What two main enzymes control glycogen metabolism?
And VERY generally what activates/deactivates them?
Glycogen Synthase - deactivated by phosphorylation
Glycogen Phosphorylase - activated by phosphorylation
What common signalling molecule increases phosphorylation of glycogen regulating enzymes?
How is cAMP formed?
And via what hormonal messengers?
cAMP is formed from ATP via adenylyl cyclase (producing also PPi)
- Glucagon, Epinephrine, Norepinephrine all stimulate cAMP synthesis
How is cAMP broken down?
- breaks cAMP down into 5' AMP
What hormone stimulates cAMP breakdown?
And what other hormones' effects are thereby inhibited?
- stimulated by insulin in the liver
- stops the [cAMP] increase ---> phosphorylation-increasing effects of nor-/epinephrine and glucagon
What enzyme catalyzes activation of the main glycogenolysis-performing enzyme?
- phosphorylates inactive Phosphorylase B into active Phosphorylase A
What 2 things allosterically inhibit the main glycogen breakdown enzyme in both liver and muscle tissue?
ATP + Glucose-6-phosphate both inhibit active Phosphorylase A
- because both indicate plenty of free, usable energy in the cell and no need for glycogenolysis
What allosteric effector molecule binds only to muscle-type phosphorylase?
How does it effect the enzyme?
5' AMP binds to muscle phosphorylase
- it activates the inactive phosphorylase b
How is 5' AMP formed (enzyme + products)?
What does an increase in its concentration indicate?
- formed when increased [ADP] is altered by Adenylate Kinase to form ATP and 5'AMP
- it indicates a need for increased substrate metabolism (and thus activates glycogenolysis to free up glucose) for ATP formation
What is the regulatory chain of events leading to glycogenolysis, starting from hormonal messengers?
Glucagon (liver, due to low [Glc]) Norepinephrine (muscle)
- Increase in concentration of cAMP
- Activation of cAMP-Dependent Protein Kinase (PKA)
- Phosphorylation of Phosphorylase Kinase > A form
- Phosphorylation of Phosphorylase B > A form
How are muscle contraction and glycogenolysis synchronized?
- increased intracellular [Ca++] during contraction also activates muscular phosphorylase kinase
How does Ca++ activate glycogenolysis?
(Including info about the structure of the enzyme it affects.)
Phosphorylase kinase is a tetramer:
- Alpha/Beta: Serines phosphorylated by PKA
- Delta: Calmodulin - binds 4 Ca++ + activates gamma
- Gamma: Catalytic site
How does cAMP-independent glycogenolysis work and in what tissue?
Start with the receptor...
Alpha-1 Adrenergic Receptors in the liver
- activated by nor-/epinephrine
- activate Gq > IP3 ^ > ER Ca++ release
- activation of Phosphorylase Kinase, etc.
What other (non-adrenergic) hormones activate cAMP-independent glycogenolysis?
- Angiotensin II
What enzyme can inactivate both phosphorylase + phosphorylase kinase?
- dephosphorylates both enzymes to inhibit glycogenolysis
What specifically inhibits protein phosphatase-1 and how is it activated?
Why is its activation unique?
- activated by PKA
- PKA therefore controls both activation and inhibition of phosphorlyase
What hormone reinforces the effect of protein phosphatase-1 and how?
- increases glucose uptake thereby increasing [G6P] which inhibits phosphorylase kinase
Generally, how is glycogen synthase activated/inactivated?
What does this mean for the effect of the following molecules on it....
Dephosphorylation activates glycogen synthase, so...
- Phosphorylase Kinase: phosphorylates + deactivates
- PKA: phosphorylates + deactivates
- Insulin: Raises G-6-P, stimulates dephosphorylation + activates
- Protein Phosphatase-1: Dephosphorylates + Activates