Ch 21 - Glycogen Metabolism

Main role of glycogen

Rapidly mobilized glucose storage polymer.

Where is glycogen stored most?

Muscle and liver.

Muscle glycogen purpose

Fast movement; fuels anaerobic glycolysis during bursts.

Liver glycogen purpose

Maintains blood glucose between meals.

Glycogen bond in linear chains

α-1,4 glycosidic bonds.

Glycogen branch bond

α-1,6 glycosidic bond.

Branch frequency in glycogen

About every ~12 residues.

Why branching is useful

Increases solubility and creates many nonreducing ends.

Where does glycogen grow and shrink?

At nonreducing ends.

Glycogenin function

Primes glycogen synthesis by starting a short glucose chain.

What is glycogenolysis?

Glycogen degradation.

Three steps of glycogenolysis

Release G1P, remodel branches, convert G1P → G6P.

Key control enzyme for glycogen degradation

Glycogen phosphorylase.

Glycogen phosphorylase uses what to cleave?

Orthophosphate (phosphorolysis), not water.

Product of phosphorolysis

Glucose-1-phosphate (G1P).

Why phosphorolysis is “ATP-saving”

Makes G1P directly without ATP investment.

Where does glycogen phosphorylase start?

Nonreducing ends.

How does phosphorylase remove glucose units?

One glucose at a time (processive).

Why phosphorylase is processive

Chain threads into active site one residue at a time.

Glycogen phosphorylase cofactor

Pyridoxal phosphate (PLP) prosthetic group.

How is PLP attached to phosphorylase

Schiff base linkage to a lysine.

PLP phosphate role in catalysis

Acts as general acid/base in the mechanism.

Does orthophosphate attack C1 directly?

No; α-configuration is retained.

Phosphorylase mechanism key idea

Carbocation-like intermediate attacked by phosphate.

Why branches block phosphorylase

Main chain must pass a narrow crevice to reach active site.

How close to a branch does phosphorylase stop?

About four residues away from the branch.

What enzyme fixes the “branch problem”?

Debranching enzyme (two activities).

Debranching enzyme activity 1

Transferase moves a block of 3 glucose to the main chain.

Debranching enzyme activity 2

α-1,6-glucosidase hydrolyzes the α-1,6 branch bond.

What does α-1,6-glucosidase release?

Free glucose (not G1P) from the branch point.

After debranching, what continues degradation?

Glycogen phosphorylase continues on the now-linear chain.

Conversion of G1P to G6P enzyme

Phosphoglucomutase.

Phosphoglucomutase does what?

Reversibly interconverts G1P and G6P.

Phosphoglucomutase active-site residue

Phosphoserine.

Phosphoglucomutase intermediate

Glucose-1,6-bisphosphate.

What enzyme exists in liver but not muscle

Glucose-6-phosphatase.

Why muscle lacks glucose-6-phosphatase

Muscle uses G6P internally; it does not export glucose.

Fate of G6P in muscle

Glycolysis to make ATP.

Fate of G6P in liver

Can be dephosphorylated to glucose for blood release.

Another fate of G6P (general)

Pentose phosphate pathway → ribose + NADPH.

Glycogen phosphorylase regulation modes

Phosphorylation + allosteric effectors.

Phosphorylase a vs b difference

a is phosphorylated; b is dephosphorylated.

Which is mostly active: phosphorylase a or b?

Phosphorylase a is mostly active (mostly R state).

Which is mostly inactive: phosphorylase a or b?

Phosphorylase b is mostly inactive (mostly T state).

R state means what?

Relaxed, higher activity.

T state means what?

Tense, lower activity.

Both a and b can exist as what conformations?

They interconvert between R and T.

How do allosteric effectors work here?

Shift the R/T equilibrium.

Default phosphorylase form in muscle

Phosphorylase b.

Why muscle wants phosphorylase off most of the time

Muscle needs glycogen breakdown only in short bursts.

Muscle negative regulator: G6P

G6P stabilizes T state (feedback inhibition).

Muscle negative regulator: ATP

ATP binds as a negative allosteric regulator (high energy charge).

Muscle activator: AMP

AMP allosterically activates phosphorylase b (signals low energy).

