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:1.2.1.13 (glyceraldehyde-3-phosphate dehydrogenase)
6,511 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

D-Glyceraldehyde irreversibly inhibited rat liver glucokinase in a concentration-dependent manner. The inactivation of glucokinase by glyceraldehyde was blocked by the presence of its substrates such as glucose and mannose. Glucokinase was highly sensitive to glyceraldehyde compared with some other glycolytic enzymes (from animal tissues) including hexokinase, glucose-6-phosphate isomerase, 6-phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase, and pyruvate kinase. The amino acid analysis of untreated and glyceraldehyde-treated glucokinase suggested that glyceraldehyde-induced inactivation of glucokinase is caused by glycation of Lys residues of the enzyme by the triose. Treatment of pancreatic islets with 6 mM glyceraldehyde for 1 h at 37 degrees C caused both inactivation of glucokinase and inhibition of glucose-induced insulin secretion. Another glucose-phosphorylating enzyme (hexokinase) in pancreatic islets, however, was little affected by glyceraldehyde. In addition, glyceraldehyde did not affect the insulin secretory responses of islets to nonglucose secretagogues such as glyceraldehyde and Leu. When pancreatic islets were cultured with a lower concentration (1 mM) of glyceraldehyde for a longer time (17 h) in the presence of 10 mM glucose to mimic the in vivo conditions, both glucokinase activity and glucose-induced insulin secretion were again decreased. This study demonstrates that glucose-induced insulin secretion is impaired by glyceraldehyde through the inactivation of glucokinase. The implication of this finding in the pathophysiology of type II diabetes is discussed.
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PMID:Inhibition of glucose-induced insulin secretion through inactivation of glucokinase by glyceraldehyde. 851 67

Chronic elevation in glucose has pleiotropic effects on the pancreatic beta-cell including a high rate of insulin secretion at low glucose, beta-cell hypertrophy, and hyperplasia. These actions of glucose are expected to be associated with the modulation of the expression of a number of glucose-regulated genes that need to be identified. To further investigate the molecular mechanisms implicated in these adaptation processes to hyperglycemia, we have studied the regulation of genes encoding key glycolytic enzymes in the glucose-responsive beta-cell line INS-1. Glucose (from 5 to 25 mM) induced phosphofructokinase-1 (PFK-1) isoform C, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (4-fold), and L-pyruvate kinase (L-PK) (7-fold) mRNAs. In contrast the expression level of the glucokinase (Gk) and 6-phosphofructo-2-kinase transcripts remained unchanged. Following a 3-day exposure to elevated glucose, a similar induction was observed at the protein level for PFK-1 (isoforms C, M, and L), GAPDH, and L-PK, whereas M-PK expression only increased slightly. The study of the mechanism of GAPDH induction indicated that glucose increased the transcriptional rate of the GAPDH gene but that both transcriptional and post transcriptional effects contributed to GAPDH mRNA accumulation. 2-Deoxyglucose did not mimic the inductive effect of glucose, suggesting that increased glucose metabolism is involved in GAPDH gene induction. These changes in glycolytic enzyme expression were associated with a 2-3-fold increase in insulin secretion at low (2-5 mM) glucose. The metabolic activity of the cells was also elevated, as indicated by the reduction of the artificial electron acceptor 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium. A marked deposition of glycogen, which was readily mobilized upon lowering of the ambient glucose, and increased DNA replication were also observed in cells exposed to elevated glucose. The results suggest that a coordinated induction of key glycolytic enzymes as well as massive glycogen deposition are implicated in the adaptation process of the beta-cell to hyperglycemia to allow for chronically elevated glucose metabolism, which, in this particular fuel-sensitive cell, is linked to metabolic coupling factor production and cell activation.
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PMID:Induction by glucose of genes coding for glycolytic enzymes in a pancreatic beta-cell line (INS-1). 900 60

