Lecture 11: Glycogen Phosphorylase

What does glycogen phosphorylase do?

Glycogen phosphorylase breaks down a glycogen chain to create free glucose

What are the two forms of phosphorylase, are they phosphorylated, and what are their favored states?

A form

• phosphorylated [serine residue]

• R [active] state is favored

B form

• not phosphorylated

• T [less active] state is favored

What enzyme catalyzes conversion of A form to B form?

Phosphatase 1 → removed 2 phosphates via 2 H2O molecules

What enzyme catalyzes the conversion of B form to A form?

Phosphorylase B Kinase → USES 1 ATP

What is the default state of glycogen phosphorylase in LIVER?

A form in the R state because liver phosphorylase generates blood glucose

• this means that the presence of glucose changes the R [active] form into the T [inactive] form

What happens if glucose is abundant and binds to phosphorylase A?

If glucose is abundant, there’s no need to break down glycogen to create more. Binding of glucose leads to phosphorylase A shifting to the T state, inactivating the enzyme

What is the default state of glycogen phosphorylase in MUSCLE?

B form in the T state because when energy is needed → AMP increases → AMP binds to phosphorylase → shifts to R state

What is muscle phosphorylase stabilized by?

ATP and glucose 6-phosphate [NEGATIVE FEEDBACK], because if there's ATP and glucose present, there’s no need to break down glycogen to form glucose

What is phosphorylase kinase?

A regulatory enzyme that converts phosphorylase B [inactive] to phosphorylase A [active] through the addition of a phosphate.

What does phosphorylase kinase do specifically?

Remove a peptide loop from an active site of B form, making the enzyme more active

Which part of the (alpha,beta,gamma,delta)4 subunit has the active site?

Gamma

How does activation of phosphorylase kinase occur stepwise?

1. Calcium binds to delta [delta subunit is calcium sensor calmodulin]

2. Phosphorylation via PKA [protein kinase A]

What are epinephrine and glucagon?

Epinephrine is the hormone involved in the fight/flight response, which requires glycogen breakdown in order to produced glucose for energy

Glucagon is the hormone that is activated when blood glucose levels are low

What do epinephrine and glucagon do to phosphorylase kinase?

Epinephrine and Glucagon signal the need for glycogen breakdown

What is the 1st step in the cascade for these two hormones? As in, what receptors do they bind to?

Epinephrine or glucagon binds to one of the 7 transmembrane receptors, leading to Gs protein activation

• Epinephrine binds to the beta-adrenergic receptor in muscle

• Glucagon binds to the glucagon receptor in the liver

What is the second step in the cascade? As in, what does GTP do?

GTP binds to Gs adenylate cyclase, which turns ATP into cAMP

What does increased cAMP lead to?

Increased cAMP activates PKA, which phosphorylates phosphorylase kinase alongside Ca2+ binding to the kinase’s delta subunit.

How does increased cAMP affect glycogen synthase?

Since increased cAMP helps begin the breakdown of glycogen, glycogen synthase will be phosphorylated and rendered inactive.

What does the phosphorylation of phosphorylase kinase lead to?

The phosphorylation of phosphorylase kinase activates glycogen phosphorylase [turns inactive glycogen phosphorylase b into active glycogen phosphorylase a], which breaks down glycogen into glucose 1-phosphate

What two enzymes render glycogen synthase inactive?

Protein kinase A [PKA] and glycogen synthase kinase 3, as they both phosphorylate glycogen synthase, which renders glycogen synthase inactive

Which form of glycogen synthase is active/inactive. Which form gets phosphorylated?

A form is active

B form is inactive

B form gets phosphorylated [the opposite of glycogen phosphorylase, in which the A form gets phosphorylated]