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)

Significant dephosphorylation of glucose 6-phosphate due to glucose-6-phosphatase activity in rat brain in vivo was recently reported (Huang, M., and Veech, R.L. (1982) J. Biol. Chem. 257, 11358-11363). The evidence was an apparent more rapid 3H than 14C loss from the glucose pool and faster [2-3H]glucose than [U-14C]glucose utilization following pulse labeling of the brain with [2-3H,U-14C]glucose. Radiochemical purity of the glucose and quantitative recovery of the labeled products of glucose metabolism isolated from the brain were obviously essential requirements of their study, but no evidence for purity and recovery was provided. When we repeated these experiments with the described isolation procedures, we replicated the results, but found that: 1) the precursor glucose pool contained detritiated, 14C-labeled contaminants arising from glucose metabolism, particularly 2-pyrrolidone-5-carboxylic acid derived from [14C]glutamine; 2) [14C]glucose metabolite were not quantitatively recovered; 3) the procedure used to isolate the glucose itself produced detritiated, 14C-labeled derivatives of [2-3H,U-14C]glucose. These deficiencies in the isolation procedures could fully account for the observations that were interpreted as evidence of significant glucose 6-phosphate dephosphorylation by glucose-6-phosphatase activity. When glucose was isolated by more rigorous procedures and its purity verified in the present studies, no evidence for such activity in rat brain was found.
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PMID:Over-estimation of glucose-6-phosphatase activity in brain in vivo. Apparent difference in rates of [2-3H]glucose and [U-14C]glucose utilization is due to contamination of precursor pool with 14C-labeled products and incomplete recovery of 14C-labeled metabolites. 284 37

The liver is the "glucostat" of the organism and serves at the same time as an "ammonia-sink and pH stat". The key enzymes involved in glucose uptake and release and in urea and glutamine formation are reciprocally distributed over the liver parenchyma: The glucogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK), fructosebisphosphatase (FBPase) and glucose-6-phosphatase (G6Pase) as well as the ureagenic enzyme carbamoylphosphate synthetase (CAPS) are predominant in the periportal zone. The glycolytic enzymes glucokinase (GK) and pyruvate kinase type L (PKL) as well as the glutaminogenic enzyme glutamine synthetase (GluNS) are prevalent in the perivenous zone. This heterogeneity appears to be a prerequisite for the normal "glucostat, ammonia-sink and pH-stat" function of the liver. After birth the liver is a gluconeogenic organ, only with weaning it becomes a "glycolytic/gluconeogenic" glucostat. In the rat zonation of PEPCK, G6Pase and CAPS developed gradually after birth and was completed before weaning, i.e. before it would be functionally required. After 2/3 partial hepatectomy the liver looses its normal glucostat function and becomes a gluconeogenic organ. With this change the zonation of PEPCK and PKL were also lost; it was restored only during the second week after operation. During starvation the liver also looses its glucostat function to become the major glucose supplier of the organism. Zonation of PEPCK and PKL were diminished to such an extent that the major function of the perivenous zone was altered from glucose uptake to release. In diabetes the liver does not loose its glucostat function; however, the function is severely impaired. Zonation of PEPCK was increased and that of PKL decreased in such a manner that the major function of the perivenous zone, glucose uptake, was not entirely changed but only diminished. It can be concluded that in the various physiological states studied the zonation of enzymes correlated well with the glucostat function of the liver.
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PMID:Dynamics of zonal hepatocyte heterogeneity. Perinatal development and adaptive alterations during regeneration after partial hepatectomy, starvation and diabetes. 301 Mar 76

