenous fraction of PT fragments was prepared by enzymatic digestion (collagenase + Dispase) of chick (3- to 5-day-old) kidneys, followed by Percoll gradient centrifugation. The PT fraction was enriched in glucose-6-phosphatase, a proximal enzyme marker, and reduced in specific activity of hexokinase, a distal marker. PT fragments were grown to confluence in serum-free media on collagen-coated permeable filter supports. Electron microscopy of confluent monolayers revealed numerous microvilli and mitochondria, central cilia, and tight junctions, all characteristic of PT cells. gamma-Glutamyltranspeptidase, a proximal brush-border enzyme, showed threefold higher activity on apical than on basolateral sides of the monolayer. The electrophysiological characteristics of monolayers were investigated by voltage-clamp techniques. Monolayers displayed low transepithelial resistances (40-60 Omega . cm2), lumen-negative potentials, and baseline currents of 6-12 microA/cm2 (with or without 5 mM glucose). Both alpha-methyl-D-glucose (2 mM), a nonmetabolizable hexose, and phenylalanine (2 mM) significantly stimulated short-circuit current when added to the mucosal side of glucose-free monolayers. Phloridzin, a specific inhibitor of Na+-coupled glucose transport, significantly inhibited short-circuit current, as did 10(-5) M amiloride. Monolayers also expressed net secretory transport of urate. This cell culture preparation may provide a useful working model for the study of avian PT transport.
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PMID:Characterization of a primary cell culture model of the avian renal proximal tubule. 968 82

In hepatocytes glucokinase (GK) and glucose-6-phosphatase (Glc-6-Pase)(1) have converse effects on glucose 6-phosphate (and fructose 6-phosphate) levels. To establish whether hexose 6-phosphate regulates GK binding to its regulatory protein, we determined the effects of Glc-6-Pase overexpression on glucose metabolism and GK compartmentation. Glc-6-Pase overexpression (4-fold) decreased glucose 6-phosphate levels by 50% and inhibited glycogen synthesis and glycolysis with a greater negative control coefficient on glycogen synthesis than on glycolysis, but it did not affect the response coefficients of glycogen synthesis or glycolysis to glucose, and it did not increase the control coefficient of GK or cause dissociation of GK from its regulatory protein, indicating that in hepatocytes fructose 6-phosphate does not regulate GK translocation by feedback inhibition. GK overexpression increases glycolysis and glycogen synthesis with a greater control coefficient on glycogen synthesis than on glycolysis. On the basis of the similar relative control coefficients of GK and Glc-6-Pase on glycogen synthesis compared with glycolysis, and the lack of effect of Glc-6-Pase overexpression on GK translocation or the control coefficient of GK, it is concluded that the main regulatory function of Glc-6-Pase is to buffer the glucose 6-phosphate concentration. This is consistent with recent findings that hyperglycemia stimulates Glc-6-Pase gene transcription.
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PMID:Glucose-6-phosphatase overexpression lowers glucose 6-phosphate and inhibits glycogen synthesis and glycolysis in hepatocytes without affecting glucokinase translocation. Evidence against feedback inhibition of glucokinase. 1045 19


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