Glycogen Metabolism

Question 1

In muscle glycogen is broken down to…

Answer 1

Glucose-6-phosphate

Which enters glycolysis to generate energy during muscle contraction

Question 2

In liver…glycogen is boken down to …

Answer 2

Glucose and released into the bloodstream to maintain blood

Liver glycogen —> G6P —> glucose +Pi

Question 3

Glycogen structure

Answer 3

Glucose added lineraly in repeating

Alpha-1,4 linkages

Branches with alpha-1,6 links

Question 4

Glycogen synthesis-phosphoglucomutase

Answer 4

Step1: G6P —> G1P

(Phosphoglucomutase)

Reversible (glycogen breakdown pathway)

Question 5

Glycogen syn.

UDP-glucose pyrophosphorylase

Answer 5

Step2:
G1P + UTP —> UDP-glucose +2Pi

Glucose is activated with a UDP carrier molecule

Pyrophosphate is hydrolyzed to drive activation

Question 6

Glycogen syn.

Glycogen synthase

Answer 6

Step 3: addition fo glucose to glycogen

Generates the alpha-1,4 linkage and extends linear polymer N+1

Question 7

Glycogen synthase deficiency

Answer 7

Causes Type O glycogen storage disease

Affects liver cells mostly

Less glycogen —> less blood glucose —> more ketone bodies —> death

Question 8

Glycogen syn.

Glycogen branching enzyme (glycosyl 4,6 transferase)

Answer 8

Generates brach points containing a-1,6 linkages

Transferes flucose to C-6 hydroxyl of more interior positioned glucose

Increase…

1. # of ends for rapid addition and removal
2. Amount glucose stored
3. Solubility

Question 9

Branching enzyme deficiency —>

Answer 9

Type IV (or Andersens) glycogen storage disease

Liver and muscle cells

Causes hepatomegaly, splenomegaly, and damage to muscle can results in myoglobin detected in the urine

Question 10

De novo glycogen synthesis

Answer 10

Initiation of glycogen beings with protein Glycogenin, a glycogen ‘primer’

Glycogenin catalyzes the transfer of glucose from UDP-glucose to glycogenin to make a short cahin of alpha1,4-linked residues

Question 11

Glycogen breakdown

Glycogen phosphorylase

Answer 11

1. Removes a1,4 linkages off linear nonreducing ends —> G1P

2. Pyridoxal phosphate (PLP, active Vitamin B6) is an essential cofactor of glycogen phosphorylase

Question 12

Glycogen phosphorylase deficiency

Answer 12

Type V (or McArdle) glycogen storage disease in muscle (excercise induced muscle crampls and pain, myoglobin in blood)

OR

Type VI (or Hers) glycogen storage disease in liver (hepatomegaly)

Question 13

Breakdown - debranching enzyme

Answer 13

Glucosyl 4,4-transglycosidase:

Transfers 3 glucose residues (yellow) to another linear chain

A-1,6-glucosidase:

Removes single a-1,6 linked residues to produce glucose

Question 14

Major product of breakdown

Answer 14

G1P

Converted to G6P by phosphoglucomutase —> glycoysis or gluconeogensis depending on tissue

Question 15

Debranching enzyme deficiency

Answer 15

Type IIIa (Cori or Forbes) diseae

Affects liver, skeletal muscle, cardiac muscle,

Hepatomegaly in infants and generalized myopathy

Liver-specific deficiency = Type IIIb…hepatomegaly in infants

Question 16

Type VII disease

Answer 16

Muscle PFK-1 is fucked

Exercised induced cramps and pain

Hemolytic anemia

Question 17

Type XI disease (Fanconi-Bickel)

Answer 17

GLUT2 fucked

Liver

Failure to thrive, enlarge liver, rickets, kidney dysfunction

Question 18

Clinical case:

Cyanotic, limp at birth due to bradycardia during contractions

Mother had numerous UTIs, sever loss of appetite and recurrent vomiting

Therefore newborn is malnourished, low weight…heart and resp. Rates are rapid

Low serum glucose

WHAT IS GOING ON????

Answer 18

1. Fetal glycogen is major fuel in early hours of life
2. Healthy full term babies are born with adequate glycogen stores to survive short term (12 hours) postnatal caloric deprivation
3. B/c mother was markedly anorexic during last trimester…when fetal liver normally stores glycogen,,,fetal liver glycogen stores were below normal
4. Patient became profoundly hypoglycemic within 5 hours of birth because of low to depleted glycogen stores

NOTE: during labor, neonates produce Epinephrine…

Question 19

Regulation of glycogen metabolism

Answer 19

1. Phosphorylation
   =glycogen synthase
   =glycogen phosphorylase
   =phosphorlase kinase
2. High blood glucose —> glycogen synthesis
3. Low blood glucose —> breakdown

Question 20

Regulation of epinephrine/glucagon cascade

Answer 20

1. Binding of Epi (muscle) or glucagon (liver cells, epi) activates GPCR Gsalpha
2. Rise [cAMP] —> activates PKA phosphorylation cascade begins
3. PKA phosphorylates/activates
   - phosphorylase kinase —> phosphorylates/activates glycogen phosphorylase
4. Cascade and allosteric regulators amplify signal
5. Glycogen breakdown provides glucose

Muscle: glucose for glycolysis muscle contraction

Liver - glucocse to elevate blood glucose level

Question 21

Regulation of glycogen phosphorylase

Answer 21

Dephosphorylated GS = active

Phosphorylated = inactive

Phosphorylation status mediated by opposing activites of GSK3 and PP1

Glucagon (from alpha cells) = fast activation

Epi (from adrenal medulla) = fast activation

Cortisol (adrenal cortex) = chronic activation

Insulin (betal cells) = inactivation