MCB 2000 Ch 25: Glycogenesis

The activated form of glucose used in glycogen synthesis is:

UDP-glucose; activation requires an energy-rich nucleotide sugar

Which nucleotide triphosphate is consumed during the formation of the activated glucose carrier molecule from glucose-1-phosphate?

UTP; used by UDP-glucose pyrophosphorylase to activate glucose-1-phosphate, forming UDP-glucose and releasing pyrophosphate

The primer protein that initiates glycogen synthesis is called:

glycogenin; catalyzes the attachment of the first few glucose residues to its own tyrosine residues, creating the primer for glycogen synthase to extend.

Glycogen synthase forms which type of glycosidic bond when adding glucose residues to a growing glycogen chain?

α-1,4 glycosidic bonds; linear chain elongation

True/False: Glycogenin autocatalytically adds the first 8-10 glucose residues to itself before glycogen synthase can begin elongating the chain.

true; serves as the primer protein by catalyzing its own glucosylation at tyrosine-194, after 8-10 subunits, glycogen synthase takes over for further elongation

Calculate the net energy cost (in ATP equivalents) to incorporate one glucose molecule from free glucose into glycogen.

2; high-energy phosphate bonds consumed in each step: glucose phosphorylation and UDP-glucose formation

In muscle tissue during rest, protein phosphatase 1 (PP1) is constitutively active. What is the default phosphorylation state of glycogen synthase under these conditions?

Fully dephosphorylated; PP1 is active in resting muscle, it continuously dephosphorylates glycogen synthase, maintaining it in the active a-form. This allows muscle to store glucose as glycogen during rest periods when energy demands are low.

A research team discovers that branching enzyme transfers segments of exactly 7 glucose residues to create new branch points. What is the primary metabolic advantage of this branching pattern?

Branching creates more non-reducing ends for simultaneous synthesis and breakdown

During the fed state in liver, elevated glucose levels cause glucose to bind to …, which releases …, allowing it to dephosphorylate glycogen synthase to the … form.

glycogen phosphorylase a (senses high glucose in liver), protein phosphatase 1 (becomes active when released), active a

If glycogen synthesis and breakdown were equally active, the net result would be:

A futile cycle wasting ATP and UTP

Evaluate why evolution favored separate pathways for glycogen synthesis and breakdown rather than simple reversal of one pathway:

It prevents futile cycling and allows independent control; prevents wasting molecules

T/F – A cell lacking PP1 activity would struggle to activate glycogen synthesis.

true; PP1 dephosphorylates glycogen synthase (activating it) and phosphorylase (inactivating it), coordinating reciprocal regulation of synthesis and breakdown.

T/F – Reciprocal regulation of synthase and phosphorylase prevents futile cycling.

true; futile cycling would have synthesis and break down occurring simultaneously

A patient with McArdle disease (muscle phosphorylase deficiency) would most likely experience:

Exercise intolerance and cramps; prevents glycogen breakdown during exercise

A patient presents with normal fasting blood glucose but experiences severe muscle cramps during exercise that improve after several minutes (the "second wind" phenomenon). Muscle biopsy shows abnormally high glycogen content. Which enzyme is most likely deficient?

Muscle glycogen phosphorylase; muscle cannot break down its own glycogen due to phosphorylase deficiency, causing exercise intolerance and glycogen accumulation. The "second wind" occurs when alternative fuels (fatty acids, blood glucose) become available

Severe fasting hypoglycaemia with hepatomegaly (enlarged/swollen liver) suggests deficiency of:

Glucose-6-phosphatase; without glucose-6-phosphatase, the liver cannot convert glucose-6-phosphate to free glucose, causing fasting hypoglycaemia while glycogen accumulates

The "second wind" in McArdle disease occurs because alternative fuels become available after several minutes.

true; After several minutes, increased blood flow delivers fatty acids and glucose to muscles, allowing a shift to oxidative metabolism of alternative fuels.

