Metabolism - Glycogen Metabolism

120 flashcards covering glycogen structure, synthesis, breakdown, regulation, clinical glycogen storage diseases, and related carbohydrate metabolism (fructose, sorbitol, and galactose pathways) based on lecture notes.

What is the primary purpose of glycogen?

A rapidly mobilizable storage form of glucose.

Where is most glycogen stored and what is its key function?

Liver and skeletal muscle; liver maintains blood glucose between meals.

What staining method is used to visualize glycogen in tissues?

Periodic acid-Schiff (PAS) staining.

What is the basic structure of glycogen?

A branched-chain polymer of glucose with α-(1→4) linkages and α-(1→6) branches.

How often do α-(1→6) branches occur in glycogen?

Every 8–12 glucose residues.

What are the non-reducing end and reducing end of glycogen?

Non-reducing end is the end without a free aldehyde group; reducing end has a free aldehyde group.

Which enzyme is responsible for forming UDP-glucose from glucose-1-phosphate?

UDP-glucose pyrophosphorylase.

Why is the UDP-glucose synthesis step effectively irreversible?

Hydrolysis of pyrophosphate (PPi) to inorganic phosphate (Pi) drives the reaction forward.

Which enzyme adds UDP-glucose to glycogen during elongation?

Glycogen synthase.

What initiates glycogen synthesis by creating a primer?

Glycogenin (protein primer and scaffold).

How many glucose residues are needed for the glycogen primer?

At least 4 glucose residues.

What are the two activities of the debranching enzyme?

4:4 glucan transferase activity and α-1,6-glucosidase activity.

What is the immediate product of glycogen breakdown by glycogen phosphorylase?

Glucose-1-phosphate (G-1-P).

Which cofactor is involved in the glycogen phosphorylase reaction?

Pyridoxyl phosphate (PLP, vitamin B6) via inorganic phosphate.

What catalyzes the debranching step in glycogenolysis?

Debranching enzyme (bifunctional 4:4 transferase and α-1,6-glucosidase).

After debranching, what is rapidly formed from glycogen breakdown?

Glucose-6-phosphate (G-6-P) via phosphoglucomutase.

Where is glucose-6-phosphatase present and what does it do?

In liver and kidney (not muscle); converts G-6-P to free glucose in the ER.

Why doesn’t skeletal muscle release free glucose from glycogen?

Muscle lacks glucose-6-phosphatase; keeps G-6-P for glycolysis to generate ATP.

What percent of glycogen is degraded by lysosomes?

About 1–3%.

What disease results from deficiency of lysosomal α-1,4-glucosidase?

Pompe disease.

What are the two key enzymes in regulating glycogen metabolism?

Glycogen synthase and glycogen phosphorylase.

Which hormones regulate glycogen metabolism at a high level?

Insulin, glucagon, and epinephrine.

What are the main allosteric regulators of glycogen metabolism?

Glucose-6-phosphate (G-6-P), ATP, AMP, and glucose.

How does insulin affect glycogen synthesis in liver and muscle?

Promotes glycogen synthesis by activating PP-1 and increasing glycogen synthase activity.

How do glucagon and epinephrine regulate glycogen breakdown?

They raise cAMP, activate PKA (and other kinases), and promote glycogenolysis.

What signaling cascade is activated by glucagon in the liver leading to glycogen breakdown?

cAMP → PKA → phosphorylation of target enzymes.

Which second messengers are produced by phospholipase C in glucagon signaling?

IP3 and DAG.

What effect does IP3 have in glycogen regulation?

Increases Ca2+ release from the endoplasmic reticulum.

Which kinases are activated by Ca2+ and contribute to glycogen breakdown?

Ca2+-calmodulin-dependent kinase and phosphorylase kinase (and PKC).

What is the overall effect of Ca2+ and DAG on glycogen synthase?

They promote phosphorylation and inactivation of glycogen synthase.

What is the effect of insulin on cAMP in the liver?

Decreases cAMP by stimulating cAMP phosphodiesterase.

What is the role of protein phosphatase-1 (PP-1) in glycogen metabolism?

Dephosphorylates glycogen synthase (activating it) and phosphorylase kinase (inactivating it).

In the fasted state, what is the phosphorylation state of glycogen synthase and glycogen phosphorylase?

