GLUCONEOGENESIS

• Gluconeogenesis


  A vital metabolic process in the human body that is responsible for generating glucose from non-carbohydrate sources, such as amino acids, lactate, and glycerol
• Gluconeogenesis


  • Occurs mainly in the liver and kidney
  • Plays a critical role in maintaining blood glucose levels during fasting or periods of low carbohydrate intake
• The daily glucose requirement of the brain in a typical adult human being is about 120 g, which accounts for most of the 160 g of glucose needed daily by the whole body
• The direct glucose reserves are sufficient to meet glucose needs for about a day
• Gluconeogenesis


  Especially important during a longer period of fasting or starvation
• The major site of gluconeogenesis is the liver, with a small amount also taking place in the kidney
• Little gluconeogenesis takes place in the brain, skeletal muscle, or heart muscle
• Gluconeogenesis in the liver and kidney helps to maintain the glucose concentration in the blood, from which it can be extracted by the brain and muscle to meet their metabolic demands
• Gluconeogenesis


  Converts pyruvate into glucose

  
• Noncarbohydrate precursors of glucose


  • Lactate
  • Amino acids
  • Glycerol

  
• Lactate is readily converted into pyruvate in the liver by the action of lactate dehydrogenase

  
• Amino acids are derived from proteins in the diet and, during starvation, from the breakdown of proteins in skeletal muscle
• The hydrolysis of triacylglycerols in fat cells yields glycerol and fatty acids

  
• Glycerol may enter either the gluconeogenic or the glycolytic pathway at dihydroxyacetone

  
• Gluconeogenesis is not a complete reversal of glycolysis
• Several reactions must differ because the equilibrium of glycolysis lies far on the side of pyruvate formation

  
• The actual free energy change for the formation of pyruvate from glucose is about -90 kJ mol-1 (-22 kcal mol-1) under typical cellular conditions

  
• Most of the decrease in free energy in glycolysis takes place in the three irreversible steps catalyzed by hexokinase, phosphofructokinase, and pyruvate kinase
• In gluconeogenesis, these irreversible reactions of glycolysis must be bypassed
• The conversion of pyruvate into phosphoenolpyruvate


  1. Begins with the formation of oxaloacetate

  2. Catalyzed by pyruvate carboxylase in the mitochondria

  
• Pyruvate carboxylase


  Requires biotin as a covalently attached prosthetic group that serves as the carrier of activated CO2

  
• Carboxylation of pyruvate by pyruvate carboxylase


  Occurs in three stages

  
• Pyruvate carboxylase


  • Functions as a tetramer composed of four identical subunits
  • Each subunit consists of four domains

  
• The first partial reaction of pyruvate carboxylase, the formation of carboxybiotin, depends on the presence of acetyl CoA

  
• Acetyl CoA has no effect on the second partial reaction
• Oxaloacetate is shuttled into the cytoplasm and converted into phosphoenolpyruvate


  1. Oxaloacetate is first reduced to malate by malate dehydrogenase

  2. Malate is transported across the mitochondrial membrane and reoxidized to oxaloacetate by a cytoplasmic NAD+-linked malate dehydrogenase

  3. Oxaloacetate is simultaneously decarboxylated and phosphorylated by phosphoenolpyruvate carboxykinase (PEPCK) to generate phosphoenolpyruvate

  
• The sum of the reactions catalyzed by pyruvate carboxylase and phosphoenolpyruvate carboxykinase is: Pyruvate + CO2 + GTP -> Phosphoenolpyruvate + GDP + Pi

  
• The formation of phosphoenolpyruvate from pyruvate in the gluconeogenic pathway has a ΔG°' of +0.8 kJ mol-1 (+0.2 kcal mol-1)

  
• The hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate and Pi is an irreversible step in gluconeogenesis

  
• Fructose 1,6-bisphosphatase


  The enzyme responsible for the hydrolysis of fructose 1,6-bisphosphate, and it is an allosteric enzyme that participates in regulation of gluconeogenesis

  
• The generation of free glucose

  1. Glucose 6-phosphate is transported into the lumen of the endoplasmic reticulum, where it is hydrolyzed to glucose by glucose 6-phosphatase

  2. Glucose and Pi are then shuttled back to the cytoplasm by a pair of transporters

  
• Six high-transfer-potential phosphoryl groups are spent in synthesizing glucose from pyruvate in gluconeogenesis, whereas only two molecules of ATP are generated in glycolysis in the conversion of glucose into pyruvate

  
• The extra cost of gluconeogenesis is four high-phosphoryl-transfer-potential molecules for each molecule of glucose synthesized from pyruvate

  
• Gluconeogenesis and glycolysis are coordinated so that, within a cell, one pathway is relatively inactive while the other one is highly active
• The key regulation site in the reciprocal regulation of gluconeogenesis and glycolysis is the energy charge of the cell
• Glycolysis


  Pathway that breaks down glucose to produce ATP
• Gluconeogenesis


  Pathway that synthesizes glucose from non-carbohydrate sources

  
• If both glycolysis and gluconeogenesis were highly active at the same time, the net result would be the hydrolysis of four nucleoside triphosphates (two ATP molecules plus two GTP molecules) per reaction cycle

  
• Both glycolysis and gluconeogenesis are exergonic under cellular conditions, and so there is no thermodynamic barrier to such simultaneous activity
• The activities of the distinctive enzymes of each pathway are controlled so that both pathways are not highly active at the same time