In incubated colonocytes isolated from rat colons, the rates of utilization O2, glucose or glutamine were linear with respect to time for over 30 min, and the concentrations of adenine nucleotides plus the ATP/ADP or ATP/AMP concentration ratios remained approximately constant for 30 min. Glutamine, n-butyrate or ketone bodies were the only substrates that caused increases in O2 consumption by isolated incubated colonocytes. The maximum activity of hexokinase in colonic mucosa is similar to that of 6-phosphofructokinase. Starvation of the donor animal decreased the activities of hexokinase and 6-phosphofructokinase, whereas it increased those of glucose-6-phosphatase and fructose-bisphosphatase. Isolated incubated colonocytes utilized glucose at about 6.8 mumol/min per g dry wt., with lactate accounting for 83% of glucose removed. These rates were not affected by the addition of glutamine, acetoacetate or n-butyrate, and starvation of the donor animal. Isolated incubated colonocytes utilized glutamine at about 5.5 mumol/min per g dry wt., which is about 21% of the maximum activity of glutaminase. The major end-products of glutamine metabolism were glutamate, aspartate, alanine and ammonia. Starvation of the donor animal decreased the rate of glutamine utilization by colonocytes, which is accompanied by a decrease in glutamate formation and in the maximum activity of glutaminase. Isolated incubated colonocytes utilized acetoacetate at about 3.5 mumol/min per g dry wt. This rate was not markedly affected by addition of glucose or by starvation of the donor animal. When colonocytes were incubated with n-butyrate, both acetoacetate and 3-hydroxybutyrate were formed, with the latter accounting for only about 19% of total ketones produced.
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PMID:Fuel utilization in colonocytes of the rat. 407 34

The metabolic response to the first fast experienced by all mammals has been studied in the newborn rat. Levels of fuels and hormones have been compared in the fetal and maternal circulations at term. Then, after cesarean section just before the normal time of birth, sequential changes in the same parameters were quantified during the first 16 h of the neonatal period. No caloric intake was permitted, and the newborns were maintained at 37 degrees C. Activities of three key hepatic enzymes involved in glucose production were estimated. Marked differences in maternal and fetal hormones and fuels were observed. Lower levels of glucose, free fatty acids, and glycerol but higher levels of lactate, alpha-amino nitrogen, alanine, and glutamine were present in the fetus. Pyruvate, glutamate, and ketone bodies were not significantly different. The combination of a strikingly higher fetal immunoreactive insulin and a slightly lower immunoreactive glucagon (pancreatic) resulted in a profound elevation in the insulin-to-glucagon ratio, a finding consistent with an organism in an anabolic state. The rat at birth presents a body composition with respect to fuels available for mobilization and conversion which is dominated by carbohydrate and protein, since little fat is present. However, at birth a transient period of hypoglycemia occurred, associated with a rapid fall in insulin and rise in glucagon, causing reversal of the insulin-to-glucagon relationship toward ratios such as were observed in the mother. After a lag period, hepatic activities of phosphorylase, glucose-6-phosphatase, and phosphoenolpyruvate carboxykinase increased. Concurrent with these enzyme changes, the blood glucose returned to levels at or above those of the fetus. Interestingly, the fall observed in levels of the gluconeogenic precursors, lactate and amino acids, preceded the rise in enzyme activities and restoration of blood glucose. After 4 h, however, hypoglycemia recurred, during a period of decreasing hepatic glycogen content and blood lactate, pyruvate, and glycerol levels but of stable or increasing amino acid concentrations. Hepatic gluconeogenesis in this phase of depleted glycogen stores was insufficient to maintain euglycemia. Substrates derived from fat showed early changes of smaller magnitude. The rise in free fatty acids which occurred was less than twofold the value at birth, though this rise persisted up to 6 h. Whereas glycerol rose transiently, acetoacetate did not change and beta-hydroxybutyrate concentration fell. Both ketone bodies showed a marked rise at 16 h. at a time of diminished free fatty acid levels. Plasma growth hormone, though higher in the fetal than the maternal circulation, showed no consistent change during the period of observation. The changes in levels of the endocrine pancreatic hormones at birth were appropriate in time, magnitude, and direction to be implicated as prime regulators of the metabolic response during the neonatal period in the rat.
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PMID:Fuels, hormones, and liver metabolism at term and during the early postnatal period in the rat. 475 Apr 49