What is the key difference in how protein phosphatase 1 (PP1) is regulated in muscle versus liver tissue?

Muscle PP1 is inhibited by PKA-mediated phosphorylation (prevents dephosphorylation and inactivating glycogen synthase during energy mobilization); liver PP1 is released by glucose binding to phosphorylase a (promotes phosphorylase and synthase when glucose is abundant)

During intense exercise, epinephrine activates PKA in muscle cells. Evaluate the combined effect on both glycogen phosphorylase and glycogen synthase. Which statement best describes the outcome?

Both enzymes become phosphorylated; phosphorylase is activated while synthase is inactivated

If you were designing a drug to treat type 2 diabetes by promoting glycogen storage, the best target would be:

Activating glycogen synthase or inhibiting its phosphorylation; enhance glucose storage as glycogen, directly lowering blood glucose levels in type 2 diabetes.

T/F: A metabolic engineer could improve cellular efficiency by eliminating reciprocal regulation and allowing synthesis and breakdown to occur simultaneously.

false; Simultaneous synthesis and breakdown would create wasteful futile cycling consuming ATP and UTP without net metabolism, which is why reciprocal regulation evolved.

Match each scenario with the most likely regulatory outcome.

• Post-meal state with high insulin

• Exercise with high epinephrine and AMP

• Overnight fasting with high glucagon

Post-meal state with high insulin: favored glycogen synthesis, breakdown inhibited

Exercise with high epinephrine and AMP: favors muscle & liver breakdown

Overnight fasting with high glucagon: liver breakdown, muscle glycogen stable

A pharmaceutical company develops a compound that prevents the phosphorylation of glycogen synthase but has no effect on other enzymes. In a patient with type 2 diabetes who takes this drug, predict the effects on glycogen metabolism and blood glucose during a fasting period.

Persistent glycogen synthesis despite fasting signals; worsening hypoglycemia; glycogen would continue to be stored in the liver and it would be unable to reach other parts of the body

A geneticist discovers a mutation in the glycogenin gene that eliminates its autocatalytic activity but preserves its ability to bind glycogen synthase. Predict the most likely metabolic consequence.

Inability to initiate new glycogen particles; severely reduced glycogen stores; new glycogen cannot be initiated without glycogenin primer

In liver, the PP1 catalytic subunit is normally tethered to phosphorylase a via the GL targeting subunit. A missense mutation now prevents GL from binding phosphorylase a, leaving PP1 free even in the fasted state. Which fasting-state phenotype is most likely?

Correct: Impaired glycogen breakdown; fasting hypoglycaemia; If GL cannot bind phosphorylase a, PP1 remains free and active when it should be inhibited, dephosphorylating phosphorylase a to the less active b form and impairing glucose release during fasting.

Hepatocytes are treated with a low dose of FCCP, a chemical that can partially uncouple the inner mitochondrial membrane. One hour after a high-carbohydrate meal, which outcome best describes the cell’s response?

Glycogen synthesis slows; glycolysis and O₂ use climb to offset lower ATP yield; ATP production would be lowered (reduced efficiency), and glycolysis would speed up to replace the energy needed

In liver hepatocytes after a high-carbohydrate meal, insulin signaling activates Akt. Trace the regulatory cascade: How many distinct kinases that target glycogen synthase are now inhibited, and what is the net effect on glycogen metabolism?

One kinase inhibited (GSK); modest increase in glycogen synthesis; With insulin high and glucagon low, both major pathways that phosphorylate (inactivate) glycogen synthase are turned off: (1) the PKA → phosphorylase kinase pathway is inactive, and (2) Akt directly inhibits GSK

A patient with a mitochondrial myopathy has skeletal muscle with severely impaired ATP synthase function, reducing oxidative ATP production by 70%. After a carbohydrate-rich meal, predict the fate of glucose in the patient's muscle tissue.

Reduced glycogen synthesis; glucose diverted to lactate production via glycolysis; cell prioritizes immediate ATP generation