Skip to content

Gluconeogenesis

Where it happens

  • primarily in the liver
  • only in extreme starvation, the kidney starts gluconeogenesis
  • exists even when glycogen is sufficient

Major substrates

  • glycerol
  • amino acids
  • lactate

Relationship to glycolysis

  • overall pathway is similar to glycolysis except for key bypass steps.

Entry points and key bypass enzymes

Pyruvate → oxaloacetate → phosphoenolpyruvate

Sources feeding into pyruvate/oxaloacetate:

  • alanine, lactate, amino acids → pyruvate → oxaloacetate

Steps:

  • pyruvate carboxylase converts pyruvate to oxaloacetate
  • phosphoenolpyruvate carboxykinase converts oxaloacetate to phosphoenolpyruvate

Glycerol → DHAP

  • glycerol → glycerol 3-phosphate → DHAP

Amino acids → TCA

  • amino acids enter the TCA cycle

Specific conversions (enzyme-level)

Lactate → pyruvate

  • lactate dehydrogenase converts lactate → pyruvate
  • converts 1 NAD\(^+\) to NADH

Alanine → pyruvate

  • alanine aminotransferase converts alanine → pyruvate
  • source note: from muscle degrading

Glycerol → DHAP

  1. glycerol → glycerol 3-phosphate via glycerol kinase (uses ATP)

  2. glycerol 3-phosphate → DHAP via glycerol 3-phosphate dehydrogenase

  3. converts 1 NAD\(^+\) to NADH

Pyruvate → oxaloacetate (matrix)

  • pyruvate → oxaloacetate using:

  • CO\(_2\)

  • ATP
  • biotin
  • acetyl-CoA (from fat breakdown)
  • location: mitochondrial matrix

Oxaloacetate → phosphoenolpyruvate

  • oxaloacetate → phosphoenolpyruvate via phosphoenolpyruvate carboxykinase
  • uses GTP and releases CO\(_2\)
  • location note: matrix, cytoplasm and matrix; proceeding enzymes are in cytoplasm

F-1,6-BP → F-6-P

  • fructose-1,6-bisphosphate → fructose-6-phosphate via fructose-1,6-bisphosphatase

G-6-P → glucose (ER membrane)

  • glucose-6-phosphate → glucose via glucose-6-phosphatase on the ER membrane

Energy cost / yield accounting

Per 1 pyruvate

  • 1 ATP, 1 GTP, 1 NADH, 1 ATP
  • 5.5 ATP equivalents per pyruvate
  • 11 ATP equivalents per glucose

Per 1 glycerol

  • 1 ATP, -1 NADH
  • 1.5 ATP equivalents (gained) per glycerol
  • 3 ATP equivalents (gained) per glucose

Regulation

Glucagon (low blood glucose)

  • under low blood glucose, glucagon leads to phosphorylation signaling
  • fat breaks down; fatty acids form acetyl-CoA and enter liver to support oxaloacetate
  • glucagon stimulates transcription of phosphoenolpyruvate carboxykinase
  • PKA from glucagon pathway phosphorylates pyruvate kinase (inactivates it)

F-2,6-P\(_2\) regulation

  • F-2,6-P\(_2\):

  • activates PFK-1

  • deactivates fructose-1,6-bisphosphatase
  • fructose-1,6-bisphosphatase transcription can be increased by glucagon pathway

Under fasting:

  • phosphatase domain is turned on if phosphorylated to remove and reduce glycolysis (glucagon)

Insulin

  • insulin acts in the opposite direction (vice versa)

Additional notes

  • glucose-6-phosphate → glucose regulation includes transcription of glucose-6-phosphate changing (as noted)
  • glucokinase has high \(K_m\)

Clinical

Fructose-1,6-bisphosphatase deficiency

  • enlarged liver (from glycerol)
  • acidosis (build-up of products after F-1,6-P)