scholarly journals The pyruvate carboxylase-pyruvate dehydrogenase axis in islet pyruvate metabolism: Going round in circles?

Islets ◽  
2011 ◽  
Vol 3 (6) ◽  
pp. 302-319 ◽  
Author(s):  
Mary C. Sugden ◽  
Mark J. Holness
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Pyruvate Carboxylase ◽  
Pyruvate Metabolism

scholarly journals Metabolism of pyruvate and malate by isolated fat-cell mitochondria

1971 ◽  
Vol 125 (1) ◽  
pp. 105-113 ◽  
Author(s):  
B. R. Martin ◽  
R. M. Denton
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Pyruvate Carboxylase ◽  
Adenine Nucleotides ◽  
Acid Synthesis ◽  
Fat Cells ◽  
Fat Cell ◽  
Pyruvate Metabolism ◽  
Flow Rates ◽  
Citrate Cycle ◽  
End Products

1. Metabolism of pyruvate and malate by isolated fat-cell mitochondria incubated in the presence of ADP and phosphate has been studied by measuring rates of pyruvate uptake, malate utilization or production, citrate production and oxygen consumption. From these measurements calculations of the flow rates through pyruvate carboxylase, pyruvate dehydrogenase and citrate cycle have been made under various conditions. 2. In the presence of bicarbonate, pyruvate was largely converted into citrate and malate and only about 10% was oxidized by the citrate cycle; citrate and malate outputs were linear after lag periods of 6–9min and 3min respectively, and no other end products of pyruvate metabolism were detected. On the further addition of malate or hydroxymalonate, the lag in the rate of citrate output was less marked but no net malate disappearance was detected. If, however, bicarbonate was omitted then net malate uptake was observed. Addition of butyl malonate was found to greatly inhibit the metabolism of pyruvate to citrate and malate in the presence of bicarbonate. 3. These results are in agreement with earlier conclusions that in adipose tissue acetyl units for fatty acid synthesis are transferred to the cytoplasm as citrate and that this transfer requires malate presumably for counter transport. They also support the view that oxaloacetate for citrate synthesis is preferentially formed from pyruvate through pyruvate carboxylase rather than malate through malate dehydrogenase and that the mitochondrial metabolism of citrate in fat-cells is restricted. The possible consequences of these conclusions are discussed. 4. Studies on the effects of additions of adenine nucleotides to pyruvate metabolism by isolated fat-cell mitochondria are consistent with inhibition of pyruvate carboxylase in the presence of ADP and pyruvate dehydrogenase in the presence of ATP.

Mechanism of the acceleration of CO2 production from pyruvate in liver mitochondria by HCO3-

1997 ◽  
Vol 273 (1) ◽  
pp. C92-C100 ◽  
Author(s):  
Y. Taguchi ◽  
Y. Ono ◽  
L. Lin ◽  
B. T. Storey ◽  
S. J. Dodgson ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Initial Phase ◽  
Pyruvate Carboxylase ◽  
Liver Mitochondria ◽  
Co2 Production ◽  
O2 Consumption ◽  
Pyruvate Metabolism ◽  
Mitochondrial Suspension ◽  
Beta Hydroxybutyrate ◽  
Guinea Pig Liver

To investigate the mechanism by which HCO3- accelerates pyruvate metabolism in guinea pig liver mitochondria, we measured continuously, at pH 7.4 and 37 degrees C, 13C16O2 production from [1-13C]pyruvate by mass spectrometry and NADH concentration by fluorescence and analyzed total malate, citrate, and beta-hydroxybutyrate produced by standard biochemical methods. When [1-13C]pyruvate is added to the mitochondrial suspension, 13C16O2 concentration rises steeply in the first seconds and then slows to a steady lower rate. Carbonic anhydrase (CA) eliminates this initial phase, which shows that decarboxylation of pyruvate produces CO2, not HCO3-, and it does this more rapidly than it can equilibrate without CA. HCO3- (25 mM) increased 13C16O2 production, O2 consumption and total malate and citrate production and decreased NADH concentration and total beta-hydroxybutyrate production. After obtaining the total amount of 13C16O2, malate, citrate, and beta-hydroxybutyrate produced, we calculated that the addition of 25 mM HCO3- to the suspension medium increased the amount of pyruvate decarboxylated by pyruvate dehydrogenase (PDH) 16% and increased the amount carboxylated by pyruvate carboxylase 300%. This supports our initial proposal that HCO3- accelerates the pyruvate carboxylation, which in turn consumes ATP directly and NADH and acetyl CoA secondarily, all of which increase PDH activity. However, we found no acceleration of pyruvate decarboxylation by 0.5 and 1 microM free Ca2+ concentration, unless the mitochondria were uncoupled and ATP was added.

