reciprocal regulation of gluconeogenesis and glycolysis
reciprocally regulated so that glucose is not simultaneously degraded and synthesized
-avoid substrate (Futile) cycling occurs where two opposing enzymes are active at the same time
Fed State
-flux in the glycolytic direction in the fed state, when the insulin/glucagon ratio is high
insulin/glucagon ratio is high
flux in the glycolytic direction
Fasting state
- net flux in the gluconeogenic direction in the fasting state, when the insulin/ratio is low
insulin/glucagon ratio is low
flux in the gluconeogenesis direction
List the regulatory enzymes of glycolysis and gluconeogenesis
� Hexokinase (Glycolysis)
� Phosophofructokinase I (Glycolysis)
� Fructose 1,6-bisphoshatase (Gluconeogenesis)
� Pyruvate Kinase (Glycolysis)
� Pyruvate Carboxylase (Gluconeogenesis)
� PEPCK (Gluconeogenesis)
Hexokinase
-1st irreversible step in glycolysis
-Phosphorylates glucose
-inhibited by Glucose 6-phosphotate (Product)
Hexokinase Inhibited by
Glucose 6-phosphotate (product)
Glucokinase
-in the liver
-exclusively specific for glucose
-required to convert glucose to glycoge
-not inhibited by product
-inhibited by frucotse 6-phophate which is overcome by fructose 1-phosphate
-never saturated
Phosphofructokinase I (PFK I)
-Catalyzes the first irreversible reaction that is unique to the glycolytic pathway
- the committed step
-inhibited by ATP, Citrate
-Activated by AMP, Fructose 2,6-Bisphospahte (Most potent activator of PFK I)
Phosphofructokinase I (PFK I) inhibited by...
-inhibited by:
-ATP
-Citrate
Phosphofructokinase I (PFK I) activated by...
-Activated by:
-AMP, ADP
- Fructose 2,6-Bisphospahte (Most potent activator of PFK I)
Fructose 1,6- Bisphosphatase
-works in the opposite direction of PFK I
- Inhibited by AMP, Fructose 2,6-Bisphospahte
-Activated by Citrate
Pyruvate Kinase
-converts PEP to Pyruvate
-inhibited by ATP, Alanine
Activated by Fructose 1,6 Bisphosphate (feed forward activation)
Pyruvate Kinase activated by...
Fructose 1,6 Bishoshpate
Pyruvate Kinase inhibited by...
ATP, alanine
Glucagon stimulated phosphorylaiton...
Glucagon stimulated phosphorylation (inactivation) of hepatic pyruvate kinase by protein kinase A
Pyruvate Kinase A
-dephosphorylated
-more active
Pyruvate Kinase B
-Phosphorylated
-less active
Low Blood Sugar
-glucagon is secreted
- glucagon mediated phosphorylation inhibits pyruvate kinase
Pyruvate carboxylase
-bypass the pyruvate kinase step in glycolysis
-mitochondrial enzyme
-allosteric control
-Requires Acetyl-SCoA
Fructose 2,6 Bisphosphate
-produced by a bifunctional enzyme
-MOST POTENT ACTIVATOR OF GLYCOLYSIS
-ACTIVATES GLYCOLYSIS BY ACTIVATING PFK I
Phosphofructokinase 2
-Bifunctional enzyme
-under allosteric and hormonal control
-work as a kinase & phosphatse
-activity influenced by fructose 6-phosphate
-when acting as a kinase (PFK II ) F2,6P levels rise
Phosphofructokinase 2 (Phosphorylated)
-PFK II is phosphorylated enzyme works as a phosphatase in the liver
-Decrease F2,6P levels
-Activated by glucagon
- inhibited by fructose 6-phosphate
Phosphofructokinase 2 (Dephosphorylated)
-PFK II is dephosphorylated enzyme works as a kinase in the liver
-raise F2,6P levels
-inhibits by glucagon
-stimulated by Fructose 6-phosphate
Fructose 2,6 Bisphosphatase
removes a phosphate group from Fructose 2, 6 forming Fructose 6 Phosphate
Phosphofructo-2-kinase
-phosphorylates Fructose 6-phosphate forming fructose 2,6 bisphosphate
Endocrine mechanisms
-hormones can affect the amount of enzyme produced- by induction or repression
-they can also cause their covalent modification and thus alter their activity
Insulin
-secreted during the fed state
-increase all anabolic pathways that decrease blood glucose levels
-increases the irreversible enzymes in the glycolytic pathway
-REPRESSES the enzymes in the gluconeogenic pathway
Insulin Induction
-Glucokinase (Liver)
-Phosphofructokinase I
-pyruvate kinase
Insulin Repression
- G 6-Pase
- PEP Carboxykinase
- FBPase I
- Pyruvate Carboxylase
Glucagon
-Induction of gluconeogenic enzymes during periods of starvation
-stimulates phosphorylation and inactivation of PFK II
-stimulates phosphoryation and activation of F2,6-Pase and reduce F2,6P levels
Cortisol
can induce gluconeogenic enzymes and oppose the actions of insulin