scholarly journals Hepatic carbon flux after re-feeding in the glycogen-storage-disease (gsd/gsd) rat

1987 ◽  
Vol 248 (3) ◽  
pp. 969-972 ◽  
Author(s):  
M J Holness ◽  
T N Palmer ◽  
E B Worrall ◽  
M C Sugden
Keyword(s):  
Glycogen Storage Disease ◽  
Pyruvate Dehydrogenase ◽  
Carbon Flux ◽  
Storage Disease ◽  
Pyruvate Dehydrogenase Complex ◽  
Glycogen Storage ◽  
Hepatic Glucose Output ◽  
Hepatic Glucose ◽  
Glucose Output ◽  
Dehydrogenase Complex

In this study we utilized the phosphorylase b kinase-deficient (gsd/gsd) rat as a model of hepatic substrate utilization where there is a constraint on glycogenesis imposed by the maintenance of high glycogen concentrations. Glucose re-feeding of 48 h-starved gsd/gsd rats led to suppression of hepatic glucose output. In contrast with the situation in normal rats, activation of the pyruvate dehydrogenase complex and lipogenesis was observed. It is suggested that impeding glycogenic flux may divert substrate into lipogenesis, possibly via activation of the pyruvate dehydrogenase complex.

scholarly journals Pyruvate production by Escherichia coli using pyruvate dehydrogenase variants

2021 ◽  
Author(s):  
W. Chris Moxley ◽  
Mark A. Eiteman
Keyword(s):  
Escherichia Coli ◽  
Pyruvate Dehydrogenase ◽  
Carbon Flux ◽  
Metabolic Flux ◽  
Pyruvate Dehydrogenase Complex ◽  
Cost Effective ◽  
Specific Productivity ◽  
Synthesis Methods ◽  
Additional Tool ◽  
Dehydrogenase Complex

Altering metabolic flux at a key branchpoint in metabolism has commonly been accomplished through gene knockouts or by modulating gene expression. An alternative approach to direct metabolic flux preferentially toward a product is decreasing the activity of a key enzyme through protein engineering. In Escherichia coli, pyruvate can accumulate from glucose when carbon flux through the pyruvate dehydrogenase complex is suppressed. Based on this principle, 16 chromosomally expressed AceE variants were constructed in E. coli C and compared for growth rate and pyruvate accumulation using glucose as the sole carbon source. To prevent conversion of pyruvate to other products, the strains also contained deletions in two nonessential pathways: lactate dehydrogenase (ldhA) and pyruvate oxidase (poxB). The effect of deleting phosphoenolpyruvate synthase (ppsA) on pyruvate assimilation was also examined. The best pyruvate-accumulating strains were examined in controlled batch and continuous processes. In a nitrogen-limited chemostat process at steady-state growth rates of 0.15 – 0.28 h−1, an engineered strain expressing the AceE[H106V] variant accumulated pyruvate at a yield of 0.59-0.66 g pyruvate/g glucose with a specific productivity of 0.78 – 0.92 g pyruvate/g cells·h. These results provide proof-of-concept that pyruvate dehydrogenase complex variants can effectively shift carbon flux away from central carbon metabolism to allow pyruvate accumulation. This approach can potentially be applied to other key enzymes in metabolism to direct carbon toward a biochemical product. Importance Microbial production of biochemicals from renewable resources has become an efficient and cost-effective alternative to traditional chemical synthesis methods. Metabolic engineering tools are important for optimizing a process to perform at an economically feasible level. This study describes an additional tool to modify central metabolism and direct metabolic flux to a product. We have shown that variants of the pyruvate dehydrogenase complex can direct metabolic flux away from cell growth to increase pyruvate production in Escherichia coli. This approach could be paired with existing strategies to optimize metabolism and create industrially relevant and economically feasible processes.

GLUCOSE-6-PHOSPHATASE DEFICIENCY GLYCOGEN STORAGE DISEASE

PEDIATRICS ◽  
1962 ◽  
Vol 29 (4) ◽  
pp. 553-565
Author(s):  
R. Rodney Howell ◽  
Doris M. Ashton ◽  
James B. Wyngaarden
Keyword(s):  
Glycogen Storage Disease ◽  
Storage Disease ◽  
Glycogen Storage ◽  
Serum Triglycerides ◽  
Normal Limits ◽  
Hepatic Glucose ◽  
Low Glucose ◽  
The One ◽  
Physical Findings ◽  
Glucose 6 Phosphate Dehydrogenase