Adenovirus-mediated overexpression of the glucose phosphorylating enzyme glucokinase causes large changes in glycolytic flux and glucose storage in isolated rat hepatocytes, but not in pancreatic islets. We have used the well-differentiated insulinoma cell line INS-1 to investigate the basis for these apparent cell-type specific differences. We find that 2- or 5-[3H]glucose usage is increased at low (</=5 mM) but not high glucose concentrations in INS-1 cells treated with a recombinant adenovirus containing the glucokinase cDNA (AdCMV-GKI), while glucose usage is increased at both low and high glucose concentrations in similarly treated hepatocytes. Utilization of 2-[3H]glucose in INS-1 cells is suppressed in glucokinase overexpressing INS-1 cells in a rapid, glucose concentration-dependent, and reversible fashion, while such regulation is largely absent in hepatocytes. Levels of hexose phosphates (glucose-6-phosphate, fructose-6-phosphate, and fructose-1,6-bisphosphate) were profoundly and rapidly elevated following the switch to high glucose in either AdCMV-GKI-treated INS-1 cells or hepatocytes relative to controls. In contrast, triose phosphate levels (glyceraldehyde-3-phosphate + dihydroxyacetone phosphate) were much higher in AdCMV-GKI-treated INS-1 cells than in similarly treated hepatocytes, suggesting limited flux throught the glyceraldehyde-3-phosphate dehydrogenase (G3PDH) step in the former cells. Hepatocytes were found to contain approximately 62 times more lactate dehydrogenase (LDH) activity than INS-1 cells, and this was reflected in a 3-fold increase in lactate production in AdCMV-GKI-treated hepatocytes relative to similarly treated INS-1 cells. Since the amounts of G3PDH activity in INS-1 and hepatocyte extracts are similar, we suggest that flux through this step in INS-1 cells is limited by failure to regenerate NAD in the LDH reaction and that a fundamental difference between hepatocytes and islet beta-cells is the limited capacity of the latter to metabolize glycolytic intermediates beyond the G3PDH step.
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PMID:Fundamental metabolic differences between hepatocytes and islet beta-cells revealed by glucokinase overexpression. 952 75

The cellular uptake of glucose catalysed by the facilitated glucose transporter (GLUT) family is further regulated by metabolites and hormones, most importantly by insulin. All of the six isoforms known in this family possess a large cytoplasmic domain of divergent amino acid sequence. A body of evidence indicates that this domain is important for GLUT regulation. Exactly how this domain participates in the regulation, however, is not known. A likely possibility is that a specific cellular protein interacts with GLUT at this domain, and thus modulates the function. This putative, glucose transporter binding protein (GTBP) may be an enzyme, or a non-enzymic adaptor or docking protein. Indeed, we have identified several cellular proteins that bind to the cytoplasmic domain of GLUT proteins; these include glyceraldehyde-3-phosphate dehydrogenase, glucokinase, GTBP70, GTBP85, GTBP28 and L-3-hydroxyacyl-CoA dehydrogenase. Some of these GLUT-GTPB interactions are functionally coupled. Whether any of these interactions actually participates in the insulin-induced GLUT regulation is yet to be determined.
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PMID:Proteins that interact with facilitative glucose transporters: implication for function. 956 88

Artificial rearing of 4-day-old rat pups on a high-carbohydrate (HC) milk formula results in the immediate onset of hyperinsulinemia. To evaluate these early changes, studies on pancreatic function were carried out on 12-day-old HC rats and compared with age-matched mother-fed (MF) pups. The plasma insulin and glucagon contents were increased sixfold and twofold, respectively, in HC rats compared with MF rats. There was a distinct leftward shift in the glucose-stimulated insulin secretory pattern for HC islets. HC islets secreted insulin in the absence of any added glucose and in the presence of Ca(2+) channel inhibitors. The activities of glucokinase, hexokinase, glyceraldehyde-3-phosphate dehydrogenase, and pyruvate dehydrogenase complex were significantly increased in HC islets compared with MF islets. The protein contents of GLUT-2 and hexokinase were significantly increased in HC islets. These findings indicate that a nutritional intervention in the form of a HC formula only during the suckling period has a profound influence on pancreatic function, causing the onset of hyperinsulinemia.
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PMID:A dietary intervention (high carbohydrate) during the neonatal period causes islet dysfunction in rats. 1060 Jul 96

