Carb Metab Regulation Flashcards
Which bypass is not suitable for regulation of glycolysis and why?
- Bypass 3
- G6P is required for other pathways
What are good points in glycolysis for regulation?
- PFK
- Pyruvate Kinase
PFK regulation
- PFK is in the glycolysis pathway
- Allosterically inhibited by ATP as a feedback inhibitor
- High ATP levels will turn PFK off
- High AMP/ADP levels will compete with ATP for binding at the allosteric site and signal the speeding up of glycolysis
- F2,6BP is also an activator of glycolysis (competes with ATP for binding)
Mechanism of PFK regulation by ATP
- When an activator binds (AMP/ADP), stabilizing positive charges are placed near where the substrate binds
- When an inhibitor binds (ATP), destabilizing negative charges are placed near where the substrate binds.
FBPase regulation
- FBPase is in the gluconeogenesis pathway
- AMP and F2,6BP will bind an allosteric site and inhibit–serves to slow gluconeogenesis while glycolysis is active
Synthesis and breakdown of F2,6BP
- Regulated by bifunctional enzyme
- Dephosphorylated state: catalytic site in the kinase domain is active (PFK-2)
- Phosphorylated state: catalytic site in phosphatase domain is active (FBPase-2)
- Phosphorylation state is under hormonal control
Impact of low blood glucose
low glucose–> increased glucagon secretion–> increased cAMP–> increased enzyme phosphorylation–> activation of FBPase-2 and inactivation of PRK-2–> decreased F2,6P–> Inhibition of PFK and activation of FBPase–> increased gluconeogenesis
Impact of high blood glucose
high glucose–> increased insulin secretion–> decreased enzyme phosphorylation–> increased F2,6P–> increased glycolysis
Regulation of pyruvate kinase
- Activated by FBP (earlier substrate of the pathway), inhibited by feedback inhibitors (Acetyl-CoA and ATP)
- Inhibited by cAMP dependent phosphorylation induced by glucagon
Regulation of pyruvate carboxylase
-Activated by Acetyl-CoA
Impact of glucagon
- Decrease in the level of glycolytic enzymes (glucokinase and PFK)
- Increase in gluconeogenic enzymes (PEPCK, FBPase, and G6Pase)
Impact of insulin
-Decrease in level of gluconeogenic enzyme PEPCK
Three methods of reciprocal regulation of glycolysis and gluconeogenesis
- Allosteric ligands (ATP, ADP, AMP, F26BP, FBP, Acetyl-CoA)
- Protein kinase/phosphatases
- Hormonal regulation
What is the only shared enzyme in the reciprocal regulation of glycogen synthesis and breakdown?
-Phosphoglucomutase (converts G1P to G6P and vice versa)
Regulation of glycogen synthesis
- Glycogen synthase is regulated through reversible protein phosphorylation
- Increase in cAMP activates PKA which inhibits glycogen synthase and phosphoprotein phosphatase 1
- Insulin increases glycogen synthesis
Regulation of glycogen breakdown
- Glycogen phosphorylase is regulated
- Increase in cAMP activates PKA which activates phosphorylate kinase which activates glycogen phosphorylase and stimulates breakdown
Impact of epinephrine on muscle cells
-Epi increases cAMP and consequently glycogen degradation.
Impact of insulin on glucose transporters
- Increases Glu transporters at the cell surface and consequently the uptake of Glu
- Doesn’t occur in brain or liver
- Results in increased glycogen synthesis in the muscle
- Results in increased synthesis of triacylglycerols in adipocytes
Allosteric regulation of glycogen phosphorylase
- When blood glucose is low, phosphorylase will be in the phosphorylated form (the active R conformation)
- When blood glucose is high, ATP and G6P will be high and dephosphorylated phosphorylase will be in the inactive T conformation. Can become activated if levels of AMP are high.
Regulation of the pyruvate dehydrogenase complex
- Pyruvate dehydrogenase complex has its own regulatory enzymes E4 and E5 that both act on E1
- Kinase is activated by NADH and acetyl coA to phosphorylate and inactivate E1
- Pyruvate and ADP inhibit the kinase and serve to keep E1 active
- In F or F response calcium activates the phosphatase to convert E1 back to the active form
- Product inhibition of E3 by NADH and E2 by acetyl-coA
CAC regulation
- Product inhibition:
- Citrate inhibits citrate synthase
- iCitrate DHase inhibited by NADH
- Alpha KG DHase inhibited by NADH and Succ-CoA
- Feedback inhibition: Cit synthase inhibited by Succ-CoA
- Allosteric inhibition: iCit DHase activated by ADP and inhibited by ATP
