Gluconeogenesis

Summary

The body needs to keep blood-glucose levels high in order to fuel glucose-dependent cells, like red blood cells and those in the brain. The main function of gluconeogenesis is to maintain blood-glucose levels when (1) there is insufficient glucose intake (2) and we’ve already run out of glycogen. While the pathway produces glucose, it does not produce energy--it actually consumes energy—and this energy usually comes from the breakdown of fats. The ATP produced by fat breakdown can be used to convert non-carbohydrate molecules into glucose, thereby raising blood-glucose levels.

Gluconeogenesis primarily occurs in the liver, and all but the first step of the pathway occurs in the cytoplasm of liver cells. Gluconeogenesis essentially reverses glycolysis to produce glucose, so to learn the pathway, learn the steps that differ from glycolysis—specifically the irreversible steps.

Key Points

• Gluconeogenesis
  • Etymology
    • Gluconeogenesis = the generation of ‘new’ glucose
      • Gluco = glucose
      • Neo = new
      • Genesis = generation (of something)
  • Summary
    • Gluconeogenesis is a biochemical pathway that generates glucose from non-carbohydrate sources
      • Helps the body maintain blood glucose levels when there is insufficient glucose intake (fasted state)
        • As glycogen stores get used up, gluconeogenesis plays an increasingly large role in maintaining blood glucose levels
          • Given a long enough fast, gluconeogenesis eventually becomes the only source of glucose
        • Produces glucose but consumes energy as ATP
    • Proceeds as glycolysis in reverse but differs at the irreversible steps
      • Glycolysis has 3 irreversible steps
        • These steps require an alternative path
  • Location
    • Gluconeogenesis occurs primarily in the liver
      • Occurs to a lesser extent in the kidneys
      • Most steps occur in the cytosol of the cell
        • The formation of oxaloacetate occurs in the mitochondrial inner matrix
  • Starting substrates
    • Sourced from non-carbohydrate molecules that are present during a glucose-depleted state
      • Such as fats, proteins, lactate
    • Can enter the pathway at different points
      • Glycerol-3-phosphate
        • Converted to DHAP to enter the pathway
      • Lactate
        • Converted to pyruvate to enter the pathway
          • Cori cycle
      • Amino acids
        • Converted to pyruvate, oxaloacetate, or some other TCA cycle intermediate to enter the pathway
        • Most amino acids can be feed into gluconeogenesis
          • Not leucine or lysine
  • Reaction steps (Unique to gluconeogenesis)
    • Pyruvate + CO2 + ATP → [pyruvate carboxylase] Oxaloacetate + ADP
      • Pyruvate kinase reaction is irreversible--1st step around
        • Pyruvate carboxylase is in the mitochondria
          • Pyruvate must be transported into the mitochondria from the cytosol
      • Powered by the hydrolysis of 1 ATP
      • Irreversible
    • Oxaloacetate + GTP → [PEP carboxykinase] Phosphoenolpyruvate + GDP + CO2
      • Pyruvate kinase reaction is irreversible--2nd step to get around
        • Phosphoenolpyruvate carboxykinase is in the cytosol
          • For this reaction to occur, oxaloacetate must be transported from the mitochondria to the cytosol
            • This transport is done via the malate-aspartate shuttle
      • Powered by the hydrolysis of 1 GTP
        • 1 GTP = 1 ATP (energetically)
      • Irreversible
    • Fructose 1,6 bishphosphate → b fructose-6-phosphate
      • Phosphofructokinase-1 reaction is irreversible, so fructose-1,6,-bisphosphatase (F-1,6-BP) reverses that step
      • Fructose-1,6-bisphosphatase is a phosphatase
        • Phosphatases remove a phosphate group via hydrolysis
          • Phosphatases often catalyze the reverse reaction of a Kinase
      • Irreversible
    • Glucose-6-phosphate → [glucose-6-phosphatase] glucose
      • Glucokinase reaction is irreversible, so glucose-6-phosphatase reverses that step
        • Glucose-6-phosphate cannot diffuse out of the cell
          • free glucose can diffuse out of the cell to enter the bloodstream to help maintain blood glucose levels
      • Irreversible
  • Regulation
    • Regulated by the energy needs of liver cells and by blood glucose levels
      • Liver cells must be energetically satisfied before they can produce glucose for the rest of the body
      • Gluconeogenesis is only needed when blood glucose levels are low
    • Regulated at the irreversible steps
    • Gluconeogenesis speeds up (activation)
      • Energy needs of liver cells are met
        • acetyl-CoA
          • High levels of acetyl-CoA accumulate from the catabolism of fatty acids for energy
          • Activates Pyruvate carboxylase
          • Inhibits Pyruvate dehydrogenase
            • Pyruvate dehydrogenase sends pyruvate along the path to the TCA cycle
        • ATP
      • Low blood glucose levels
        • Glucagon
          • Glucagon lowers fructose-2,6-bisphosphate (F26BP) levels
          • F26BP inhibits gluconeogenesis
    • Gluconeogenesis slows down (inhibition)
      • Energy needs of liver cells are not met
        • AMP
      • High blood glucose levels
        • Insulin
          • Insulin increases fructose-2,6-bisphosphate levels
            • F26BP inhibits gluconeogenesis