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 fiberscapable of sustained activity but stores glycogen for periods of increased demand

Most skeletal muscles of humans are a mixture of red and white fibers.

Duck breast Turkey breast

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 - glycogeninGS - glycogen synthaseGP - glycogen phosphorylase

PhK - phosphorylase kinaseRG1 - phosphatase reg. subunitCS1 - phosphatase catal. subunit

Glycogen Branching Enzyme

- transfers a ~7 glucose segment

Glycogen breakdownDietary:

Involves a amylase Creates limit dextrins and maltoseDebranchingHydrolysis produces 2 glucose from one maltose

Metabolic-intracellularInvolves glycogen phosphorylaseDebranchingProduces Glucose-1-phosphatePhosphoglucomutase 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 β-amylases 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 EnzymeThe enzyme has 2 different

activities:1. oligo-(-1,4-1,4)-

glucantransferase 2. 2. amylo--(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 by Phosphorylation and by Calcium Ions

Ca2+

release

Ca2+-free kinase

inactive

Ca2+kinasePhosphorylated kinase

partly active fully active

Muscle contraction Hormone-triggered

cyclic AMP release

Phosphorylase kinase is activated by phosphorylation by an enzyme called protein kinase A (PKA).

Ca2+

release

Ca2+-free kinase

inactive

Ca2+kinasePhosphorylated kinase

partly active fully active

Muscle contraction Hormone-triggered

cyclic AMP release

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-dependent protein kinase A (PKA) is activated when the two regulatory subunits bind cAMP and then release the active catalytic subunits.

Cyclic AMP activation of protein kinase A

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.