What is gluconeogenesis?
“Genesis of new glucose”; During fasting, glycolysis reactions are reversed to maintain blood-glucose levels (non-carbohydrate molecules -> glucose)
- Brain, RBCs, kidney medulla, eye lens/cornea, testes, and exercising muscles all require continuous glucose supply
- Glycogen in liver only meets this need for 10-18 hours
What does gluconeogenesis require and where does it occur?
Requires both mitochondrial and cytosolic enzymes; 90% in the liver
What are the major precursors of gluconeogenesis?
Lactate (NOT to be confused with Lactose!!!!), glycerol and amino acids (particularly alanine)
What is the source of lactate?
From pyruvate when you do anaerobic glycolysis in exercising muscle and RBCs
Lactate -> Pyruvate (via lactate dehydrogenase)
-Generates NADH
What is the source of glycerol?
From fat, stored as TAG in adipose -> 3 FAs + glycerol
Glycerol -> Glycerol 3-P (via glycerol kinase)
Glycerol 3-P -> Dihydroxyacetone phosphate or DHAP (via glycerol 3-P dephydrogenase)
-DHAP is a glycolytic intermediate
What is the source of amino acids?
When insulin is low, muscles are breaking down -> liver
Alanine -> Pyruvate (via alanine aminotransferase)
-during this rxn: alpha-ketoglutarate -> glutamate
-ALT is measured in liver function panel because will be increased in liver disease
T or F: All the reactions of gluconeogenesis are the reversal of glycolysis.
False; 3 key steps are not
What is the 1st unique step in gluconeogenesis?
Pyruvate -> phosphoenolpyruvate (multi-step)
1) Pyruvate -> Oxaloacetate (via pyruvate carboxylase)
- CO2 is required (3C -> 4C)
- ATP -> ADP + P
- Biotin coenzyme
2) Oxaloacetate -> Phosphoenolpyruvate (via phosphoenolpyruvate carboxylase aka PEPCK)
- Releases CO2
- GTP -> GDP
- There is mitochondrial or cytosolic PEPCK (50/50)
What is the 2nd unique step in gluconeogenesis?
Fructose 1,6-biphosphate -> fructose 6-P (via fructose 1,6-biphosphatase)
-bypasses phosphofructokinase-1
What is the 3rd unique step in gluconeogenesis?
Glucose 6-phosphate -> glucose (via glucose 6-phosphatase)
- Hydrolyzes the Pi from G6P
- Not the exact reversal of hexokinase/glucokinase because ATP is not produced
- Liver and kidney = only organs that release free glucose
What is the cori cycle?
Glucose converted by exercising muscle to lactate -> diffuses into blood -> taken up by liver -> reconverted to glucose -> released back into circulation
How is gluconeogenesis regulated?
1) Glucagon
2) Substrate availability
3) Allosteric activation by acetyl CoA
4) Allosteric inhibition by AMP
How does [glucagon] regulate gluconeogenesis?
Increase in [glucagon] -> gluconeogenesis
- Decrease in fructose 2,6-biphosphate -> fructose 1,6-biphosphatase activation + PFK-1 inhibition
- Activation of hepatic cAMP-depndent protein kinase
- Induction of PEP-carboxykinase
How does substrate availability regulate gluconeogenesis?
Mainly gluconeogenic amino acids (with low levels of insulin); more AAs available, more gluconeogenesis
