Gluconeogenesis – Making Glucose from Non-Carbohydrate Sources

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Introduction

Gluconeogenesis is the metabolic pathway by which glucose is synthesized from non-carbohydrate precursors like lactate, glycerol, and amino acids. This process is crucial during periods of fasting, prolonged exercise, or when carbohydrate intake is low, as it ensures that blood glucose levels remain stable for tissues that depend on glucose, such as the brain and red blood cells.

Step-by-Step Breakdown of Gluconeogenesis

  1. Conversion of Pyruvate to Oxaloacetate
    Gluconeogenesis begins in the mitochondria, where pyruvate is converted into oxaloacetate by the enzyme pyruvate carboxylase. This reaction requires ATP and CO₂.

  2. Transport of Oxaloacetate to the Cytosol
    Oxaloacetate cannot cross the mitochondrial membrane directly, so it is reduced to malate by malate dehydrogenase. Malate is then transported into the cytosol, where it is reoxidized to oxaloacetate.

  3. Formation of Phosphoenolpyruvate (PEP)
    In the cytosol, oxaloacetate is converted to phosphoenolpyruvate (PEP) by phosphoenolpyruvate carboxykinase (PEPCK). This step uses GTP and releases carbon dioxide.

  4. Reverse Glycolysis Steps
    The next several steps essentially reverse the reactions of glycolysis, with some key differences:

    • Fructose-1,6-bisphosphate is converted to fructose-6-phosphate by fructose-1,6-bisphosphatase (an irreversible step).
    • Glucose-6-phosphate is converted to glucose by glucose-6-phosphatase in the final step of gluconeogenesis, releasing free glucose into the bloodstream.

Precursors for Gluconeogenesis

  • Lactate: Produced in muscles during anaerobic respiration, lactate is transported to the liver where it is converted back to pyruvate and enters gluconeogenesis. This is part of the Cori Cycle.
  • Glycerol: Released during fat breakdown, glycerol can be converted to dihydroxyacetone phosphate (DHAP), an intermediate in gluconeogenesis.
  • Amino Acids: Glucogenic amino acids (e.g., alanine) can be converted into pyruvate or intermediates of the citric acid cycle, which then enter gluconeogenesis.

Importance of Gluconeogenesis

  • Maintaining Blood Glucose Levels: During fasting or intense exercise, gluconeogenesis provides a continuous supply of glucose to critical tissues like the brain and red blood cells.
  • Energy Homeostasis: Gluconeogenesis ensures that the body can produce glucose even when dietary carbohydrate intake is insufficient, making it vital for survival in low-glucose environments.

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