MMT: glycogen metabolism I and II Flashcards
Where is glycogen stored in a cell?
In glycogen granules in the cytoplasm.
Describe the basic structure of glycogen.
It is a branched molecule with a-1,4 bonds and branching a-1,6 attachments with one reducing end.
What is the significance of the reducing end in glycogen?
It is where we initiate synthesis.
Where do we build up or break down the glycogen molecule?
At the nonreducing ends.
What are the rate limiting enzymes for glycogen metabolism?
Glycogen phosphorylase and glycogen synthase.
What are major differences in the function of glycogen metabolism between the liver and muscle?
The liver breaks and builds glycogen to buffer our blood glucose, while muscle holds onto glucose as glycogen to be able to use it for energy when needed. As a result, muscle has glucose-6P but cannot convert it to free glucose.
Where do we find glucokinase?
In the liver; used for glycogenesis.
Describe glycogenesis in the liver.
- Glucose is trapped in the cell via glucokinase. 2. Phosphoglucomutase forms glucose 1-P from glucose 6-P. 3. UDP glucose is formed. 4. Glycogen synthase forms glycogen.
Describe glycogenolysis in the liver.
- Phosphorylase breaks glycogen into glucose 1-P. 2. Phosphoglucomutase turns glucose 1-P to glucose 6P. 3. Glucose-6-phosphatase converts glucose 6P back to glucose that can leave the liver.
What tissues express glucose-6-phosphatase?
The adrenal cortex and liver only.
What is the difference in glycogen synthesis in muscle cells?
They use hexokinase instead of glucokinase (aka hexokinase IV).
Does hexokinase or glucokinase have a higher affinity for glucose?
Hexokinase.
Describe MODY2 in terms of glycogen metabolism.
Mutations in glucokinase prevent proper export of insulin from beta cells by preventing glucose use in generation of ATP to fuel K+ channels that result in calcium influx and insulin secretion.
Does glycogen synthesis require energy?
Yes!
What is glycogenin?
An autocatalytic enzyme that synthesizes glycogen de novo; it adds glucose residues to itself using UDP glucose.
Glycogen synthase creates __ linkages.
a-1,4.
How does branching of glucose happen?
A branching enzyme moves a 7-glucose unit by breaking an a-1,4 bond and creating an a-1,6 bond.
Why is glycogen so branched?
To increase the solubility and create more terminal residues to enhance the rate of synthesis and degradation.
What powers glycogenolysis?
Inorganic phosphate.
Why does fasting only deplete liver glycogen?
Skeletal muscle does not express glucagon receptors and thus does not respond to glucagon.
Insulin ___ glycogenolysis.
Inhibits.
Glucocorticoids ___ glycogenolysis.
Inhibit.
In glycogenolysis, what is the fate of glucose 6P in the muscle and brain?
Formation of pyruvate that will lead to lactate and ATP.
In glycogenolysis, what is the fate of glucose 6P in the liver?
Formation of free glucose for use in other tissues or entering the pentose phosphate pathway.
Where does glycogenolysis usually occur?
In the cytoplasm.
Describe the steps of glycogenolysis.
- Glycogen phosphorylase breaks a-1,4 links to pull a glucose 1P molecule off glycogen.
- Debranching enzyme moves 3 glucose units to the non-reducing end of another branch, breaking and making an a-1,4 link and leaving a single glucose linked by a-1,6.
- A-1,6 glucosidase debranching enzyme hydrolyzes and releases a single free glucose.
- Phosphorylase continues until it encounters the next branch.
In the liver, which molecules promote glycogenolysis?
Glucagon and epinephrine.
In the muscle, what molecule(s) promote glycogenolysis?
Epinephrine.
Glucagon and epinephrine use what second messenger?
PKA.
How does PKA activate glycogenolysis?
It activates phosphorylase kinase, which then activates phosphorylase a that is involved in the first step of glycogenolysis.
How does PKA inactivate glycogenesis?
It inhibits glycogen synthase. It also phosphorylates an inhibitor that binds protein phosphatase 1, which would normally reverse the phosphorylation processes that promote glycogenolysis. Keeping glycogenolysis turned on helps keep glycogenesis turned off.
How does insulin activate glycogenesis?
They activate phosphatases that dephosphorylate PP1. PP1 then deactivates glycogen phosphorylase and activates glycogen synthase.
Describe how glucose in excess can prevent glycogenolysis.
Glucose can allosterically bind phosphorylase, causing a conformational change that exposes the phosphate to PP1. PP1 can then dephosphorylate and deactivate the enzyme.
How do glucocorticoids impact glycogen/glucose metabolism?
They stimulate glycogenesis enzymes while also stimulating glucogenesis.
What causes von Gierke disease?
A lack of glucose-6P meaning we cannot free glucose from the liver, leading to an overload of glycogen in the liver.
What are clinical signs of von Gierke disease?
Hepatomegaly, hypoglycemia, ketosis, HLD, lactate acidemia.
How do we treat von Gierke disease?
Frequent feedings of carbs in small amounts to allow the person to buffer their blood glucose.
What causes Pompe disease?
Defective lysosomal a-1,4 glucosidase leads to accumulation of glycogen in lysosomes; this impacts all organs.
What are clinical signs of Pompe disease?
Cardiorespiratory failure and early death; may not see a huge impact on blood glucose levels.
What causes Cori disease?
Defective debranching enzymes result in glycogen granules with short outer branches.
What are clinical signs of Cori disease?
Fasting hypoglycemia, hepatomegaly, myopathic features. Less severe than von Gierke.
What organs are affected by Cori disease?
Skeletal muscle and liver.
What causes Anderson’s disease?
Defective branching enzyme results in glycogen molecules with super long outer branches; these super long chains are not as soluble as they should be and lead to issues in the cell.
What is seen histologically in Anderson’s disease?
Deposition of glycogen in the hepatocytes.
What are clinical signs of Anderson’s disease?
Liver cirrhosis and liver failure.
What organs are impacted by Anderson’s disease?
The liver.
What causes McArdle disease?
Defective muscle glycogen phosphorylase.
What are clinical signs of McArdle disease?
Muscle pain/cramps/weakness/myoglobinuria.
What can aid symptoms of McArdle disease?
Sucrose ingestion prior to exercise.
