Gluconeogenesis

• Gluconeogenesis


  The synthesis of glucose from non-carbohydrate precursors.
• Why gluconeogenesis is needed

  • Between meals blood glucose levels drop
  • In the absence of insulin, most of the body utilises Fatty Acid for energy, but the brain and red blood cells use glucose
  • Glycogen stores in liver are limited (enough for overnight fast) and muscles can't release glucose (from glycogen) into the blood
• Cori cycle


  Glucose → Pyruvate → Lactate → Glucose
• Glucogenic Amino Acids

  Amino acids that can be converted to glucose through gluconeogenesis. When they are broken down, their carbon skeletons form intermediates that enter the gluconeogenesis pathway. This process typically occurs in the liver and, to a lesser extent, in the kidneys.
• Ketogenic Amino Acids

  Amino acids that can be converted to ketone bodies through ketogenesis. When they are broken down, their carbon skeletons form intermediates that are used to produce acetyl-CoA or acetoacetate, which can then be converted into ketone bodies. These ketone bodies can be used as an alternative energy source, especially during periods of fasting or low carbohydrate intake
• Alanine


  • Quantitatively the most important glucogenic amino acid
  • Muscle catabolism releases Ala into blood
  • Converted to pyruvate via catabolism/transamination
• What is gluconeogenesis?

  Gluconeogenesis is the synthesis of glucose from non-carbohydrate sources, such as lactate, glycerol, and glucogenic amino acids. It primarily occurs in the liver and kidneys
• Why is gluconeogenesis important?

  Gluconeogenesis is important because it helps maintain blood glucose levels during periods of fasting, low carbohydrate intake, or intense exercise, providing glucose for the brain and red blood cells when glycogen stores are depleted
• What are the three irreversible steps in gluconeogenesis?

  1. Conversion of pyruvate to phosphoenolpyruvate (PEP) via pyruvate carboxylase and PEP carboxykinase.
  2. Conversion of fructose 1,6-bisphosphate to fructose 6-phosphate via fructose 1,6-bisphosphatase.
  3. Conversion of glucose 6-phosphate to glucose via glucose 6-phosphatase
• What role does the Cori cycle play in gluconeogenesis?

  The Cori cycle involves the conversion of lactate, produced by anaerobic glycolysis in muscles, back to glucose in the liver. This glucose can then be returned to the muscles to be used as energy, thus helping to maintain glucose levels during intense exercise
• Which amino acid is most important for gluconeogenesis and why?

  Alanine is quantitatively the most important amino acid for gluconeogenesis. Muscle catabolism releases alanine into the blood, where it is transported to the liver and converted to pyruvate, which then enters the gluconeogenesis pathway to produce glucose
• What are the key enzymes involved in the first irreversible step of gluconeogenesis?

  The key enzymes involved in the first irreversible step of gluconeogenesis are pyruvate carboxylase and phosphoenolpyruvate carboxykinase (PEPCK). Pyruvate carboxylase converts pyruvate to oxaloacetate (OAA), and PEPCK converts OAA to PEP
• How does glycerol contribute to gluconeogenesis?

  Glycerol, released from the breakdown of triglycerides in adipose tissue, is converted into dihydroxyacetone phosphate (DHAP), which enters the gluconeogenesis pathway to form glucose
• What are the primary sources of substrates for gluconeogenesis?

  The primary sources of substrates for gluconeogenesis are lactate, glycerol, and glucogenic amino acids. These substrates provide the carbon skeletons needed to synthesize glucose
• Why can't fatty acids be converted into glucose through gluconeogenesis?

  Fatty acids cannot be converted into glucose because they are metabolized into acetyl-CoA, which cannot be converted into pyruvate or any other gluconeogenic intermediates. However, glycerol, a component of triglycerides, can be converted into glucose
• What is the significance of glucose-6-phosphatase in gluconeogenesis?