Glycogen synthase is phosphorylated (inactive); glycogen phosphorylase is phosphorylated (active).

What is the effect of the fed state on glycogen metabolism at the phosphorylation level?

Glycogen synthase is dephosphorylated (active); glycogen phosphorylase is dephosphorylated (inactive).

What is the muscle-specific allosteric activator of glycogen phosphorylase?

AMP (low energy).

How does glucose-6-phosphate affect liver glycogen phosphorylase?

Acts as an allosteric inhibitor in liver.

How does AMP affect muscle glycogen phosphorylase?

AMP activates the muscle isozyme glycogen phosphorylase a (via b to a conversion).

What is the difference in regulation of glycogen metabolism between liver and muscle?

Glucagon affects liver only; AMP is the allosteric activator in muscle; Ca2+ signaling influences muscle during exercise; glucose-6-phosphate inhibits liver phosphorylase.

What is a essential feature of glycogen structure that makes it more soluble and accessible for rapid metabolism?

Branching (α-1,6 linkages) increases non-reducing ends.

Which end of the glycogen molecule is used for adding and removing glucose units?

Non-reducing end.

What enzyme converts G-1-P to G-6-P?

Phosphoglucomutase.

What is the role of UDP-glucose pyrophosphorylase in glycogen synthesis?

Activates glucose-1-phosphate to UDP-glucose.

What is the site of glycogen synthesis in the liver?

Cytosol with glucokinase (liver) involvement.

Which enzyme catalyzes the first glucose residue addition to the growing glycogen chain by glycogenin?

Autoglycosylation by glycogenin on a tyrosine residue.

Why is primer formation by glycogenin necessary?

Primer provides a starting point for glycogen synthase to extend glycogen.

What are the specific roles of S3 in glycogen synthesis?

Glycogen primer formation and extension; glycoenzyme complex steps.

What happens to UDP-glucose after it is added to the glycogen chain?

UDP is released after the glucose is added via α-1,4 linkage.

Why is branching important for glycogen metabolism speed?

More non-reducing ends allow faster synthesis and degradation.

What is the enzymatic step that removes glucose residues during glycogen breakdown?

Glycogen phosphorylase cleaves α-1,4 linkages using Pi.

What is the fate of glucose-1-phosphate after debranching and phosphoglucomutase?

Converted to glucose-6-phosphate.

What organ specifically uses glucose-6-phosphatase to release glucose into blood?

Liver (and kidney) but not muscle.

What is von Gierke disease (Type Ia) characterized by?

Inability to release glucose into blood; hepatomegaly and hypoglycemia.

What enzyme is deficient in Pompe disease?

Lysosomal α-1,4-glucosidase (acid maltase).

Which glycogen storage disease is due to debranching enzyme deficiency (4:4 transferase and 1:6 glucosidase)?

Cori disease (Type III).

Which glycogen storage disease is caused by skeletal muscle glycogen phosphorylase deficiency?

McArdle syndrome (Type V).

Which glycogen storage disease is caused by branching enzyme deficiency?

Andersen disease (due to amylo-1,6-glucosidase deficiency).

What glycogen storage disease is linked to a GLUT2 transporter defect (Fanconi-Bickel syndrome)?

Type VII.

Which disease is associated with lysosomal storage of glycogen in muscles and potential cardiomegaly?

Pompe disease.

Which steps connect the glycogen pathway to glycolysis in the liver?

Glucose-6-phosphate enters glycolysis; glucokinase initiates glucose trapping in liver.

What is the role of glycogenin beyond primer creation?

Serves as a scaffold for extending the initial glucose chain.

What is the extra hepatic enzyme that initiates breakdown in liver for glucose release?

Glucose-6-phosphatase in the ER.

Which tissues lack glucose-6-phosphatase and thus cannot release free glucose from glycogen?

Skeletal muscle.

How does insulin influence phosphorylation status of glycogen-related enzymes?

Promotes dephosphorylation, activating glycogen synthase and inhibiting glycogen phosphorylase.

What is the role of PP-1 in glycogen regulation during fed state?

Promotes dephosphorylation of glycogen synthase and inhibits phosphorylase.

Which enzyme is activated by cortisol/stress to promote glycogen breakdown in liver and muscle?