The effects of benfluorex and two of its metabolites (S 422-1 and S 1475-1) on fatty acid and glucose metabolic fluxes and specific gene expression were studied in hepatocytes isolated from 24-h fasted rats. Both benfluorex and S 422-1 (0.1 or 1 mmol/l) reduced beta-oxidation rates and ketogenesis, whereas S 1475-1 had no effect. At the same concentration, benfluorex and S 422-1 were more efficient in reducing gluconeogenesis from lactate/pyruvate than S 1475-1. Benfluorex inhibited gluconeogenesis at the level of pyruvate carboxylase (45% fall in acetyl-CoA concentration) and of glyceraldehyde-3-phosphate dehydrogenase (decrease in ATP/ADP and NAD(+)/NADH ratios). Accordingly, neither benfluorex nor S 422-1 inhibited gluconeogenesis from dihydroxyacetone, but both stimulated gluconeogenesis from glycerol. In hepatocytes cultured in the presence of benfluorex or S 422-1 (10 or 100 micromol/l), the expression of genes encoding enzymes of fatty acid oxidation (carnitine palmitoyltransferase [CPT] I), ketogenesis (hydroxymethylglutaryl-CoA synthase), and gluconeogenesis (glucose-6-phosphatase, PEPCK) was decreased, whereas mRNAs encoding glucokinase and pyruvate kinase were increased. By contrast, Glut-2, acyl-CoA synthetase, and CPT II gene expression was not affected by benfluorex or S 422-1. In conclusion, this work suggests that benfluorex mainly via S 422-1 reduces gluconeogenesis by affecting gene expression and metabolic status of hepatocytes.
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PMID:Effects of benfluorex on fatty acid and glucose metabolism in isolated rat hepatocytes: from metabolic fluxes to gene expression. 1214 46

We have constructed a model of the upper part of the glycolysis in the pancreatic beta-cell. The model comprises the enzymatic reactions from glucokinase to glyceraldehyde-3-phosphate dehydrogenase (GAPD). Our results show, for a substantial part of the parameter space, an oscillatory behavior of the glycolysis for a large range of glucose concentrations. We show how the occurrence of oscillations depends on glucokinase, aldolase and/or GAPD activities, and how the oscillation period depends on the phosphofructokinase activity. We propose that the ratio of glucokinase and aldolase and/or GAPD activities are adequate as characteristics of the glucose responsiveness, rather than only the glucokinase activity. We also propose that the rapid equilibrium between different oligomeric forms of phosphofructokinase may reduce the oscillation period sensitivity to phosphofructokinase activity. Methodologically, we show that a satisfying description of phosphofructokinase kinetics can be achieved using the irreversible Hill equation with allosteric modifiers. We emphasize the use of parameter ranges rather than fixed values, and the use of operationally well-defined parameters in order for this methodology to be feasible. The theoretical results presented in this study apply to the study of insulin secretion mechanisms, since glycolytic oscillations have been proposed as a cause of oscillations in the ATP/ADP ratio which is linked to insulin secretion.
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PMID:A model of phosphofructokinase and glycolytic oscillations in the pancreatic beta-cell. 1282 70

