Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.9 (glucose-6-phosphatase)
 3,081 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycogen storage disease (GSD) type 1a is caused by the deficiency of D-glucose-6-phosphatase (G6Pase), the key enzyme in glucose homeostasis. Despite both a high incidence and morbidity, the molecular mechanisms underlying this deficiency have eluded characterization. In the present study, the molecular and biochemical characterization of the human G6Pase complementary DNA, its gene, and the expressed protein, which is indistinguishable from human microsomal G6Pase, are reported. Several mutations in the G6Pase gene of affected individuals that completely inactivate the enzyme have been identified. These results establish the molecular basis of this disease and open the way for future gene therapy.
 ...
PMID:Mutations in the glucose-6-phosphatase gene that cause glycogen storage disease type 1a. 821 Nov 87

The diagnosis of glycogen storage disease type Ia currently uses enzyme analysis of liver tissue. This requires liver biopsy in the at-risk neonate or fetus. Conflicting reports have appeared in the literature on the use of peripheral platelet glucose-6-phosphatase activity for the diagnosis of this disorder. We have applied a sensitive radiometric assay system to the measurement of glucose-6-phosphatase activity in peripheral platelets. Two families with affected members were analysed, revealing no differences in glucose-6-phosphatase activity as compared with control values. Platelet measurement of glucose-6-phosphatase does not appear to be useful for the diagnosis of glycogen storage disease type Ia.
 ...
PMID:Unreliability of platelet glucose-6-phosphatase for the diagnosis of glycogen storage disease type Ia. 829 99

The glycogen storage disorders (GSD)-I, -III, -VI and -VIII are associated with hypertriglyceridaemia or mixed hyperlipidaemia which poses the question whether these patients have an increased risk for atherosclerosis. The atherogenicity of triglycerides has remained controversial, while increased plasma cholesterol levels are generally accepted as a significant risk factor for coronary heart disease. However, clinical data show that one has to differentiate between metabolic conditions where triglycerides are atherogenic and those which are not significantly related to early onset of atherosclerosis but may cause other disorders such as pancreatitis. Among the disorders of carbohydrate metabolism patients with diabetes mellitus frequently have enhanced plasma triglycerides associated with a higher risk for coronary heart disease, while patients with certain types of glycogen storage disease have high triglyceride levels but do not seem to have an enhanced risk for atherosclerosis. Here we have compared the biochemical abnormalities and the atherogenic risk of three different disorders of glucose metabolism including GSD-I (glucose-6-phosphatase deficiency), favism (glucose-6-phosphate dehydrogenase deficiency), and diabetes mellitus which are related to either hyper- or hypolipidaemia. The available data indicate that glucose-6-phosphate (Glc-6-P) is a central molecule in cellular glucose metabolism which critically influences pentose phosphate cycle activity and, via NADPH2-generation, regulates glutathione peroxidase activity for radical detoxification and also cholesterol and triglyceride synthesis. Radical detoxification is a major protective factor for cell membrane integrity and together with an appropriate renewal of membrane lipids may protect against the development of atherosclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Glucose-6-phosphate: a key compound in glycogenosis I and favism leading to hyper- or hypolipidaemia. 831 30

The understanding of type 1 glycogen storage diseases (GSDs) has been greatly hindered by a lack of knowledge of the molecular basis of glucose-6-phosphatase (Glc-6-P'ase). The problem has been the complete failure of many laboratories, including our own, to purify to homogeneity a single polypeptide with high levels of Glc-6-P'ase activity. The best preparations to date all contain five or six different polypeptide bands and have specific activities in the range 17-50 mumoles/min per milligram. The two major reasons for failure have been that Glc-6-P'ase is extremely difficult to solubilise from the microsomal membrane (large amounts of detergents are needed) and that it is not a single polypeptide as originally thought, but a multicomponent system. Recent studies of patients with type 1 GSD have proved that Glc-6-P'ase comprises at least five different polypeptides. Four of the proteins have now been purified and three have been cloned. We have assayed the Glc-6-P'ase system in over 600 human biopsy samples and developed microassays to diagnose deficiencies of each of the proteins. Ways of avoiding possible problems which have the potential to lead to the wrong diagnosis will be discussed.
 ...
PMID:The molecular basis of the genetic deficiencies of five of the components of the glucose-6-phosphatase system: improved diagnosis. 839 42

The discovery of glucose-6-phosphatase (EC 3.1.3.9) and of its physiological function in releasing glucose from the liver are discussed briefly. The identification by the Coris of glucose-6-phosphatase deficiency as the underlying defect in certain cases of glycogenosis (type I glycogenosis; von Gierke disease) is described. Characteristics of the catalyst, with a focus on its multiplicity of functions and multicomponent character, are considered with an emphasis on the human liver enzyme. Pioneering studies from the author's laboratory leading to the characterization of two variants of type I glycogenosis, types Ib and Ic, are described.
 ...
PMID:Human microsomal glucose-6-phosphatase system. 839 43

A multiple purification of phosphohydrolase (PH) and phosphotranslocase (PT) of the human liver microsomal glucose-6-phosphatase system has been obtained by a rapid two-step procedure using affinity chromatography. Sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) of the final products showed one major band each at 63 and 37 kDa for PH and PT respectively. The immunoblot analysis of SDS-PAGE of various purification steps for human liver using rabbit antibodies raised against the enzyme preparations also showed major bands at 63 and 37 kDa for PH and PT respectively. A major band at 260 kDa was observed by the Western blot of native PAGE of the enzyme preparation for PH. Cross-reacting materials at the positions of 63 and 37 kDa were detected only in liver, kidney and intestine. From five liver samples of patients suffering from type Ia glycogenosis there were diminished amounts of crossreacting materials at 63 kDa only in two samples. The uptake of glucose-6-phosphate has taken place in liposomes of Sepharose affinity purified products suggesting that this preparation may be a complex of PH and glucose-6-phosphate translocase.
 ...
PMID:Purification of human microsomal liver glucose-6-phosphatase system by affinity chromatography and immunodetection. 839 44

