Glycogen Metabolism and Glycogen Storage Diseases

Question 1

explain how glycogen degradation can be allosterically activated by calcium

Answer 1

• glycogen phosphorylase kinase contains the subunits αβγδ
  
  • α and β can be phosphorylated
  • γ has catalytic activity
  • δ acts as calmodulins
• binding of Ca to the δ subunit results in a conformational shift that activates the enzyme without being phosphorylated
• allosteric Ca activation takes place in muscle during muscle contraction and in the liver following binding of hormones that use the Ca ion messenger system

Question 2

muscle contraction generates ____ and ____ which are allosteric activators of muscle glycogen degradation

Answer 2

muscle contraction generates Ca ions and AMP which are allosteric activators of muscle glycogen degradation

• Ca ions activate the dephosphorylated glycogen phosphorylase kinase
  
  • GPK phosphorylates and activates glycogen phosphorylase
    
    • glycogen phosphorylase is phosphorylated
• AMP activates the dephosphorylated glycogen phosphorylase

Question 3

summarize regulation of glycogen synthase

Answer 3

Question 4

summarize glycogen phosphorylase kinase regulation

Answer 4

Question 5

summarize glycogen phosphorylase regulation

Answer 5

Question 6

describe Von Gierke Disease

Answer 6

• Type I
• high glycogen content in liver and kidney with normal structure
  
  • hepato-nephro megaly
• glucose 6-phosphatase is deficient in liver and kidney
• treatment = uncooked corn starch or nocturnal gastric glucose infusions
• clinical features:
  
  • hepato-nephro-megaly
  • very severe fasting hypoglycemia
  • lactic acidemia
  • hyperuricemia
  • hyperlipidemia
• 2 types:
  
  • 1a = deficiency of G6Pase in the ER
  • 1b = deficiency of G6P translocase (ER)

Question 7

describe Pompe Disease

Answer 7

• type II
• deficiency of lysosomal a1,4 glucosidase (aka acid maltase)
  
  • ​some cytosolic glycogen is always captured in autophagosomes and delivered to lysosomes; acid maltase cleaves this glycogen to release free glucose into the cytosol
• lysosomal glycogen accumulation in heart, muscle and liver
  
  • massive cardiomegaly

Question 8

describe Cori Disease

Answer 8

• Type III
• deficiency of the debranching enzyme (4:4 transferase)
• abnormal glycogen structure with short outer branches (limit dextrinoses)
• muscular weakness, mild hypoglycemia, cardiomyopathy
• considered a muscular dystrophy

Question 9

describe Andersen Disease

Answer 9

• type IV
• abnormal glycogen synthesis and structure
• deficiency of the glycogen branching enzyme (4:6 transferase)
  
  • characterized by abnormal glycogen structure with long glucose chains and less branches

Question 10

describe McArdle Syndrome

Answer 10

• type V
• abnormal gylcogen degradation in muscle; deficiency of muscle phosphorylase
• high levels of glycogen with normal structure in muscle
• patients show rhabdomyolysis after forced exercise due to lack of ATP, serum CK-MM is increased
• muscle weakness test for diagnosis:
  
  • normal = lactate increases during exercise
  • McArdle = no lactate increase because the muscle glycogen degradation is reduced and less lactate is formed

Question 11

describe Hers Disease

Answer 11

• type VI
• abnormal glycogen degradation in the liver
• high levels of hepatic glycogen (normal structure)
• deficiency of hepatophosphorylase (muscle isozyme is normal)
• clinical features:
  
  • hepatomegaly
  • mild fasting hypoglycemia

Question 12

describe Tarui Disease

Answer 12

• type VII
• reduced activity of the of PFK-1 in the muscle (MM) and RBCs (ML)
  
  • liver isozyme (LL)= normal
• clinically similar to McArdle leading to muscle cramping due to lack of ATP
• hemolysis occurs due to PFK-1 deficiency in RBCs