Although glycolysis is a biochemical pathway that evolved under ancient anaerobic terrestrial conditions, recent studies have provided evidence that some glycolytic enzymes are more complicated, multifaceted proteins rather than simple components of the glycolytic pathway. These glycolytic enzymes have acquired additional non-glycolytic functions in transcriptional regulation [hexokinase (HK)-2, lactate dehydrogenase A, glyceraldehyde-3-phosphate dehydrogenase (GAPD) and enolase 1], stimulation of cell motility (glucose-6-phosphate isomerase) and the regulation of apoptosis (glucokinase, HK and GAPD). The existence of multifaceted roles of glycolytic proteins suggests that links between metabolic sensors and transcription are established directly through enzymes that participate in metabolism. These roles further underscore the need to consider the non-enzymatic functions of enzymes in proteomic studies of cells and tissues.
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PMID:Multifaceted roles of glycolytic enzymes. 1575 86

An efficient in planta sugarcane-based production system may be realized by coupling the synthesis of alternative products to the metabolic intermediates of sucrose metabolism, thus taking advantage of the sucrose-producing capability of the plant. This was evaluated by synthesizing sorbitol in sugarcane (Saccharum hybrids) using the Malus domestica sorbitol-6-phosphate dehydrogenase gene (mds6pdh). Mature transgenic sugarcane plants were compared with untransformed sugarcane variety Q117 by evaluation of the growth, metabolite levels and extractable activity of relevant enzymes. The average amounts of sorbitol detected in the most productive line were 120 mg/g dry weight (equivalent to 61% of the soluble sugars) in the leaf lamina and 10 mg/g dry weight in the stalk pith. The levels of enzymes involved in sucrose synthesis and cleavage were elevated in the leaves of plants accumulating sorbitol, but this did not affect sucrose accumulation in the culm. The activity of oxidative reactions in the pentose phosphate pathway and the non-reversible glyceraldehyde-3-phosphate dehydrogenase reaction were elevated to replenish the reducing power consumed by sorbitol synthesis. Sorbitol-producing sugarcane generated 30%-40% less aerial biomass and was 10%-30% shorter than control lines. Leaves developed necrosis in a pattern characteristic of early senescence, and the severity was related to the relative quantity of sorbitol accumulated. When the Zymomonas mobilis glucokinase (zmglk) gene was co-expressed with mds6pdh to increase the production of glucose-6-phosphate, the plants were again smaller, indicating that glucose-6-phosphate deficiency was not responsible for the reduced growth. In summary, sorbitol hyperaccumulation affected sugarcane growth and metabolism, but the outcome was not lethal for the plant. This work also demonstrated that impressive yields of alternative products can be generated from the intermediates of sucrose metabolism in Saccharum spp.
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PMID:Growth and metabolism in sugarcane are altered by the creation of a new hexose-phosphate sink. 1730 79

Pseudomonas putida KT2440 channels glucose to the central Entner-Doudoroff intermediate 6-phosphogluconate through three convergent pathways. The genes for these convergent pathways are clustered in three independent regions on the host chromosome. A number of monocistronic units and operons coexist within each of these clusters, favoring coexpression of catabolic enzymes and transport systems. Expression of the three pathways is mediated by three transcriptional repressors, HexR, GnuR, and PtxS, and by a positive transcriptional regulator, GltR-2. In this study, we generated mutants in each of the regulators and carried out transcriptional assays using microarrays and transcriptional fusions. These studies revealed that HexR controls the genes that encode glucokinase/glucose 6-phosphate dehydrogenase that yield 6-phosphogluconate; the genes for the Entner-Doudoroff enzymes that yield glyceraldehyde-3-phosphate and pyruvate; and gap-1, which encodes glyceraldehyde-3-phosphate dehydrogenase. GltR-2 is the transcriptional regulator that controls specific porins for the entry of glucose into the periplasmic space, as well as the gtsABCD operon for glucose transport through the inner membrane. GnuR is the repressor of gluconate transport and gluconokinase responsible for the conversion of gluconate into 6-phosphogluconate. PtxS, however, controls the enzymes for oxidation of gluconate to 2-ketogluconate, its transport and metabolism, and a set of genes unrelated to glucose metabolism.
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PMID:A set of activators and repressors control peripheral glucose pathways in Pseudomonas putida to yield a common central intermediate. 1824 93


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