The subcellular localization of glutamine synthetase, an enzyme fundamental to the compartmentation of glutamate hypothesis, was investigated using brain tissue of adult rats. The distribution of this enzyme in relation to the distribution of glucose-6-phosphatase, glutamate dehydrogenase and acetycholine esterase was studied using a fractionation scheme which had been previously extensively characterized in terms of intramitochondrial enzyme complements. Glutamine synthetase was found to be predominantly localized at the nerve terminal and a number of results suggested a possibble association with the synaptic membrane. The observations are discussed in relation to the compartmentation of glutamate metabolism. Acetate and ammonia are precursors of the 'small' pool of glutamate from which most of the synthesis of glutamine occurs. Since one population of synaptic mitochondria has previously been shown to be enriched in glutamate dehydrogenase and acetyl CoA synthetase and in view of the current observtions that synaptosomes are probably in association with a large proportion of brain glutamine synthetase, it is tentatively suggested that the synaptic complex represents at least in part the site of the 'small' glutamate pool.
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PMID:The distribution of glutamine synthetase in subcellular fractions of rat brain. 610 1

Severe hepatic damage with submassive necrosis induced in rats by an intraperitoneal injection of a single dose of galactosamine hydrochloride was studied. In the severely damaged liver, the remarkable decreases of glycogen and UDPG in the damaged liver were seen. This means extreme decrease in the reserve power of glycolysis. Moreover, the activities of glucose-6-phosphatase and fructose-1,6-diphosphatase decreased. Therefore, the glucose release from liver into the blood stream decreases and the inhibition of gluconeogenesis occurs. In the damaged liver, the decrease of UTP which is essential for the synthesis of sugar moiety of polysaccharide, was seen. Further, the activities of L-glutamine: D-fructose-6-phosphate amidotransferase and UDP N-acetylglucosamine 2'-epimerase which are two key enzymes of polysaccharide synthesizing enzyme were seen to decrease remarkably. In the damaged liver, the glycoprotein fraction decreased more strikingly than the acid mucopolysaccharide fraction. Moreover, the decrease of fructose-1,6-diphosphatase activity seems also to effect on the inhibition of polysaccharide synthesis. In these respects, in the severe hepatic damage, the synthesis of glycoprotein which is essential for liver cell seems to be inhibited.
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PMID:Studies on severe hepatic damage induced by galactosamine. 617 14

Gluconeogenic enzymes and substrates were measured in the livers of fasted and suckled newborn pigs in the first 48 h postpartum. The activities at birth of glucose-6-phosphatase, fructose-1,6-diphosphatase, pyruvate carboxylase and phosphoenolpyruvate carboxykinase were, respectively, 70%, 45%, 117% and 35% of adult values. At birth, cytosolic phosphoenolpyruvate carboxykinase represented 35% of total activity, a similar distribution to that in the adult. In suckled piglets, all activities were greater at 24 and 48 h that at birth. In starved piglets, the increases were greater in all cases; the increase in cytosolic phosphoenolpyruvate carboxykinase was much more pronounced than for that for the particulate enzyme, with the former representing more than 50% of total at 48 h. The levels of gluconeogenic enzymes in the piglets in the early neonatal period would appear to be adequate for their needs and do not provide an explanation for their fasting hypoglycaemia. Hepatic levels of lactate, pyruvate, phosphoenolpyruvate, ketone bodies, and amino acids were determined in these piglets. No significant differences were observed in these metabolites between fasted and suckled animals except that glutamine was doubled in fed piglets, Evidence for the metabolic block in the livers of fasted animals was lacking and ketone bodies did not accumulate. These observations suggest that the limitations to gluconeogenesis result from unavailability of energy substrates and/or carbon precursors to the liver or the deficiency in their uptake.
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PMID:Development of gluconeogenic enzymes in the liver of fasting or suckling newborn pigs. 733 8

Amino acids are known to stimulate glycogen synthesis via an increase in cell volume [Baquet, A., Hue, L., Meijer, A. J., van Woerkom, G. M. & Plomp, P. J. A. M. (1990) J. Biol. Chem. 265, 955-959]. It has recently been postulated, however, that carbamoyl phosphate, an intermediate of ureagenesis, can function as a substrate for glucose phosphorylation via carbamoyl-phosphate:glucose phosphotransferase activity of the glucose-6-phosphatase system. This hypothesis would account for the stimulation of glycogenesis by amino acids such as glutamine and proline [Bode, A. M. & Nordlie, R. C. (1993) J. Biol. Chem. 268, 16298-16301]. To further examine the role carbamoyl phosphate may play in glycogenesis, isolated hepatocytes were incubated under a variety of conditions to manipulate ureagenesis, glycogenesis and carbamoyl-phosphate levels. Our data indicate that carbamoyl-phosphate levels do not correlate with amino-acid-stimulated glycogenesis and that ureagenesis and glycogenesis are not competing metabolic pathways.
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PMID:Carbamoyl phosphate and ureagenesis are not involved in amino-acid-stimulated glycogenesis. 805 25

