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Regulation of gluconeogenesis, Allosteric regulator of both PFK-1 + FBP-1 …
Regulation of gluconeogenesis
Hepatic gluconeogenesis
Fed state
High insulin/glucagon ratio
Reduced gluconeogenesis + glycogenoylsis
Anabolic reactions favoured e.g. muscle synthesis + storage
Fast state
Low insulin/glucagon ratio
Favours glycogenoylsis + gluconeogenesis
Epinephrine also promotes gluconeogenesis
Gluconeogenesis + glycolysis must be controlled in reciprocal fashion
Intracellular conditions either favour gluconeogenesis or glycolysis, not both
Major points of control (enzymes)
Glycolysis
Phosphofructokinase-1 (PFK-1)
Most important
Pyruvate kinase
Inhibited in fasting state
Favours gluconeogenesis
By PKA
Phosphoenolpyruvate not converted to pyruvate when inhibited
Gluconeogenesis
Fructose bisphosphate-1 (FBP-1)
Glucagon
In fasting state
High levels produced
Bind to receptor
Adenylate cyclase activated
Synthesises cAMP
Activates protein kinase A (PKA)
Modulates many enzymes in glycolytic pathway
Phosphorylates pyruvate kinase
Phosphorylates PFK-2/FBP-2 complex
Phosphorylation of transcription factors
Increased expression of PEPCK
Enzyme converting oxaloacetate to phosphoenolpyruvate
Facilitates increase of gluconeogenesis
Ratio of glucagon to insulin is high
Insulin
In fed state
High levels
Bind receptors
Adenylyl cyclase inhibited
Decreased levels of cAMP
No PKA produced
Dephosphorylation of PFK-2/FBP-2
Glycolysis favoured
Allosteric regulator of both PFK-1 + FBP-1
Fructose 2,6-bisphosphate
Interacts with enzyme not at active site
High levels
Increases PFK-1 activity
Flux in glycolytic pathway
Inhibit FBP-1
Low levels
Increases FBP-1 activity
Flux in gluconeogenesis pathway
Decreased activity of PFK-1
Production of fructose 2,6-bisphosphate
By enzyme phosphofructokinase-2/fructose bisphosphatase-2 (PFK-2/FBPase-2)
1 enzyme with 2 activities (bifunctional)
On separate domains of enzyme
Kinase + phosphatase activity
Can be phosphorylated by PKA
From fructose 6-phosphate
What controls the enzyme?
Phosphorylation
Kinase activity inhibited
Phosphatase activity increased
Prevent production of Fructose 2,6-bisP
Any fructose 2,6bisP present will be phosphorylated back to fructose 6-P
More gluconeogenesis
Dephosphorylation
Phosphatase activity inhibited
Kinase activity increased
More fructose 2,6-bisP produced
More glycolysis