Glycogen phosphorylase via phosphorylation cascades (PKA, etc.).

What are the two main products of phospholipase C signaling that affect glycogen metabolism?

IP3 and DAG.

What is a common clinical correlate of fructose intolerance disorders?

Hypoglycemia and impaired gluconeogenesis; fructose-1-phosphate accumulation can deplete Pi.

Which transporter mediates fructose uptake in humans?

GLUT5.

Which enzyme phosphorylates fructose to fructose-1-phosphate?

Fructokinase.

What happens in hereditary fructose intolerance (aldolase B deficiency) at the cellular level?

Fructose-1-phosphate accumulates; Pi and ATP depletion impair gluconeogenesis and glycogenolysis.

What is the fate of sorbitol under normal metabolism?

Sorbitol is converted to fructose by sorbitol dehydrogenase.

What enzyme initiates conversion of glucose to sorbitol?

Aldose reductase.

Why can excess glucose lead to cataracts in sorbitol accumulation?

Osmotic effects from sorbitol accumulation in the lens.

From what source is galactose primarily derived?

Lactose in milk and dairy products.

Which enzymes metabolize galactose?

Galactokinase, galactose-1-phosphate uridylyltransferase (GALT), UDP-hexose 4-epimerase.

What causes classic galactosemia?

Deficiency of galactose-1-phosphate uridylyltransferase (GALT).

What occurs with galactokinase deficiency?

Galactosemia/galactosuria and potential cataracts from galactitol buildup.

What dietary treatment is used for classic galactosemia?

Eliminate galactose (lactose) from the diet.

Where does UDP-glucose formation feed galactose metabolism?

UDP-glucose serves as a donor in converting galactose to glucose intermediates.

What transporter moves glucose and galactose across membranes?

GLUT2.

What is the key pathway that handles nitrogen-containing compounds as shown in the metabolic overview?

Urea cycle.

Which enzyme converts glucose-1-phosphate to glucose-6-phosphate, enabling glucose metabolism?

Phosphoglucomutase.

Where is glucokinase primarily active in glycogen metabolism?

Liver (glucokinase in liver).

Which enzyme provides the primer for glycogen synthesis on glycogenin?

Glycogenin autoglycosylates the first glucose residue on a tyrosine.

What is a characteristic feature of Type IX GSD (hepatic phosphorylase kinase deficiency)?

Hepatic glycogen phosphorylase activating system deficiency.

What is special about Type X GSD (hepatic PKA deficiency)?

Hepatic protein kinase A deficiency affecting glycogen regulation.

What is Tarui syndrome caused by?

Phosphofructokinase-1 (PFK-1) deficiency in muscle.

Which disease is characterized by exercise-induced muscle pain and cramps with myoglobinuria?

McArdle syndrome (Type V glycogen storage disease).

Which disease involves GLUT2 transporter defect leading to Fanconi-Bickel syndrome?

Type VII glycogen storage disease.

What is the distinguishing feature of Pompe disease?

Lysosomal glycogen accumulation due to α-1,4-glucosidase deficiency; cardiomegaly.

Which compound links to nucleotide sugar formation in galactose metabolism?

UDP-glucose/UDP-galactose interconversion via epimerase.

Which glycogen storage disease involves failure to release glucose, with hepatomegaly and hypoglycemia?

Von Gierke disease (Type Ia).

Which enzyme converts G-6-P to glucose in gluconeogenesis and glycogenolysis?

Glucose-6-phosphatase.

Where is glucose-6-phosphatase located?

Endoplasmic reticulum membrane.

What is the role of branching enzyme in glycogen synthesis?

Creates α-(1→6) branches by forming new branches ~4 residues from a branch point.

Which enzyme catalyzes the addition of glucose units to the non-reducing end?

Glycogen synthase.

Which molecule forms the backbone of activated glucose for glycogen synthesis?

UDP-glucose.

What is the role of glycogen phosphorylase in glycogen breakdown?

Removes glucose from the non-reducing end as glucose-1-phosphate.

What is the end product of glucose-6-phosphate after glycogenolysis in the liver continuing to blood glucose?

Glucose (after G-6-Pase in liver).

What is the role of the urea cycle in metabolism?

Disposes excess nitrogen as urea.