  Glucose-6-phosphatase is significant because it catalyzes the final step of gluconeogenesis, converting glucose-6-phosphate into free glucose, which can then be released into the bloodstream. This enzyme is located in the endoplasmic reticulum of liver and kidney cells
• What are the energy requirements for gluconeogenesis?

  Gluconeogenesis requires a total of 6 ATP equivalents per molecule of glucose synthesized: 2 ATP for the conversion of pyruvate to oxaloacetate, 2 GTP for the conversion of oxaloacetate to phosphoenolpyruvate, and 2 ATP for other steps in the pathway
• Why is gluconeogenesis not simply the reverse of glycolysis?

  Gluconeogenesis is not simply the reverse of glycolysis because glycolysis has three irreversible steps with large negative free energy changes. These steps (catalyzed by hexokinase, phosphofructokinase-1, and pyruvate kinase) are bypassed in gluconeogenesis by different enzymes (glucose-6-phosphatase, fructose-1,6-bisphosphatase, and the combination of pyruvate carboxylase and PEP carboxykinase)
• What is the function of pyruvate carboxylase in gluconeogenesis?

  Pyruvate carboxylase catalyzes the conversion of pyruvate to oxaloacetate in the mitochondria. This step requires ATP and is the first step in gluconeogenesis, bypassing the irreversible pyruvate kinase step of glycolysis
• How does the alanine cycle contribute to gluconeogenesis?

  The alanine cycle involves the transport of alanine from muscles to the liver. In the liver, alanine is converted to pyruvate by alanine aminotransferase (ALT), and pyruvate then enters the gluconeogenesis pathway to produce glucose. This cycle helps in transferring nitrogen waste to the liver for urea formation while providing substrates for gluconeogenesis
• What is the role of the enzyme fructose-1,6-bisphosphatase in gluconeogenesis?

  Fructose-1,6-bisphosphatase catalyzes the conversion of fructose-1,6-bisphosphate to fructose-6-phosphate. This hydrolysis reaction is a key regulatory step in gluconeogenesis, bypassing the irreversible phosphofructokinase-1 step of glycolysis​
• Describe the function of glucose-6-phosphatase in gluconeogenesis

  Glucose-6-phosphatase catalyzes the hydrolysis of glucose-6-phosphate to free glucose and inorganic phosphate. This reaction occurs in the endoplasmic reticulum of liver and kidney cells and allows the newly synthesized glucose to be released into the bloodstream, maintaining blood glucose levels during fasting​
• How does the glycerol backbone of triglycerides contribute to gluconeogenesis?

  The glycerol backbone of triglycerides is released during lipolysis and transported to the liver, where it is phosphorylated by glycerol kinase to form glycerol-3-phosphate. Glycerol-3-phosphate is then oxidized to dihydroxyacetone phosphate (DHAP), which enters the gluconeogenesis pathway to form glucose
• What is the significance of the enzyme phosphoenolpyruvate carboxykinase (PEPCK) in gluconeogenesis?


  PEPCK catalyzes the conversion of oxaloacetate to phosphoenolpyruvate (PEP) in the cytoplasm, using GTP as an energy source. This step is crucial for bypassing the irreversible pyruvate kinase step of glycolysis and is a key regulatory point in gluconeogenesis
• What role does the Cori cycle play in maintaining blood glucose levels?

  The Cori cycle plays a role in maintaining blood glucose levels by recycling lactate produced by anaerobic glycolysis in muscles back to glucose in the liver. The liver converts lactate to glucose via gluconeogenesis and releases it into the bloodstream, supplying energy to muscles and other tissues during anaerobic conditions
• Why is the enzyme biotin important for the activity of pyruvate carboxylase?

  Biotin is a prosthetic group for pyruvate carboxylase and is essential for its catalytic activity. It serves as a carrier of activated CO2, which is necessary for the carboxylation of pyruvate to oxaloacetate, the first step in gluconeogenesis