THIAMINE-RESPONSIVE LACTIC ACIDOSIS IN A PATIENT WITH DEFICIENT LOW-KM PYRUVATE CARBOXYLASE ACTIVITY IN LIVER

PEDIATRICS ◽  
1972 ◽  
Vol 50 (5) ◽  
pp. 702-711
Author(s):  
Michèle G. Brunette ◽  
Edgard Delvin ◽  
Bernard Hazel ◽  
Charles R. Scriver
Keyword(s):  
Lactic Acidosis ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Carboxylase ◽  
Acid Metabolism ◽  
Psychomotor Retardation ◽  
Dietary Control ◽  
Carboxylase Activity ◽  
Cultured Skin ◽  
Carbohydrate Feeding ◽  
Partial Deficiency

The cause of severe intermittent lactic acidosis was investigated in a female infant with profound psychomotor retardation. Hypoglycemia, hyperpyruvic acidemia, and hyperalaninemia were identified in the newborn period. A triad of lactate, pyruvate, and alanine accumulation persisted throughout infancy, and ACTH, anorexia, and high carbohydrate feeding further provoked their accumulation. Careful dietary control or thiamine-HCl supplementation (5 to 20 mg/day) ameliorated the metabolic abnormality. Pyruvate dehydrogenase activity (which is thiamine-dependent) was normal in leukocytes and cultured skin fibroblasts. Hepatic pyruvate carboxylase activity (which is biotin-dependent) was found to comprise more than one component. There was a partial deficiency of total hepatic pyruvate carboxylase activity in the patient. The loss of activity was confined to the low-Km component of the enzyme which serves pvruvate metabolism in the physiological range. A defect in glucogenesis causing hypoglycemia, pyruvate accumulation with lactic acidosis, and aberrant amino acid metabolism can be attributed to the abnormality of pyruvate carboxylase. The response to thiamine in our patients may reflect activation of a normal "shunt" mechanism for pyruvate disposal via pyruvate dehydrogenase.

Determination of gluconeogenesis in vivo with 14C-labeled substrates

1985 ◽  
Vol 248 (4) ◽  
pp. R391-R399 ◽  
Author(s):  
J. Katz
Keyword(s):  
Pyruvate Carboxylase ◽  
Tricarboxylic Acid Cycle ◽  
Specific Radioactivity ◽  
Tricarboxylic Acid ◽  
Pyruvate Metabolism ◽  
Acetyl Coenzyme A ◽  
Glucose Carbon ◽  
Labeling Pattern

A mitochondrial model of gluconeogenesis and the tricarboxylic acid cycle, where pyruvate is metabolized via pyruvate carboxylase and pyruvate dehydrogenase, and pyruvate kinase is examined. The effect of the rate of tricarboxylic acid flux and the rates of the three reactions of pyruvate metabolism on the labeling patterns from [14C]pyruvate and [24C]acetate are analyzed. Expressions describing the specific radioactivities and 14C distribution in glucose as a function of these rates are derived. Specific radioactivities and isotopic patterns depend markedly on the ratio of the rates of pyruvate carboxylation and decarboxylation to the rate of citrate synthesis, but the effect of phosphoenolpyruvate hydrolysis is minor. The effects of these rates on 1) specific radioactivity of phosphoenolpyruvate, 2) labeling pattern in glucose, and 3) contribution of pyruvate, acetyl-coenzyme A, and CO2 to glucose carbon are illustrated. To determine the contribution of lactate or alanine to gluconeogenesis, experiments with two compounds labeled in different carbons are required. Methods in current use to correct for the dilution of 14C in gluconeogenesis from [14C]pyruvate are shown to be erroneous. The experimental design and techniques to determine gluconeogenesis from 14C-labeled precursors are presented and illustrated with numerical examples.

Noninvasive probing of citric acid cycle intermediates in primate liver with phenylacetylglutamine

1996 ◽  
Vol 270 (5) ◽  
pp. E882-E889 ◽  
Author(s):  
D. Yang ◽  
S. F. Previs ◽  
C. A. Fernandez ◽  
S. Dugelay ◽  
M. V. Soloviev ◽  
...  
Keyword(s):  
Citric Acid ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Carboxylase ◽  
Citric Acid Cycle ◽  
Human Subjects ◽  
Flux Ratio ◽  
Peripheral Tissues ◽  
Acid Cycle ◽  
Labeling Pattern ◽  
Made In

In human and primate liver, phenylacetate and glutamine form phenylacetylglutamine, which is excreted in urine. Probing noninvasively the labeling pattern of liver citric acid cycle intermediates with phenylacetylglutamine assumes that the labeling pattern of its glutamine moiety reflects that of liver alpha-ketoglutarate. To validate this probe, we infused monkeys with [U-13C3]lactate, [3-13C]lactate, [1, 2-13C2]acetate, [2-13C]acetate, [U-13C3]glycerol, or 2-[3-13C]ketoisocaproate and compared the labeling patterns of urinary phenylacetyl-glutamine with those of glutamate and glutamine in liver, plasma, muscle, and kidney and liver alpha-ketoglutarate. Only with [U-13C3]lactate or [3-13C]lactate does the labeling pattern of phenylacetylglutamine reflect patterns of liver alpha-ketoglutarate and glutamate. With [13C]acetate, muscle and kidney glutamate are more labeled than liver metabolites. This confirms that with [13C]acetate, the labeling pattern of liver metabolites is influenced by 13CO2 and [13C]glutamine made in peripheral tissues. Our data validate the use of phenylacetylglutamine labeled from [3-13C]lactate or [3-13C]pyruvate to probe noninvasively the pyruvate carboxylase-to-pyruvate dehydrogenase flux ratio in human subjects.

