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Glycogen Regulation and Storage Diseases
Terms in this set (71)
Which pathway follows glycogen degradation in the muscle?
In the muscle, glycolysis follows glycogen degradation
Which pathway is inactive during glycogen degradation in the liver?Which pathway is active during glycogen degradation in the liver?
In the liver, glycolysis is inactive during glycogen degradation. Gluconeogenesis and glycogen degradation are both activated by glucagon
How is glycogen degradation connected to muscle contraction
by calcium and AMP availability
What is the purpose of glycogen metabolism?
fast synthesis of glycogen when G6P is abundant and fast degradation when G6P is needed
What is the difference between glycogen stores in the liver vs the muscle?
liver: used for release of glucose to blood stream, muscle:used for glycolysis
Can you use the glycogen stores in muscle for release of glucose into the blood during severe starvation?
The glycogen stores in the muscle can never be used for release of glucose into the blood, as muscle does not contain the enzyme glucose 6-phosphatase.
What is the advantage of using glycogen degradation to form glucose 6-P in comparison to free glucose?
Glycogen degradation generates glucose 6-P without usage of ATP. This saves one ATP in the investment phase of glycolysis.
Where is glycogen in the body?
found in skeletal muscle and highest  in liver
Where is glycogen in the cell?
stored in glycogen granules
Where are glycogen enzymes in the cell?
Which liver enzyme is used directly or eventually by both the pathways of gluconeogenesis and glycogen degradation?
Glucose 6-phosphatase is needed for the release of glucose into the blood following both pathways.
What allows many enzymes to act on glycogen at the same time?
its branched structure
Can synthases and phosphorylases act on glycogen at the same time?
Function of phosphoglucomutase?
reversibly forms either G6P or G1P
During glycogen synthesis what is formed G6P or G1P?
How is UDP-glucose formed
UTP + G1P
Phosphoglucomutase convert ______ from _______ during glycogen degradation
G6P from G1P
Allosteric regulation in liver and muscle by G6P?
activates glycogen synthase and inhibits glycogen phosphorylase
During night time, right after dinner what is the level of liver glycogen?
Are the reducing ends or are the non-reducing ends used for glycogen synthesis and glycogen degradation?
The nonreducing ends are used for glycogen synthase or for glycogen phosphorylase
What is glycogenin, what is its purpose and where is it found?
Glycogenin is a protein that can act as an enzyme and initiate glycogen synthesis. It uses UDP-glucose and links it to its tyrosine residue. After elongation to a short alpha 1,4-glycosidic chain, the enzyme glycogen synthase can elongate further on. Glycogenin is found in the core of the glycogen granule.
Describe the action of glycogen synthase, what is special, what does it use, what does it form?
Glycogen synthase is a special enzyme that needs a primer, it cannot link UDP-glucose to a "free" glucose molecule. It elongates glycogen using UDP-glucose, the activated form of glucose and forms 1,4-bonds
Can glycogen synthase form glycogen without a primer?
no needs a glycogen chain
What forms glycogen when all glycogen is depleted?
Where does glycogenin reside after creation of glycogen?
inside newly formed glycogen granule
When UDP-glucose is formed does G1P lose its phosphate group?
no it stays and is joined to a UDP group
What enzyme forms the alpha 1-4 glycosidic bonds in glycogen?
What enzyme forms the alpha 1-6 glycosidic bonds in glycogen?
Describe the action of the glycogen branching enzyme.
It cleaves an 1,4-bond found about 6-8 residues from the nonreducing end.It transfers this glucose chain to a non-terminal glucosyl residue and forms with its second enzyme activity an 1,6 linkage. These newly formed branch points allow again glycogen synthase action to elongate with 1,4 linkages.
What is the mechanism of glycogenin and glycogen synthase to make glycogen?
glycogenin adds 8 UDP-glucose to a tyrosine residue and glycogen synthase can then add glucose to nonreducing ends
Activation of glycogen synthase by covalent modification
insulin activates protein phosphatases which dephosphorylate glycogen synthase thus activating it, glucagon/epinephrine activate PKA (via cAMP) which phosphorylates glucogen synthase
Function of glycogen phosphorylase
uses a Pi to cleave glycogen and form G1P
What is the coenzyme of glycogen phosphorylase?
pyridoxal phosphate formed from vitamin B6
For each G1P formed by glycogen phosphorylase how many net ATP can be made by glycolysis?
What is a limit dextrin?
a glycogen branch of 4 glucose units
When can glycogen synthase not phosphorolytically cleave glycogen?
once a limit dextrin has been reached
What is the function of the debranching enzyme?
removes the outer three glucose residues of the limit dextran and adds them to a longer branch (4:4 transferase). It then removes the last glucose by an 1:6 glucosidase activity releasing a glucose
Active and inactive form of glycogen phosphorylase?
active- A form, inactive- B form
What are the ways glycogen phosphorylase can be activated in muscle and liver?
In both muscle and liver, phosphorylation of glycogen phosphorylase kinase by PKA phosphorylates Glycogen phosphorylase. In muscle, allosteric activation is found at high AMP levels that can be generated during anaerobic exercise or severe anoxia.
