What is gluconeogenesis?
Synthesis of glucose from non-carbohydrate precursors (lactate, amino acids, glycerol).
When does gluconeogenesis occur?
During fasting, starvation, or intense exercise.
What are the main precursors for gluconeogenesis?
Lactate and alanine, which are converted to pyruvate/intermediates.
How are fats involved in gluconeogenesis?
From fat breakdown, they are converted to DHAP.
What are the bypass steps of glycolysis in gluconeogenesis?
- Oxaloacetate to phosphoenol pyruvate
- Pyruvate carboxylase + PEP carboxykinase
- Fructose-1,6-bisphosphate to fructose-6-phosphate
- Fructose-1,6-bisphosphatase
- Glucose-6-phosphate to glucose
- Glucose-6-phosphatase, only in liver & kidney.
What is the energy requirement for gluconeogenesis?
1 glucose costs 4 ATP + 2 GTP + 2 NADH.
Is gluconeogenesis energetically possible?
Yes, despite glycolysis being exergonic.
What is the relationship between gluconeogenesis and glycolysis?
They are reciprocally regulated.
What stimulates glycolysis and inhibits gluconeogenesis?
AMP and F-2,6-bisP.
What stimulates gluconeogenesis?
Citrate.
What is the role of insulin in gluconeogenesis?
Insulin inhibits gluconeogenesis in the fed state.
What is the role of glucagon in gluconeogenesis?
Glucagon stimulates gluconeogenesis during fasting.
What enzyme regulates the levels of F-2,6-bisP?
The bifunctional enzyme PFK-2/FBPase-2.
What is the Cori Cycle?
Muscle produces lactate, which is transported to the liver, reconverted to glucose, and returned to muscle.
When is the Cori Cycle important?
It is important during anaerobic exercise.
What is a clinical connection related to gluconeogenesis?
In type 2 diabetes, the liver fails to shut down gluconeogenesis, leading to hyperglycemia.
Why is gluconeogenesis essential for survival during fasting?
Gluconeogenesis maintains blood glucose during fasting or starvation. The tissues that depend most on glucose include red blood cells (sole energy source), brain (main consumer), and muscle (uses glucose along with fatty acids). Without gluconeogenesis, these tissues would be deprived of energy.
Why can’t gluconeogenesis be a simple reversal of glycolysis?
Glycolysis has three steps that cannot be simply reversed due to different enzymes in gluconeogenesis that bypass these steps: hexokinase/glucokinase, phosphofructokinase-1, and pyruvate kinase. Direct reversal would result in a positive Gibbs free energy change (+22 kcal/mol).
How do lactate, glycerol, and amino acids enter the gluconeogenesis pathway?
Lactate is produced by anaerobic glycolysis in muscle, enters the blood, and is taken up by the liver where it is converted back to pyruvate by lactate dehydrogenase. Amino acids from protein breakdown are converted to pyruvate or TCA intermediates that feed into gluconeogenesis. Glycerol from fat breakdown is converted in the liver to DHAP via glycerol kinase and glycerol phosphate dehydrogenase.
Why is oxaloacetate transported as malate out of the mitochondria instead of directly?
There is no oxaloacetate transporter in mitochondria. Instead, oxaloacetate is reduced to malate, transported out, and re-oxidized to oxaloacetate in the cytosol.
Why is gluconeogenesis energetically favorable?
Gluconeogenesis consumes 6 high-energy molecules (4 ATP + 2 GTP + 2 NADH) but is overall exergonic (ΔG = -38 kJ/mol) compared to the endergonic reversal of glycolysis (-22 kcal/mol).
ATP inhibits PFK-1 in glycolysis, while citrate signals inhibition of glycolysis and stimulation of gluconeogenesis.
What role does fructose 2,6-bisphosphate play in coordinating glycolysis and gluconeogenesis?
Fructose 2,6-bisP is a powerful allosteric regulator that activates phosphofructokinase-1 (stimulating glycolysis) and inhibits fructose-1,6-bisphosphatase (slowing gluconeogenesis).
Its concentration is hormonally controlled by insulin (increases F-2,6-BP) and glucagon (decreases F-2,6-BP).
How does glucagon stimulate gluconeogenesis at the molecular level?
Low blood sugar triggers glucagon release, activating the cAMP signaling cascade, which phosphorylates the bifunctional enzyme (PFK-2/FBPase-2), inhibiting kinase activity and activating phosphatase activity, lowering [F-2,6-BP], leading to less glycolysis and more gluconeogenesis.
Why is gluconeogenesis restricted to the liver and kidney?
Only the liver and kidney express glucose-6-phosphatase, the enzyme that produces free glucose from G6P.
Muscle lacks this enzyme, preventing it from releasing glucose.