There now is compelling evidence that hydrolysis of glucose-6-phosphate (Glc-6-P) in intact hepatic endoplasmic reticulum (ER) membrane preparations involves four integral components of the membrane: a Glc-6-P specific transporter (T1), a nonspecific enzyme (E) with its active site facing the lumen, and two other transport systems to mediate rapid and reversible fluxes of the hydrolytic products, inorganic phosphate (Pi) and glucose, i.e. (T2) and (T3), respectively. T2 also mediates transport of inorganic pyrophosphate (PPi) and carbamylphosphate. This concept readily and completely reconciles all known characteristics of the glucose-6-phosphatase (Glc-6-P'ase) system provided appropriate considerations are given to: (1) the quantitative contribution of E residing in membranes lacking a permeability barrier; (2) the kinetic restrictions imposed by T1 and T2; and (3) the influences of the endocrine, developmental and nutritional state on the kinetic relationship between the capacities to transport and hydrolyze. A broader-based understanding and application of these principles in the study of Glc-6-P'ase is needed to ensure accurate diagnosis of type 1 glycogen storage disease (GSD) and minimize unnecessary controversy. The view that the enzyme in native ER membranes is conformationally constrained is not supported by direct measurements of the catalytic turnover number. Finally, we describe the marked deficiencies of rapid filtration assays of Glc-6-P and PPi "uptake" as a direct method of diagnosis of types 1b and 1c GSD.
 ...
PMID:Glucose-6-phosphatase and type 1 glycogen storage disease: some critical considerations. 839 48

Despite increasing understanding of the genetic control of cell growth and the identification of several involved chemical and infectious factors, the pathogenesis of clinical and experimental hepatocellular carcinoma remains unknown. Available evidence is consistent with the possibility that selected changes in the hepatocellular metabolism of long-chain fatty acids may contribute significantly to this, process. Specifically, studies of the peroxisome proliferators, a diverse group of xenobiotics that includes the fibrate class of hypolipidemic drugs, suggest that increased fatty acid oxidation by way of extramitochondrial pathways (i.e., omega-oxidation in the smooth endoplasmic reticulum and beta-oxidation in the peroxisomes) results in a corresponding increase in the generation of hydrogen peroxide and, thus, oxidative stress. This in turn leads to alterations in gene expression and in DNA itself. We also review evidence supporting a potentially decisive influence of particular aspects of hepatocellular fatty acid metabolism in determining the activity of the extramitochondrial pathways. Moreover, certain intermediates of extramitochondrial fatty acid oxidation (e.g., the long-chain dicarboxylic fatty acids) impair mitochondrial function and are implicated as modulators of gene expression through their interaction with the peroxisome proliferator-activated receptor. Finally, the occurrence of hepatic tumors in type I glycogen storage disease (glucose-6-phosphatase deficiency) may exemplify this general mechanism, which may also contribute to nonneoplastic liver injury and to tumorigenesis in other tissues.
 ...
PMID:Fatty-acid metabolism and the pathogenesis of hepatocellular carcinoma: review and hypothesis. 839 60

Glycogen storage disease (GSD) type 1a (von Gierke disease) is caused by a deficiency in glucose-6-phosphatase, the key enzyme in glucose homeostasis catalyzing the terminal step in gluconeogenesis and glycogenolysis. Despite its clinical importance, this membrane-bound enzyme has eluded molecular characterization. Here we report the cloning and characterization of a murine glucose-6-phosphatase cDNA by screening a mouse liver cDNA library differentially with mRNA populations representing the normal and the albino deletion mouse known to express markedly reduced glucose-6-phosphatase activity. Additionally, we identified the gene that consists of 5 exons. Biochemical analyses indicate that the in vitro expressed enzyme is indistinguishable from mouse liver microsomal glucose-6-phosphatase exhibiting essentially identical kinetic constants, latency, thermal lability, and vanadate sensitivity. The characterization of the murine glucose-6-phosphatase gene opens the way for studying the molecular basis of GSD type 1a in humans and its etiology in an animal model.
 ...
PMID:Isolation of the gene for murine glucose-6-phosphatase, the enzyme deficient in glycogen storage disease type 1A. 840 95

Glycogen storage disease type Ia (GSD-Ia) (von Gierke's disease) was identified in two 47-day-old littermate Maltese puppies. The puppies were presented for necropsy with a history of failure to thrive, mental depression, and poor body condition. Gross findings included small body size and emaciation (212 and 246 g versus 595 g for normal littermate), severely enlarged pale livers (48 and 61 g), and pale kidneys. Histologically, there was marked diffuse vacuolation of hepatocytes with large amounts of glycogen and small amounts of lipid. Renal tubular epithelium was mildly to moderately vacuolated. Soft tissue mineralization was present in renal tubules and pulmonary alveolar septa. Biochemical analysis showed that levels of glucose-6-phosphatase were markedly reduced in liver (0.3 and 0.4 microM/minute/g tissue versus 4.7 +/- 1.5 microM/minute/g tissue for controls) and kidney (0.45 and 0.4 microM/minute/g tissue versus 4.1 microM/minute/g tissue for controls) and that glycogen content was increased in liver (9.4% and 9.4% versus 1.3% +/- 1.4% for controls). This is the first confirmed report of animals with glycogen storage disease type Ia.
 ...
PMID:Glycogen storage disease type Ia in two littermate Maltese puppies. 857 35


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>