Glycogen Metabolism

Glycogen is a glucose polymer used by the liver and muscle to store glucose

primarily a 1,4 linkages (like amylose) – also highly branched by means of a 1,6 linkages (more exposed strand ends)

bound to glycogenin (37 kD) – glycogen attached to tyrosine – never less than eight glucose molecules attached

Liver: total 300 kcal of glucose in 70 kg person, enough for 8 hours of energy (e.g., at night)

Muscle: used only by that muscle, after ATP and creatine phosphate are used up (30 seconds of work)

Glycogen Synthesis – four enzymes:

(1) Phosphoglucomutase – glucose-6P (from hexokinase/glucokinase) Þ glucose-1P

(2) UDP-pyrophosphorylase – glucose-1P + UTP Þ UDP-glucose + pyrophosphate – irreversable

UDP-glucose is the building block – "primed" for addition to glycogen

(3) Glycogen Synthase – forms a 1,4 linkage to existing glycogen strand - cannot form linkages; rate controlling step

regulation: cAMP(-) – phosphorylation by PKA deactivates the enzyme

phosphatase 1 – removes phosphate, activating synthase – activated by insulin, deactivated by PKA

(4) Branching Enzyme – cuts off chain of seven glucoses and attaches elsewhere by a 1,6 linkage (needs to start branch at least 4 away from closest branch, therefore branch ~11 residues)

Glycogen Degradation – four enzymes:

1. Glycogen Phosphorylase – glycogen Þ glucose-1P – very tightly controlled – two subunits (80 kD each)

cannot get too close to a branch – leaves four glucoses (a limit dextran)

two modes of regulation:

(1) phosphorylation (phosphorylated form is activate) by phosphorylase kinase (97 kD)

phosphorylase kinase is itself phosphorylated (activated) by PKA so cAMP(+)

also Ca⁺⁺(+) – Ca⁺⁺ levels are high during muscle contraction; Ca activates PKA via calmodulin

phosphatase 1 (activated by insulin, deactivated by PKA) deactivates both phosphorylase and phosphorylase kinase

cAMP activates the inhibitor of phosphatase 1

two step process allows very fast and effective activation of phosphorylase (cascade amplification)

(2) allosteric – facilitate or hinder conversion to phosphorylated form

AMP(+) –indicates heavy ATP use (adenosine kinase; 2ADP Þ ATP +AMP); ATP(-), glucose-6P(-)

2. Debranching Enzyme – moves three of the four glucoses to end of chain (by a 1,4 linkage)

a 1,6 bond to single remaining glucose is then hydrolyzed off as free glucose (not glucose-1-phosphate)

3. Phosphoglucomutase – glucose-1P Þ glucose-6P – can then be used by the tissue

4. Glucose-6-Phosphatase – glucose-6P Þ free glucose (only in liver – muscles must use their own glycogen)

in its own vesicle in the ER

Overall efficiency is nearly 97%

Regulation by cAMP

cAMP (cyclic AMP) is made from ATP by adenyl cyclase (activated by glucagon and epinephrine, repressed by insulin)

glucacon and epinephrine (high when fasting) activates adenyl cyclase
insulin (low when fasting) represses formation of cAMP and accellerates its breakdown to AMP via phosphodiesterase

cAMP activates PKA (protein kinase A) by binding the regulatory region (R) and freeing the active kinase (C)

R₂C₂ + 4cAMP Þ 2 C + R₂(4cAMP)

PKA directly regulates glycogen metabolism (inactivates synthetase and phosphatase 1, activates phosphorylase kinase)

it also activates many transcription factors

Glycogen Storage Diseases

Type I (Von Gierke’s) – gl-6-Pase is defective in the ER (inhibits glycogenolysis and gluconeogenesis); can no longer make glucose (leads to severe hypoglycemia); unresponsive to glucagon/epinephrine (leading to increased amounts of these hormones in the blood

Type II (Pompe’s) – a -1,4-glucosidase deficiency – lysosomal disease associated with early cardiac death; symptoms are muscle weakness without clinical cardiac disease; Death before 19yo; muscle weakness without cardiac problems is hallmark

Type III (Cori’s) – debranching enzyme deficiency – muscle weakness, hypoglycemia, increased serum lipids; much glycogen in short branches; hepatomegaly

Type IV (Andersen’s) – branching enzyme deficiency – very long branches – liver cirrhosis, death by age 2

Type V (McArdle’s) – no skeletal muscle phosphorylase activity – painful muscle cramps; limited ability to exercise; its only when glycogenolysis is needed to maintain sustained vigorous exercise that the patient has problems

Type VI (Hers’) – no liver phosphorylase activity – elevated hepatic glycogen, hypoglycemia, hepatomegaly

Type VII (Tarui’s) – muscle phosphofructokinase deficiency – unable to mobilize muscle glycogen during exercise

Type VIII – no liver phosphorylase kinase – elevated hepatic glycogen, hypoglycemia, mild hepatomegaly

this is the only X-linked glycogen storage disease – others are autosomal recessive