Insulin favors
- Glycolysis
Glucagon favors
- Gluconeogenesis
Fructose-2,6-bisphosphate
- Activates PFK-1
- WORKS AS A KINASE OR PHOSPHATASE
In the fed state
- Insulin/glucagon ration is high
- Use insulin to convert glucose to storage, glycogen
In the starving state
- Insulin/glucagon ratio is low
Substrate (futile) cycling
- Occurs where two opposing enzymes are active at the same time
Glucokinase
- Very specific for glucose but has a high km (not saturated)
- Not inhibited by G-6-P
Glucose-6-phsphate and products
- Allosterically inhibit hexokinase
Hexokinase inhibited by
- Fructose-6-phosphate
- Overcome by fructose-1-phosphate
F2,6BP is produced by a bifunctional enzyme
- PFK-2
- As a kinase produces F2,6BP (activator of PFK I)
PFK-1 is a large oligomeric enzyme
- Catalyzes the first irreversible reaction that is UNIQUE to the glycolytic pathway
- The committed step
ATP in glycolytic pathways
- Acts as both a substrate and inhibitor
- Increases the Km of PFK-1 for substrate, inhibiting the enzyme (AMP overcomes inhibition)
Citrate inhibits
- PFK-1
Fructose-2,6-bisphosphate
- Most potent allosteric activator of PFK-1
Allosteric activators of PFK-1
- ADP
- AMP
- Fructose-2,6,-bisphosphate
Allosteric inhibitors of PFK-1
- ATP
- Citrate
Fructose-1,6-bisphosphatase inhibits
- PFK-1 activity
Activation by F-1,6-BP
- Feed forward activation
- Second most common enzymopathy in humans (after glucose-6-phosphate dehydrogenase)
Alanine production
- Produced by proteolysis
Hepatic pyruvate kinase by protein kinase A
- Glucagon stimulated phosphorylation (inactivation)
Control of pyruvate kinase activity by reversible phosphorylation
- Glucagon signals the fasting state
- Causes phosphorylation
- Turns off pyruvate kinase (glycolysis will be off)
Pyruvate kinase is activated by
- Fructose-1,6-bisphosphate
When glucose is in short supply
- Glucagon is secreted from the alpha cells of the pancreas
Low blood sugar levels
- Glucagon is secreted
- Receptor mediated activation of protein kinase A inhibits pyruvate kinase
Glucagon mediated phosphorylation
- Inhibits pyruvate kinase
Pyruvate carboxylase
- Helps bypass the pyruvate kinase step in glycolysis
- Mitochondrial enzyme
- Allosteric control
- Requires Acetyl-SCoA
Fructose-2,6-bisphosphate
- Produced by a bifunctional enzyme
- Not a glycolytic intermediate
- Most potent activator of glycolysis
- Inhibits gluconeogenesis
Fructose-2,6-bisphosphate bifunctional enzymatic activity
- Works as a kinase and phosphatase
- Phosphofructokinase 2
- Under allosteric and hormonal control
Allosteric activation of PFK-1 by F-2,6-BP
- Increasing affinity for substrate
- Reducing inhibitory effect of ATP
- Favors T –> R transition
Phosphorylation of kinase
- Turns it off
- Causes it to work as a phosphatase
F6P is a substrate for the kinase
- Activates glycolysis
Low blood sugar level favors glucagon
- Phosphorylates things
- Bifuncitonal enzyme
- Reduces glycolytic flux
Hormones (endocrine mechanism)
- Can effect the amount of enzyme produced
- Induction or repression
Endocrine mechanisms
- Cause covalent modification, thus altering activity
Secretion of insulin
- Positive post prandially (the fed state)
- Increases all anabolic pathways that decrease blood glucose levels
- Induces the irreversible enzymes in the glycolytic pathway
- Represses the enzymes in the gluconeogenic pathway
Insulin induction
- Glucokinase (liver)
- PFK-1
- Pyruvate kinase
Insulin repression
- G-6-Pase
- PEP carboxylase
- FBPase-1
- Pyruvate carboxylase
Induction of gluconeogenic enzymes during periods of starvation
- G-6-Pase
- PEP carboxykinase
- FBPase-1
- Pyruvate carboxylase
Low glucose levels increase gluconeogenesis via
- Glucagon-mediated covalent modification
Glucagon secreted from alpha cells in response to
- Low glucose
- Inhibits glycolysis
Pyruvate kinase A (PrK A) mediated phosphorylation
- Favors phosphatase activity of bifunctional enzyme
- Reduces F-2,6-BP levels
Glucagon generally causes
- Phosphorylation
Insulin generally causes
- Dephosphorylation
With dephosphorylation
- Kinase activity of the bifunctional enzyme is favored
With phosphorylation
- Phosphatase activity of bifunctional enzyme is favored
Glucagon stimulates
- Phosphorylation
- Inactivation of the hepatic PFK-2
Transcription of the gene for PEP carboxykinase
- Promoted by glucagon
- Opposed by insulin
Cortisol
- Can induce gluconeogenic enzymes
- Opposes the action of insulin
Steroid hormones
- Interact with nuclear or cytoplasmic receptors
- Alter enzyme synthesis
- Promote protein catabolism (increases amino acid availability for gluconeogenesis)
Fructose-2,6-bisonosphate inhibits
- Bisphosphatase activity of gluconeogenesis