BIOCHEMISTRY | Glycogen Metabolism

Glycogen

is the storage form of glucose found in most types of cells

liver ; skeletal muscle

The _____ and ________________ contains the largest glycogen stores

1. Carbohydrates in diet

2. Glycogen

3. Gluconeogenesis

Sources of Blood Glucose

48

glycogen stores are depleted within ___ hrs. of fast

liver

Only _______ glycogen can be completely degraded to glucose, which then is released to blood

1. no osmotic pressure

2. does not diffuse

Reasons for why body stores glucose as glycogen and not as glucose itself:

Glucose 6-phosphatase

muscle glycogen is not available for  blood glucose maintenance due to absence of ______________________

1. ATP, Creatine phosphate

2. Glucose and glycogen

3. Fats

Energy Sources for muscle:

a-1,4 ; a-1,

Glycogen is composed of glucosyl units (D-glucose) linked by _____-glycosidic bonds and_____6-glycosidic bonds.

a-1→4

Glucose residues linked to each other by ______ glycosidic linkage

1→6

Branches every 4-10 residues along the chain, linked as ______linkages

T

(true or false)

The branches occur more frequently in the center of the molecule, and less frequently in the periphery.

glycogen

is poorly soluble in water, but the heavily branched structure provides a greater solubility. (The linear structure carbohydrate of the same molecular mass will redly precipitate).

A. Synthetic phase: Formation of glycogen

B. Catabolic phase: Breakdown of glycogen

Metabolism of glycogen can be discussed under two headings:

tissues: liver, muscle

subcellular: cytosol

loction of glycogen synthesis

1. Phosphorylation of glucose

2. Formation of UDP-Glucose from Glucose 6-phosphate

3. Initiation: glycogenin

4. Elongation of chain: glycogen synthase

5. Introduction of branches: branching enzyme

steps in glycogen synthesis

Glucokinase in the liver or Hexokinases in other tissues

enzyme

Glucose to Glucose 6-phosphate

Phosphoglucomutase

enzyme

Glucose 6-phosphate to Glucose 1-phosphate

UDP-Glc pyrophosphorylase

enzyme

Formation of uridine-diphosphate-glucose (UDP-glucose)

glycogen synthase

enzyme

Elongation of chain: glycogen synthase

Glycogen Synthase

• Cannot initiate glycogen chain synthesis

• Only elongates existing chains

• only make linear a 1,4 - linked polyglucose chain

Branching enzyme (Amylol (1,4→1,6)-transglucosylase)

enzyme

Introduction of branches

Glycogenolysis

is the process by which glycogen is degraded to produce glucose monomers.

Is NOT a REVERSAL of Glycogen synthesis

Glycogen Phosphorylase

Debranching enzyme

-Phosphoglucomutase

-Glucose-6-phosphatase

Glycogen degradation requires the activity of two key enzymes

Glycogen Phosphorylase

enzyme

Release of Glucose 1-phosphate from glycogen

Glycogen Phosphorylase

• catalyzes the cleavage of terminal glucose residues from the non-reducing ends of glycogen

• breaks a1,4 glycosidic bonds, releasing glucose 1-phosphate from the periphery of the granule

• cannot break a1,6 bonds and therefore stops when it nears the outermost branch points

• cleavage continues sequentially until the branch is only 4 residues long

Limit dextrin

characterized by "abnormal" glycogen with short branches.

transferase ;  a-1,6-glucosidase

• Debranching enzyme removes branches

• has two catalytic activities: it acts as a _______________ and as an __________________

Phosphoglucomutase

enzyme

Glucose-1-P to Glucose-6-P

glucose-6-phosphatase

enzyme

Glucose-6-P to Glucose

present

absent or present

In liver and kidney, a specific enzyme glucose-6-phosphatase is__________

absent

present or absent

In muscles, enzyme glucose-6-phosphatase is _________

lysosomal acid a-glucosidase

Some degradation of glycogen also occurs within LYSOSOMES when glycogen particles become surrounded by membranes that then fuse with the lysosomal membranes.

what enzyme hydrolyzes glycogen to glucose in this case?