What inhibits glycogen phosphorylase in the muscle?
G6P and ATP
What inhibits glycogen phosphorylase in the liver?
G6P, ATP and glucose
By what pathway does epinephrine and glucagon activate glycogen phosphorylase kinase?
activation by cAMP that activates pka which phosphorylates glycogen phosphorylase kinase
What protein of glycogen metabolism has calmodulin activity?
glycogen phosphorylase kinase
What is the function of glycogen phosphorylase kinase in the muscle that is not found in the liver?
Has a calmodulin that will bind calcium and become activated without phosphorylation by pka, it can then active phosphorylase kinase
Calmodulin description and activity
binds 4 Ca2+ and undergoes a conformational change, can be a separate protein or subunit of another protein
What are the two mechanisms by which calcium is released in muscle that can activate glycogen phosphorylase kinase?
IP3/2nd messenger pathway and muscle depolarization pathway
What is defective in glycogen storage disease?
glycogen degradation or usage
Describe Von Gierke Disease (type I GCD)
A:deficiency of G6 phosphatase in ER membrane, B:deficiency of G6P translocase into ER, glycogen degradation and gluconeogenesis are impaired
What is hepatonephromegaly glykogenica?
high glycogen content in liver and kidny
What are the symptoms of von gierke disease?
inability to release glucose into blood stream during fasting (ie. in the night when asleep) hepatomegaly, severe fasting hypoglycemia, lactic acidemia, hyperuricemia and hyperlipidemia, progressive renal disease
What treatment is there for von gierke disease?
regular administration of uncooked corn starch or nocturnal gastric glucose infusions
Which enzyme in addition to glycogen phosphorylase and the debranching enzyme is needed for glycogen degradation in the lysosome?
Lysosomal acid glucosidase
What is defective in Pompe disease?
lysosomal glycogen degradation is defective due to a defect in glucosidase in lysosomes
What deficiencies occur with Pompe disease (type II GCD)
deficiency of lysosomal acid glucosidase causing lysosomal glycogen accumulation in heart, muscle and liver
What symptoms occur from Pompe disease?
weakness, progressive neuromuscular disorder, lysosomes swell and rupture, massive cardiomegaly, myopathy, hypotonia, hepatomegaly
What happens to infants with Pompe disease?
early death in first year due to heart failure
What happens to ppl with late-onset Pompe disease and how is it treated?
breathing problems, treated with enzyme replacement therapy by infusion
What is normal in Pompe?
normal blood glucose and glycogen in cytosol has normal structure
What is Cori Disease (type III GCD)
deficiency of the debranching enzyme causing mild hypoglycemia and hepatomegaly
Describe the glycogen structure in patients with Cori's disease.
Patients with Cori's disease have a deficiency of the debranching enzyme. The glycogen has short outer branches (limit dextrin)
Symptoms of Cori Disease?
muscular weakness, hypotonia and cardiomyopathy, patients need wheelchair by 50-60 years, also considered muscular dystrophy
What is Anderson Disease (type IV GCD)
deficiency of the glycogen branching enzyme, characterized by long unbranched glycogen structure leading to scarring by the attack of the body's immune system
Symptoms of Anderson Disease?
infantile hypotonia, liver cirrhosis and death by 5 years age
What is McArdle Disease (type V GCD)
deficiency of muscle glycogen phosphorylase, liver enzyme is normal, high levels of glycogen with normal structure in muscle
Symptoms of McArdle Disease
temporary weakness and muscle cramping after exercise, could cause Rhabdomyloosis after exercise due to lack of ATP, CK-MM is increased, no increase of blood lactate after strenuous exercise, myoglobinemia and myoglobinuria
What is Hers Disease (Type VI GCD)
deficiency of hepatophosphorylase causeing hepatomegaly and growth retardation, mild hypoglycemia and hyperketonemia
What disease is Hers Disease similar to?
von gierke however less severe because gluconeogenesis is working
Why do we find severe fasting hypoglycemia in patients with Von Gierke's disease and milder hypoglycemia in patients with Cori's disease or Her's disease?
Patients with Von Gierke's disease have a deficiency of glucose 6-phosphatase that is needed for the release of glucose generated by glycogen degradation AND by gluconeogenesis. This result in severe fasting hypoglycemia. Patients with Cori's disease or Her's disease have a genetic defect in glycogen degradation, but they can still generate glucose in the liver via gluconeogenesis.
Describe Tarui Disease (Type VII)
deficiency of PFK1 in muscle and RBC causing muscle cramping due to lack of ATP but also heolysis is found due to 50% PFK1 deficiency
Strenuous exercise raises blood lactate. In which patients do you not find this increase in lactate, which is also used as test for this disease?
In patients with McArdle syndrome we find no raise in lactate due to deficiency of muscle glycogen phosphorylase which provides substrates for glycolysis.
Name the glycogen storage diseases (GSD) that lead to hepatomegaly.
Type I (von Gierke), Type II (Pompe), Type III (Cori, also grouped as muscular dystrophy) Type VI (Hers)
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