When does AMP rise in muscle

During contraction when ATP/creatine phosphate are used rapidly.

Why phosphorylase a is “maximal”

It is on regardless of AMP/ATP/G6P allosteric signals.

Default phosphorylase form in liver

Phosphorylase a.

Why liver keeps phosphorylase ON

Liver exports glucose to blood almost continuously unless insulin says stop.

Liver phosphorylase responds to what molecule

Glucose (not AMP/ATP).

Glucose effect on liver phosphorylase a

Glucose binding shifts it toward T state (enables dephosphorylation).

Is glucose regulation in liver allosteric?

No; glucose promotes T-state and then PP1 can dephosphorylate.

Second key regulatory point in breakdown

Phosphorylase kinase.

Phosphorylase kinase function

Converts phosphorylase b → phosphorylase a.

Phosphorylase kinase subunit composition

(αβγδ)4 with γ catalytic.

Dual control of phosphorylase kinase

Phosphorylation by PKA + Ca2+ (muscle contraction).

What does δ subunit bind

Ca2+.

Ca2+ role during exercise

Activates phosphorylase kinase to boost glycogen breakdown.

Hormone for liver glycogen breakdown

Glucagon (also epinephrine).

Hormone for muscle glycogen breakdown

Epinephrine (muscle does not respond to glucagon).

Signal cascade summary (fasting)

Glucagon/epi → PKA → phosphorylase kinase → phosphorylase → glycogenolysis.

What happens in muscle during exercise

Glycogenolysis → anaerobic glycolysis short-term, oxidative phosphorylation longer-term.

How liver supports exercising muscle

Liver increases glycogen breakdown + gluconeogenesis; releases glucose to blood.

Cori cycle link (concept)

Muscle lactate goes to liver; liver returns glucose to blood.

Glycogen synthesis starts with what protein

Glycogenin.

Activated glucose donor for glycogen synthesis

UDP-glucose.

How is UDP-glucose made

G1P + UTP → UDP-glucose + PPi.

Why UDP-glucose formation is effectively irreversible

PPi is degraded to Pi, pulling reaction forward.

Enzyme that extends glycogen chains

Glycogen synthase.

Where does glycogen synthase add glucose

To nonreducing ends.

What bond does glycogen synthase make

α-1,4 glycosidic bond.

Branching enzyme does what

Breaks an α-1,4 bond and transfers a chain to form an α-1,6 branch.

Third key regulatory point

Glycogen synthase.

Glycogen synthase a vs b

a is dephosphorylated (mostly active); b is phosphorylated (mostly inactive).

Strong activator of glycogen synthase

Glucose-6-phosphate (G6P).

Reciprocal regulation idea

When breakdown is ON, synthesis is OFF (and vice versa).

During fasting/exercise, what does PKA do

Activates breakdown (via phosphorylase kinase) and inhibits glycogen synthase.

Glycogen synthase is also inhibited by what kinase

GSK (glycogen synthase kinase).

After a meal/rest, what enzyme removes phosphates

Protein phosphatase 1 (PP1).

PP1 effect on phosphorylase

Dephosphorylates → turns glycogen phosphorylase OFF.

PP1 effect on phosphorylase kinase

Dephosphorylates → turns phosphorylase kinase OFF.

PP1 effect on glycogen synthase

Dephosphorylates → turns glycogen synthase ON.

Insulin overall effect on glycogen

Increases glycogen synthesis (storage).

Insulin pathway activates glycogen synthase how

Insulin cascade inactivates GSK; PP1 can activate glycogen synthase.

Insulin receptor type

RTK (receptor tyrosine kinase).

Epinephrine/glucagon receptor type

7TM (GPCR) → cAMP → PKA.

Fourth key regulatory point

PP1 regulation.

PP1 structure (concept)

Heterodimer: phosphatase subunit + regulatory/scaffold subunit.

Muscle PP1 regulatory subunit name

GM.

Liver PP1 regulatory subunit name

GL.

Role of GM/GL

Scaffold: colocalizes PP1 and substrates on glycogen particles.

What does PKA do to GM in muscle

Phosphorylates GM → PP1 dissociates (less active).