Glycogen
Metabolism
Variation of liver glycogen
levels between meals and
during the nocturnal fast.
In muscle the final products of glycogen breakdown
depend on the type of muscle fiber.
Red muscle fibers
- many mitochondria and much myoglobin.
- Glucose is converted primarily to pyruvate that
can be completely oxidized to CO2 and water.
White muscle fibers
- few mitochondria and little myoglobin
- break down glucose primarily to lactate
- can do this very rapidly.
chicken breast - white muscle fibers
-capable of high energy output for short periods
chicken heart - red muscle fibers
capable of sustained activity but stores glycogen for
periods of increased demand
Duck breast
Turkey breast
Most skeletal muscles of humans are a mixture of
red and white fibers.
Structure of Glycogen
- one branch point about every ten sugars
- glycogen granules present in cytosol
- granules about 10-40 nm in diameter
- ~100,000 glucose units in a granule
Glycogen Biosynthesis
- takes place in the cytosol
- utilizes an activated form of glucose - UDP-glucose
- UDP-glucose is made from Glucose-1-phosphate and UTP
The phosphoglucomutase reaction.
UDP-Glucose Pyrophosphorylase
Glycogen Synthesis is Initiated on Glycogenin
-the first step in glycogen synthesis is the transfer of a glucose unit
from UDP-glucose to a tyrosine in glycogenin.
- glycogenin autocatalytically extends the glucan chain ~7 Glc units,
then glycogen synthase takes over, along with glycogen branching
enzyme.
Enzymes of Glycogen Metabolism Form a Complex
with the Glycogen Particle
GN - glycogenin
GS - glycogen synthase
GP - glycogen phosphorylase
PhK - phosphorylase kinase
RG1 - phosphatase reg. subunit
CS1 - phosphatase catal. subunit
Glycogen Branching Enzyme
- transfers a ~7 glucose segment
Glycogen breakdown
Dietary:
Involves a amylase
Creates limit dextrins and maltose
Debranching
Hydrolysis produces 2 glucose from one maltose
Metabolic-intracellular
Involves glycogen phosphorylase
Debranching
Produces Glucose-1-phosphate
Phosphoglucomutase converts Gluc-1-phosphate to Gluc-6-phosphate
Dietary breakdown of Starch
Figure 22.11 (a) The sites of
hydrolysis of starch by α- and βamylases are indicated.
a-amylase (saliva and pancreas)
b-amylase (in plants)
a-amylase can cleave to maltose
and maltotriose (2 glucose and 3
glucose moieties) but stops within
4 glucoses of a branch, so leave
“limit dextrins” that need
debranching.
Dietary carbohydrate breakdown
Figure 22.12 The reactions of debranching
enzyme. Transfer of a group of three
glucose residues from a limit branch to
another branch is followed by cleavage of
the bond linking the remaining residue at the
branch.
Glycogenolysis Intracellular
- glycogen breakdown is not simply a reversal of
biosynthesis - different reactions are involved.
Glycogen phosphorylase cleaves glucose residues off
the non-reducing ends of the chains by addition of
inorganic phosphate (phosphorolysis).
- the enzyme only removes glucose units that are 4 or
more residues from a branch point.
Glycogen Debranching Enzyme
The enzyme has 2 different
activities:
1. oligo-(a-1,4a-1,4)glucantransferase
2. 2. amylo-a-(1,6)-glucosidase
Glycogen phosphorylase and debranching enzyme give a
mixture containing ~10 times as much G1P as glucose.
Why phosphorolysis?
- product is already phosphorylated - no need to use an ATP
- G1P can be readily converted into G6P by phosphoglucomutase.
Phosphorylase Kinase is activated
Phosphorylation and by Calcium Ions
Phosphorylase kinase is activated by phosphorylation by
an enzyme called protein kinase A (PKA).
Muscle
contraction
Hormone-triggered
cyclic AMP release
Ca2+
release
Ca2+ -free
kinase
inactive
Ca2+ kinase
partly active
Phosphorylated
kinase
fully active
by
Muscle
contraction
Hormone-triggered
cyclic AMP release
Ca2+
release
Ca2+ -free
kinase
inactive
Ca2+ kinase
partly active
Phosphorylated
kinase
fully active
Hormonal Control of Glycogen Metabolism
Insulin, glucagon, and epinephrine
profoundly influence glycogen
metabolism.
Glucagon and epinephrine release
triggers the breakdown of
glycogen.
Glucagon and epinephrine bind to
receptors on the plasma membrane
of cells and trigger the release of
the “second messenger” cyclic
AMP.
Formation of Cyclic AMP
Cyclic AMP activation of protein kinase A
Cyclic AMP-dependent protein kinase A (PKA) is activated when
the two regulatory subunits bind cAMP and then release the active
catalytic subunits.
Activation of Phosphorylase
Protein Phosphatase 1 (PP1)
Reverses the effects of the kinases and plays an important role in
regulating glycogen metabolism.
It increases the rate of glycogen synthesis and decreases the rate of
glycogen breakdown.
Inactivation of Glycogen Synthase
Epinephrine enhances glycogen breakdown
while decreasing synthesis
Blood Glucose Levels are Regulated by
Glycogen metabolism in the Liver
The liver maintains the concentration of glucose in the blood
between 80 and 120 mg/100 ml.
The glucose sensor in the liver is phosphorylase a.
- when glucose binds it exposes the phosphate group to
protein phosphatase 1.
- although PP1is normally bound to phosphorylase a it only
cleaves off the Pi group when phosphorylase a binds
glucose.
- PP1 is released from phosphorylase b and then begins to
dephosphorylate glycogen synthase (activates it).
The infusion of glucose into the bloodstream leads to the
inactivation of phosphorylase, followed by the activation
of glycogen synthase in the liver.
Insulin Stimulates Glycogen Synthesis by
Activating Protein Phosphatase 1
The insulin-sensitive protein kinase phosphorylates the G subunit
of PP1 at a different site than PKA, making it more active.
The activated PP1 then dephosphorylates glycogen synthase,
phosphorylase kinase, and phosphorylase causing increased
glycogen synthesis and decreased glycogen breakdown.
Different Effects of Glucagon and Epinephrine
Epinephrine - “fight or flight” hormone
Also known as Adrenaline
- rate of glycolysis may increase 2000-fold
Epinephrine activates glycogen breakdown in both
muscle and liver.
Glucagon has a different role, maintaining blood
glucose levels.
Glucagon does not activate glycogen breakdown in
muscle.
Consumption of muscle glycogen during exercise.
Rate of glycogen replenishment after exhaustive exercice.
von Gierke Disease - A Glycogen Storage Disease
- enlarged abdomen, thin extremities, striking elevation
of serum triglycerides, hypoglycemia, etc.
- massive accumulation of glycogen in liver and kidneys.
- in 1952 Carl and Gerti Cori showed that it results from
the absence of glucose-6-phosphatase, which blocks the
last steps of glycogenolysis and gluconeogenesis.
- greatly increased glycolysis resulting in lactic acidosis.
- treatment attempts to maintain blood glucose levels.