Overview
- Function
- de novo glucose synthesis
- effectively glycolysis in reverse
- can maintain blood glucose when glycogen stores are exhausted
- must supply brain and RBCs which utilize glucose for energy
- is NOT a source of energy for the liver
- hepatocytes use β-oxidation to supply the energy needed for gluconeogenesis
- potential substrates
- all amino acids
- except for leucine and lysine
- lactate
- produced in anaerobic glycolysis
- glycerol-3-phosphate
- produced in fat catabolism
- propionyl-CoA
- produced in odd-carbon fatty acid catabolism
- Pathway
- location
- hepatocytes (primary)
- kidney
- enterocytes
- NOT muscle
- no glucose-6-phosphatase
- cannot release free glucose
- no glucose-6-phosphatase
- enzymes
- involves both mitochondrial and cytosolic enzymes
- several steps of glycolysis are reversible
- the non-reversible steps must be bypassed with special gluconeogenic enzymes
- pyruvate carboxylase
- pyruvate → oxaloacetate
- requires biotin and ATP
- activated by acetyl-CoA
- oxaloacetate must be converted to malate to exit the mitochondria via the malate-aspartate shuttle
- in mitochondria
- PEP carboxykinase (PEPCK)
- oxaloacetate → phosphoenolpyruvate (PEP)
- requires GTP
- activated by glucagon and cortisol
- in both cytosol and mitochondria
- fructose-1,6-bisphosphatase
- fructose-1,6-bisphosphate → fructose-6-P
- important control point of gluconeogenesis
- activated by ATP, inhibited by AMP and fructose-2,6-bisphosphate
- in cytosol
- glucose-6-phosphatase (G6P)
- glucose-6-P → glucose
- in ER of hepatocytes
- clinical relevance
- von Gierke disease = G6P deficiency
- see Glycogen metabolism
- von Gierke disease = G6P deficiency
- pyruvate carboxylase
- other enzymes
- lactate dehydrogenase
- lactate → pyruvate
- requires free NAD+
- lactate dehydrogenase
- location
- alcohol may cause elevated NADH/NAD+ ratio leading to hypoglycemia