8 ATP

6 ATP

net energy

Under aerobic conditions 2 NADH are reoxidized in mitochondria via shuttles:

• Malate-aspartate shuttle:

• Glycerol-3-phosphate shuttle:

3 ATP per glucose unit

net energy

under anaerobic conditions

insulin/glucagon ratio

blood glucose levels

epinephrine

liver glycogen degradative and synthetic pathways are regulated principally by

AMP

Muscle glycogenolysis is regulated principally by ______, which signals a lack of ATP, and by Ca+ released during contraction.

activated by: glucose-6-P

Glycogen Synthase regulator

activated by: AMP (muscle)

inhibited by: glucose-6-P, ATP, glucose (liver)

Glycogen Phosphorylase

dephosphorylated

phosphorylated or dephosphorylated

Glycogen synthase is active when ___________________

phosphorylated

phosphorylated or dephosphorylated

Glycogen phosphorylase is active when____________________

↑ ; ↓

(if fed) increase in blood glucose levels → increase in insulin → ____ glycogen synthesis + ______ glycogen degradation

↑ ; ↓

(fasting) decrease in blood glucose levels → increase in glucagon → _____ glycogen degradation + ______ glycogen synthesis

activates ; inactivates

activates ; inactivates

Glucagon ______________ glycogen phosphorylase and ________________ glycogen synthase

activates ; inactivates

activates ; inactivates

Insulin ___________ glycogen synthase and _____________ glucose phosphorylase

activates ; inactivates

activates ; inactivates

Epinephrine _________________ glycogen degradation and __________________glycogen synthesis

Glycogen storage diseases GSDS):

These are a group of inherited disorders associated with glycogen metabolism, familial in incidence and characterized by deposition of normal or abnormal type and quantity of glycogen in the tissues.

eleven

There are about ________ known types of GSD

muscles

GSD can affect the _______, the _________ or both

Hypoglycemia

Lactic acidosis

Hyperlipidemia

Hyperuricemia (gout)

main symptoms of GSDs

GSDS I or Von Gierke disease

Enzyme deficiency: Glucose-6-phosphatase

Glycogen structure - normal

GSDS I or Von Gierke disease

• present in early childhood with sweating, irritability, poor growth and muscle weakness

• Liver enlargement

• lactic acidemia

• Hyperlipidemia, hyperuricemia, short stature, doll like facies (faces with fat cheeks), protruding abdomen emaciated extremities.

giving glucose drinks frequently, cornstarch; avoidance of fructose and galactose.

treatment for GSD I or Von Gierke disease

GSD II or Pompe's Disease

Enzyme deficiency: Lysosomal acid a-1,4-glucosidase, GAA (Acid Maltase)

Glycogen Structure - Glycogen-like material

GSD II or Pompe's Disease

• presents within the first months of life, death by 2 years

• Cardiomegaly, Cardiomyopathy

• Muscle weakness

• Generalized involvement of organs seen including heart, liver, smooth and striated muscles.

• Nearly all tissues contain excessive amount of lysosomal glycogen

• Macroglossia (enlarged tongue)

NO TREATMENT only Enzyme replacement therapy (injecting alpha-glucosidase directly into bloodstream)

treatment for GSD II or Pompe's Disease

GSD III or Cori Disease

Enzyme deficiency: Debranching Enzyme (a-1,6-glucosidase)

Glycogen Structure - abnormal

GSD III or Cori Disease

• Children with this disease are often first diagnosed with a SWOLLEN ABDOMEN due to a very LARGE LIVER with short outer branches, glycogen structure

• Mild hypoglycemia and ketosis

• Normal blood lactate levels

Limit Dextrin

type of Glycogen (Glycogen structure with short outer branches of at most 4 glucose residues) deposit in the cytosol of liver and muscle cells

high protein diet and NO prolonged fasting

treatment for GSD III or Cori Disease

GSD IV or Anderson disease

• Enzyme deficiency: Branching Enzyme

• Glycogen Structure - abnormal

GSD IV or Anderson disease

• cirrhosis of the liver and heart involvement

•  severe but rare

• Large accumulations of glycogen seen with linear unbranched structure - very few branches especially toward periphery. Linear structure glycogen easily precipitates within the cells.

• Most children with this condition have died before two years of age.

NO TREATMENT apart from liver transplantation

treatment for GSD IV or Anderson disease

GSD V or McArdle disease

• Enzyme deficiency: Muscle Phosphorylase

• Glycogen Structure - normal

GSD V or McArdle disease

• ↑ glycogen in muscle, but cannot break it down

• Muscle cramps on exercise, pain, weakness and stiffness of muscles

• No lactate is formed (decreased lactate after exercise)

• Myoglobinuria

•  dark urine after exercise

• chronic fatigue syndrome

GSD V or McArdle disease

diagnosis will show raised levels of muscle creatine kinase (CK-MM)

GSD Type VI or Hers disease

• Enzyme deficiency: Liver phosphorylase • Glycogen Structure - normal

GSD Type VI or Hers disease

• Hepatomegaly

• cirrhosis

• mild to moderate hypoglycemia

• mild acidosis

• presents like mild case of type-1.