Effects of glucocorticoids on lymphocyte metabolism

1993 ◽  
Vol 264 (1) ◽  
pp. E24-E28
Author(s):  
M. A. Serrano ◽  
R. Curi ◽  
M. Parry-Billings ◽  
J. F. Williams ◽  
E. A. Newsholme
Keyword(s):  
Lymph Node ◽  
Immune System ◽  
Mechanism Of Action ◽  
Pyruvate Dehydrogenase ◽  
Incubation Medium ◽  
Culture Medium ◽  
Immunosuppressive Effect ◽  
Glutamine Metabolism ◽  
Pyruvate Metabolism

The immunosuppressive effect of glucocorticoids has been widely reported; however, the mechanism of action of these hormones on the immune system has not been fully established. In the present study, the effect of glucocorticoids on glucose, glutamine, and pyruvate metabolism in lymph node lymphocytes was investigated. Addition of dexamethasone to the incubation medium did not alter glucose and glutamine metabolism but inhibited pyruvate utilization by 40%. This latter effect took 1 h to occur and remained for up to 6 h, even after removal of dexamethasone from the culture medium. Measurements of the activity of pyruvate dehydrogenase in lymphocytes and the rate of [1–14C]-pyruvate conversion into 14CO2 in incubated lymphocyte mitochondria demonstrated that glucocorticoids decrease pyruvate utilization by inhibiting the activity of this key regulatory enzyme. The effect of such an inhibition of pyruvate utilization on the function of cells of the immune system remains to be clarified.

scholarly journals 13C NMR Metabolomic Evaluation of Immediate and Delayed Mild Hypothermia in Cerebrocortical Slices after Oxygen–Glucose Deprivation

2013 ◽  
Vol 119 (5) ◽  
pp. 1120-1136 ◽  
Author(s):  
Jia Liu ◽  
Mark R. Segal ◽  
Mark J. S. Kelly ◽  
Jeffrey G. Pelton ◽  
Myungwon Kim ◽  
...  
Keyword(s):  
Nuclear Magnetic Resonance ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Carboxylase ◽  
Mild Hypothermia ◽  
Principal Component ◽  
Glucose Deprivation ◽  
Oxygen Glucose Deprivation ◽  
Principal Component Analyses ◽  
Hypothermia Group ◽  
Selection Operator

Abstract Background: Mild brain hypothermia (32°–34°C) after human neonatal asphyxia improves neurodevelopmental outcomes. Astrocytes but not neurons have pyruvate carboxylase and an acetate uptake transporter. 13C nuclear magnetic resonance spectroscopy of rodent brain extracts after administering [1-13C]glucose and [1,2-13C]acetate can distinguish metabolic differences between glia and neurons, and tricarboxylic acid cycle entry via pyruvate dehydrogenase and pyruvate carboxylase. Methods: Neonatal rat cerebrocortical slices receiving a 13C-acetate/glucose mixture underwent a 45-min asphyxia simulation via oxygen–glucose-deprivation followed by 6 h of recovery. Protocols in three groups of N = 3 experiments were identical except for temperature management. The three temperature groups were: normothermia (37°C), hypothermia (32°C for 3.75 h beginning at oxygen–-glucose deprivation start), and delayed hypothermia (32°C for 3.75 h, beginning 15 min after oxygen–glucose deprivation start). Multivariate analysis of nuclear magnetic resonance metabolite quantifications included principal component analyses and the L1-penalized regularized regression algorithm known as the least absolute shrinkage and selection operator. Results: The most significant metabolite difference (P < 0.0056) was [2-13C]glutamine’s higher final/control ratio for the hypothermia group (1.75 ± 0.12) compared with ratios for the delayed (1.12 ± 0.12) and normothermia group (0.94 ± 0.06), implying a higher pyruvate carboxylase/pyruvate dehydrogenase ratio for glutamine formation. Least Absolute Shrinkage and Selection Operator found the most important metabolites associated with adenosine triphosphate preservation: [3,4-13C]glutamate—produced via pyruvate dehydrogenase entry, [2-13C]taurine—an important osmolyte and antioxidant, and phosphocreatine. Final principal component analyses scores plots suggested separate cluster formation for the hypothermia group, but with insufficient data for statistical significance. Conclusions: Starting mild hypothermia simultaneously with oxygen–glucose deprivation, compared with delayed starting or no hypothermia, has higher pyruvate carboxylase throughput, suggesting that better glial integrity is one important neuroprotection mechanism of earlier hypothermia.

Sign in / Sign up

Export Citation Format

Share Document