Dysregulation of phosphoenolpyruvate carboxykinase in cancers: A comprehensive analysis
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Phosphoenolpyruvate carboxykinase (PEPCK) plays a crucial role in gluconeogenesis, glycolysis, and the tricarboxylic acid cycle by converting oxaloacetate into phosphoenolpyruvate. Two distinct isoforms of PEPCK, specifically cytosolic PCK1 and mitochondrial PCK2, have been identified. Nevertheless, the comprehensive understanding of their dysregulation in pan-cancer and their potential mechanism contributing to signaling transduction pathways remains elusive.Keywords:
Gluconeogenesis
Phosphoenolpyruvate carboxylase
Metabolic pathway
Gluconeogenesis
Carbohydrate Metabolism
Metabolic control analysis
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Livers of chick embryos at different stages of incubation have been fractionated into mitochondrial and “soluble” fractions by centrifugation. The pyruvate carboxylase and phosphoenolpyruvate carboxykinase activities, which constitute the major pathway for the synthesis of phosphoenolpyruvate, have been measured in both preparations. The pyruvate carboxylase activity occurs only in the mitochondria and parallels the gluconeogenetic ability. The bulk of phosphoenolpyruvate carboxykinase activity appears in the mitochondria. Only traces can be detected in the “soluble” fraction. The level of the mitochondrial phosphoenolpyruvate carboxykinase activity varies during the incubation period in accordance with its presumed role as a major source of phosphoenolpyruvate in the gluconeogenesis. The hypothesis that the pathway of synthesis of phosphoenolpyruvate in the process of gluconeogenesis is mainly located in the mitochondria of chick embryo liver is proposed.
Gluconeogenesis
Phosphoenolpyruvate carboxylase
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Gluconeogenesis from 10 mM lactate has been studied in isolated hepatocytes from fetal, newborn, and 70-day-old rabbits. Gluconeogenesis proceeds to a very low rate in fetal rabbit hepatocytes despite substantial activities of all gluconeogenic enzymes including mitochondrial phosphoenolpyruvate carboxykinase. A tenfold increase in the rate of gluconeogenesis occurs in hepatocytes from 1- or 2-day-old fasting or suckling newborn rabbits. The emergence of gluconeogenic capacity in newborn rabbit hepatocytes is triggered by birth itself and not by a chronological factor, and it is primarily controlled by an increase in the activity of cytosolic phosphoenolpyruvate carboxykinase. Moreover, an active fatty acid oxidation is essential to support a high rate of gluconeogenesis in hepatocytes from newborn rabbits.
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Abstract Aspergillus carbonarius has a potential as a cell factory for production of various organic acids. In this study, the organic acid profile of A. carbonarius was investigated under different cultivation conditions. Moreover, two heterologous genes, pepck and ppc, which encode phosphoenolpyruvate carboxykinase in Actinobacillus succinogenes and phosphoenolpyruvate carboxylase in Escherichia coli, were inserted individually and in combination in A. carbonarius to enhance the carbon flux toward the reductive TCA branch. Results of transcription analysis and measurement of enzyme activities of phosphoenolpyruvate carboxykinase and phosphoenolpyruvate carboxylase in the corresponding single and double transformants demonstrated that the two heterologous genes were successfully expressed in A. carbonarius. The production of citric acid increased in all the transformants in both glucose- and xylose-based media at pH higher than 3 but did not increase in the pH non-buffered cultivation compared with the wild type.
Phosphoenolpyruvate carboxylase
Heterologous
Heterologous expression
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ABSTRACT Phosphoenolpyruvate carboxykinase (PEPCK) catalyses the conversion of oxaloacetate to pyruvate in the first step of gluconeogenesis. Since oxaloacetate is impermeable to the inner mitochondrial membrane, the localisation of PEPCK within the cell plays a major role in defining substrate preferences for gluconeogenesis. As a result, the immunochemically distinct isoenzymes of PEPCK found within the mitochondrial and the cytosolic cell fractions vary in their proportion to one another between organs and species and with prandial state.
Gluconeogenesis
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Gluconeogenesis from (U-<sup>14</sup>C)-lactate occurred in hepatocytes prepared from term fetuses which lack cytosolic phosphoenolpyruvate carboxykinase and was almost completely inhibited by 3-mercaptopicolinate but was relatively insensitive to amino-oxyacetate. 12 h after birth when up to 32% of the total hepatic phosphoenolpyruvate carboxykinase activity was detectable in the cytosol, glucose synthesis was increased 4.4-fold in hepatocytes from fasted neonates and was partially (37%) sensitive to amino-oxyacetate. In livers of fasted 24-hour-old neonates total phosphoenolpyruvate carboxykinase activity was distributed between the mitochondria and the cytosol in the ratio of 60:40. In hepatocytes prepared from such animals, amino-oxyacetate inhibited glucose synthesis by about 56%, suggesting that up to half of the carbon flow from lactate to glucose was via the formation of phosphoenolpyruvate in the mitochondria. These studies indicate an important role for mitochondrial phosphoenolpyruvate carboxykinase in neonatal gluconeogenesis.
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ABSTRACT. Two children are described who suffered from hypoglycemia and liver impairment. Assays of gluconeogenic enzymes in liver samples taken immediately after death demonstrated a deficiency of phosphoenolpyruvate carboxykinase, a key enzyme of gluconeogenesis. Post mortem examination demonstrated massive fat deposition in liver and kidney and to a lesser extent in other tissues. The fatty changes in liver and kidney could be explained by the absence of phosphoenolpyruvate carboxykinase, which would cause an alteration in the mitochondrial‐cytosolic processes related to gluconeogenesis.
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Gluconeogenesis
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Phosphoenolpyruvate partially inhibits the accumulation of Ca(2+) in isolated mung bean (Phaseolus aureus Roxb.) mitochondria. Succinate-supported Ca(2+) uptake is twice as sensitive to phosphoenolpyruvate inhibition as is NADH- or malate/pyruvate-supported Ca(2+) uptake. Pyruvate, atractylate, and ATP, but not ITP, reverse the phosphoenolpyruvate-induced inhibition. Oxaloacetic acid inhibits succinate-supported Ca(2+) uptake completely while partially inhibiting NADH-supported Ca(2+) uptake. The oxaloacetate inhibition of NADH-supported Ca(2+) uptake is greater than that produced by phosphoenolpyruvate. It is suggested that inhibition of Ca(2+) uptake is due to the conversion of phosphoenolpyruvate into oxaloacetate via phosphoenolpyruvate carboxykinase, with oxaloacetate responsible for the actual inhibition of Ca(2+) uptake.
Phosphoenolpyruvate carboxylase
Malate dehydrogenase
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Gluconeogenesis
Carbohydrate Metabolism
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