Three siblings with glycogen storage disease have been studied. These children demonstrated the classic physical findings of von Gierke's disease. Liver enzyme assays on one sibling revealed very low glucose 6-phosphatase activity. Hepatic phosphoglucomutase, phosphorylase, glucose 6-phosphate dehydrogenase, and fructose 1,6-diphosphatase activities were within normal limits. Erythrocyte glucose 6-phosphate dehydrogenase activity was also normal. Incubation of liver slices with glucose 1-C14 and glucose 6-C14 revealed an initial rate of C14O2 production at which CO2 from C-1 was three times that from C-6. This is strong evidence for the active operation of the phosphogluconate oxidation pathway in this patient, and taken with the normal assay value of hepatic glucose-6-phosphate dehydrogenase, constitutes a negation of the concept of a dual enzyme defect recently proposed for von Gierke's disease. Striking elevations of free fatty acids in serum, triglycerides, phospholipids, cholesterol, and blood ketones were noted. Potential mechanisms for these elevations have been discussed. Marked hyperuricemia was a persistent finding and was associated with a somewhat low renal clearance of urate in the one patient studied. All three had striking elevations of lactic acid in blood, which is known to interfere with renal urate excretion. Thus renal factors may have contributed to the hyperuricemia, previously considered solely a consequence of enhanced nucleoprotein catabolism secondary to persistent hypoglycemia. Long-term intramuscular administration of glucagon did not produce significant clinical or laboratory improvement in the one patient in whom it was employed.

scholarly journals Hepatic carbon flux after re-feeding. Hyperthyroidism blocks glycogen synthesis and the suppression of glucose output observed in response to carbohydrate re-feeding

1987 ◽  
Vol 247 (3) ◽  
pp. 627-634 ◽  
Author(s):  
M J Holness ◽  
M C Sugden
Keyword(s):  
Pyruvate Kinase ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Glycogen Synthesis ◽  
Hepatic Glycogen ◽  
Intragastric Administration ◽  
Indirect Pathway ◽  
Glucose Flux ◽  
Glucose Output ◽  
Dehydrogenase Complex

1. The work investigated hepatic glycogen synthesis and glucose output after the intragastric administration of glucose or glycerol or the provision of chow ad libitum to 48 h-starved euthyroid or hyperthyroid rats. 2. After glucose administration, glycogen synthesis via the indirect pathway [Newgard, Hirsch, Foster & McGarry (1983) J. Biol. Chem. 258, 8046-8052] occurred concomitantly with reversal of glucose flux across the liver and re-activation of pyruvate kinase in the euthyroid controls. Glycogen synthesis was decreased and net glucose output continued in the hyperthyroid rats, but normal re-activation of pyruvate kinase was observed. 3. Use of 3-mercaptopicolinate indicated that the glucose released from liver of hyperthyroid rats was synthesized from substrates metabolized via the gluconeogenic pathway. 4. Hepatic glycogen synthesis was also impaired in hyperthyroid rats after administration of glycerol or chow. Measurement of portal-minus-hepatovenous concentration differences and arterial glucose concentrations after the administration of glycerol in combination with 3-mercaptopicolinate indicated that flux from triose phosphate to glucose 6-phosphate was not decreased. 5. Inhibited glycogen synthesis after chow re-feeding was associated with accelerated re-activation of hepatic pyruvate dehydrogenase complex in the hyperthyroid rats. 6. The results indicate three distinct and independent actions of hyperthyroidism after re-feeding: (i) it inhibits the reversal of glucose flux across the liver normally observed in response to carbohydrate; (ii) it affects glycogen deposition at a site distal to glucose 6-phosphate; (iii) it allows more rapid re-activation of liver pyruvate dehydrogenase complex in response to a mixed diet.

scholarly journals Hepatic glycogen synthesis on carbohydrate re-feeding after starvation. A regulatory role for pyruvate dehydrogenase in liver and extrahepatic tissues

1986 ◽  
Vol 235 (2) ◽  
pp. 441-445 ◽  
Author(s):  
M J Holness ◽  
T J French ◽  
M C Sugden
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Glycogen Synthesis ◽  
Regulatory Role ◽  
Hepatic Glycogen ◽  
Glucose Administration ◽  
Hepatic Glucose ◽  
Extrahepatic Tissues ◽  
Lactate And Pyruvate ◽  
Dehydrogenase Complex

Glucose administration to 48 h-starved rats increased hepatic glucose, lactate, pyruvate and glycogen concentrations and re-activated PDH (pyruvate dehydrogenase complex) in kidney, but not in heart or liver. Dichloroacetate together with glucose re-activated PDH in all three tissues, decreased hepatic lactate and pyruvate concentrations and impaired glycogen resynthesis. Thus on re-feeding, delayed PDH re-activation is important for provision of precursors for hepatic glyconeogenesis.

scholarly journals Specific Reduction of Hepatic Glucose 6-Phosphate Transporter-1 Ameliorates Diabetes while Avoiding Complications of Glycogen Storage Disease

2007 ◽  
Vol 282 (26) ◽  
pp. 19113-19121 ◽  
Author(s):  
Kyle W. Sloop ◽  
Aaron D. Showalter ◽  
Amy L. Cox ◽  
Julia X. C. Cao ◽  
Angela M. Siesky ◽  
...  
Keyword(s):  
Glycogen Storage Disease ◽  
Storage Disease ◽  
Glycogen Storage ◽  
Phosphate Transporter ◽  
Hepatic Glucose
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