Glycogen storage disease (GSD) type 1a is an autosomal recessive inborn error of metabolism caused by a deficiency in microsomal glucose-6-phosphatase (G6Pase), the key enzyme in glucose homeostasis. Southern blot hybridization analysis using a panel of human-hamster hybrids showed that human G6Pase is a single-copy gene located on chromosome 17. To correlate specific defects with clinical manifestations of this disorder, we identified mutations in the G6Pase gene of GSD type 1a patients. In the G6Pase gene of a compound heterozygous patient (LLP), two mutations in exon 2 of one allele and exon 5 of the other allele were identified. The exon 2 mutation converts an arginine at codon 83 to a cysteine (R83C). This mutation, previously identified by us in another GSD type 1a patient, was shown to have no detectable phosphohydrolase activity. The exon 5 mutation in the G6Pase gene of LLP converts a glutamine codon at 347 to a stop (Q347SP). This Q347SP mutation was also detected in all exon 5 subclones (five for each patient) of two homozygous patients, KB and CB, siblings of the same parents. The predicted Q347SP mutant G6Pase is a truncated protein of 346 amino acids, 11 amino acids shorter than the wild type G6Pase of 357 residues. Site-directed mutagenesis and transient expression assays demonstrated that G6Pase-Q347SP was devoid of G6Pase activity. G6Pase is an endoplasmic reticulum (ER) membrane-associated protein containing an ER retention signal, two lysines (KK), located at residues 354 and 355. We showed that the G6Pase-K355SP mutant containing a lysine-355 to stop codon mutation is enzymatically active. Our data demonstrate that the ER protein retention signal in human G6Pase is not essential for activity. However, residues 347-354 may be required for optimal G6Pase catalysis.
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PMID:Identification of mutations in the gene for glucose-6-phosphatase, the enzyme deficient in glycogen storage disease type 1a. 818 31

L-Proline and L-glutamine were used to probe the inverse relationship between glycogenesis and ureagenesis in isolated, perfused livers from 48-h fasted rats. Both amino acids may provide nitrogen in the form of NH+4 for carbamyl-P synthesis. However, one molecule of glutamine may provide additionally for the synthesis of one molecule of the urea cycle substrate L-aspartate, but proline can provide for the synthesis of a molecule of NH+4 or one molecule of aspartate on an either/or basis only. In all perfusates, glucose was initially 30 mM (to favor phosphotransferase activity of glucose-6-phosphatase) and 0.5 mM 3-mercaptopicolinate was present (to inhibit glyconeogenesis from endogenous substrates, from the added amino acids, and via the indirect pathway). Glycogenesis from glucose, perfusate and hepatic urea formation, and levels of hepatic glucose-6-P, citrulline, PPi, and carbamyl-P were measured. The addition of glutamine to the perfusate markedly stimulated the urea cycle, but not glycogenesis. Hepatic urea level, perfusate urea concentration, and hepatic citrulline and PPi increased while carbamyl-P content decreased. In contrast, proline stimulated glycogenesis from glucose, but not ureagenesis. In the proline-supplemented compared with glutamine group, hepatic glycogenesis and carbamyl-P content increased; hepatic glucose-6-P levels showed a tendency toward increase; and hepatic urea formation, hepatic citrulline, and PPi levels were decreased. These observations are interpreted to support an hepatic mechanism whereby the relative availability of carbamyl-P to the urea cycle and as a substrate for glucose phosphorylation via phosphotransferase activity of the glucose-6-phosphatase system preliminary to glycogenesis from glucose is a major metabolic determinant.
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PMID:Reciprocal effects of proline and glutamine on glycogenesis from glucose and ureagenesis in isolated, perfused rat livers. 834 17


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