Lecture 23: Glycogen Metabolism II Flashcards
What are the rate limiting enzymes of synthesis and degradation?
synthesis: glycogen synthase
degradation: glycogen phosphorylase
What are the two forms of glycogen synthase?
active non phosphorylated ‘a’ form
inactive phosphorylated ‘b’ form
What is the most important kinase that phosphorylates glycogen synthase?
glycogen synthase kinase (GSK)
What is GSK under the control of?
insulin and PKA
What are the two forms of glycogen phosphorylase?
active ‘a’ form (R relaxed state)
inactive ‘b’ form (T tense state)
Where is the active a form found?
in liver
Where is the inactive b form found?
in muscle
What is glycogen phosphorylase regulated by?
several allosteric effectors
reversible phosphorylation
mutation in liver glycogen phosphorylase causes ____
Hers disease
mutation in muscle glycogen phosphorylase causes ____
McArdle syndrome
Describe allosteric regulation of liver glycogen phosphorylase
in default active a form
made inactive by glucose
glucose bind to active site and stabilizes confirmation in the inactive T state
this is because when glucose levels are high, there is no need to breakdown glycogen
describe allosteric regulation of muscle glycogen phosphorylase
in default inactive b form
activated by AMP
binds to active site and stabilizes conformation of b in the active R state
during muscle contraction ATP converted to AMP by myosin and adenylate kinase signaling the GP to breakdown glycogen
What are negative allosteric regulators of muscle glycogen phosphorylase
ATP and gluc-6-phosphate
glycogenesis is favored in ____ state
fed
What is the fed state?
blood glucose high
insulin high
cellular ATP high
glycogenolysis is favored in the ____ state ( and during ____)
fasting; exercise
what is the fasting state?
blood glucose low
glucagon high
What is high during exercise?
cellular calcium
AMP
What do beta cells release in the pancreas?
insulin
what are the four key proteins involved in regulation by insulin
GLUT 4
protein kinase B (PKB)
protein phosphatase 1 (PP1)
glycogen synthase kinase 3 (GSK3)
What is the net result of insulin regulation?
glycogen synthesis via activation of glycogen synthase and inactivation of glycogen phosphorylase
What causes type 2 diabetes?
reduced sensitivity to insulin ( insulin resistance)
usually caused by mutations in insulin receptor and/or downstream signaling proteins
What is considered normal blood glucose?
70-100 mg/dL (fasting)
< or = to 140 mg/dL (fed)
What is considered prediabetic/at risk blood glucose?
100-125 mg/dL (fasting)
> 140 mg/dL (fed)
What is considered diabetes mellitus blood glucose levels?
> or = to 126 mg/dL (fasting)
> or = to 199 mg/dL (fed)
low blood sugar levels release ____
glucagon
phosphorylation of a single serine does what? What is the conversion initiated by?
converts b to a
initiated by hormones
What is phosphorylation carried out by?
phosphorylase kinase
when epinephrine is released by adrenal glands, what occurs?
promotes degradation of glycogen
How does glucose 6 phosphate work as an allosteric regulator?
activates glycogen synthase, inactivates glycogen phosphorylase
How does free glucose work as an allosteric regulator?
inhibits glycogen phosphorylase in liver but not muscle
How does Ca2+ work as an allosteric regulator?
activates glycogen phosphorylase kinase
How does AMP work as an allosteric regulator?
activates glycogen phosphorylase (especially relevant during periods of exercise)
Type I (von Gierke) defective enzyme
glucose 6 phosphatase or transport system
Type I (von Gierke) organ affected
liver and kidney
Type I (von Gierke) glycogen in affected organ
increased amount; normal structure
Type II (Pompe) defective enzyme
a-1,4-glucosidase (lysosomal)
Type II (Pompe) organ affected
all organs
Type II (Pompe) glycogen in affected organ
massive increase in amount; normal structure
Type III (cori) defective enzyme
a-1,6-glucosidase (debranching enzyme)
Type III (cori) organ affected
muscle and liver
Type III (cori) glycogen in the affected organ
increased amount, short outer branches
type IV (andersen) defective enzyme
branching enzyme (a-1,4 to a-1,6)
type IV (andersen) organ affected
liver and spleen
type IV (andersen) glycogen in affected organ
normal amount, very long outer branches
type V (McArdle) defective enzyme
phosphorylase
type V (McArdle) organ affected
muscle
type V (McArdle) glycogen in affected organ
moderately increased amount, normal structure
type VI (Hers) defective enzyme
phosphorylase
type VI (Hers) organ affected
liver
type VI (Hers) glycogen in affected organ
increased amount
type VII defective enzyme
phosphofructokinase
type VII organ affected
muscle
type VII glycogen in affected organ
increased amount, normal structure
type VIII defective enzyme
phosphorylase kinase
type VIII organ affected
liver
type VIII glycogen in the affected organ
increased amount, normal structure
What is GSD 0?
deficiency in glycogen synthase, patients cannot synthesize glycogen
have muscle cramps, rely on glucose in diet, need to eat frequently and vulnerable to hypoglycemia when fasting
What is a symptom in GSD III/Cori disease
light hypoglycemia and hepatomegaly
What are symptoms of GSD IV/ Andersen disease
enlargement of liver and spleen, scarring of liver tissue
death by 5 years of age
What are symptoms in GSD V/ McArdle disease
patients unable to supply muscles with enough glucose
weakness, muscle cramps, exercise intolerance
myoglobinuria (myoglobin in urine)
tolerance by reducing strenuous exercise
GSD VI/ hers disease symptoms
prevents glycogen breakdown in liver, accumulates there and causes hepatomegaly
low blood glucose levels
how can enzyme replacement therapy (ERT) treat Pompe disease (GSD III)
GSD II is defect in acid maltase (a-glucosidase) which causes accumulation of glycogen in lysosomes and disrupts function of music end liver cells, causing progressive muscle weakness and myopathy ending with death via heart failure
ERT: Recombinate human a- glucosidase delivered via intravenous infusion in babies/young children
