Glycogen and Glucose Storage

What is glycogen? What is it held together by?

Main storage molecule for glucose
Glycosidic bonds

Chains found in glycogen

a(1-4) glucose: amylose chains
a(1-6) glucose: dextrans
Reducing end: reducing sugar (free hemiacteal on the 1-6 glucose
Non-reducing ends: amy sugar that is not the reducing sugar (non-reducing sugar)

Glycogen breakdown (steps)

• Glycogen + Pi is catalyzed by glycogen phosphorylase to produce glucose-1-phosphate.

• This is until the 3 glucose before the non-reducing end, then glucose is released through debranching enzyme. Glycogen phosphorylase continues after debranching.

• G1P converted to G6P with enzyme phosphoglucomutase

Why is glycogen breakdown favorable?

entropically favorable because it is producing smaller motile products

Debranching enzyme includes

• transferase; the glycogen debranchinng enzyme (of the 3 glucoses before the dextran to the lower row)

• glucosidase; the hydrolase activity

  • produces a free glucose of the top a(1-6) bond.

What’s the different between the phosphoglyceratemutase used in glycolysis and the phosphoglucomutase?

Phosphoglycerate used His as the P group transfer. (pulls off desired P group and adds a new one)
Phosphoglucomutase uses Serine as the P group transfer and this reaction is fully reversible.

How is Glucose release into the blood stream by G6P phosphatase regulated?

Spatial isolation of the rxn:
Hydrolysis of G6P occurs in the ER

Glycogen synthesis (steps)

• G6P converted back to G1P with phosphoglucomutase

• G1P reacts with UTP to make UDP-glucose and Pi w/ enzyme UDP-glucose pyrophosphorylase (enzyme named for the reverse rxn)

• UDP-glucose is converted to glycogen by glycogen synthase, elongating the glycogen chain as more glycogen forms a(1-4) bonds

UDP-glucose is

a sugar nucleotide, also called Leloir glycosyl donor.
Glucose donor

What kind of enzyme is glycogen synthase? What does it do in the last step of glycogen synthesis?

• It’s a glycosyltransferase enzyme

• Adds the majority of the a (1-4) glucose

• UDP is formed as a side product of the rxn

Glycogenin protein (dimer)

is a primer and enzyme that catalyzes the assembly of new chains; adds the first ~8 glucose.

How glycogenin serves as the scaffold for glycogen biosynthesis

• Uses hydroxyl group of Tyr on glycogenin to transfer a glucose w/ glucosyltransferase activity

• UDP released

• Another UDP-glucose comes in and attaches to hydroxyl on 4C of glucose attached to Tyr on glycogenin

• Chain extending activity of glycogen synthase takes over (still making UDP as a side product) and repeats this reaction 6 times.

Glycogen branching enzyme

• creates new nonreducing ends by introducing a(1-6) branch points (similar to the glycogen debranching enzyme)

• Functions as a transglycosidase, transferring segments of glucose chains to form branch point a(1-6)

Coordinated regulating of glycogen synthesis and breakdown involves

Breakdown by glycogen phosphorylase and synthesis by glycogen synthase. Both are reciprocally regulated. (Triggers a cascade)

Glycogen breakdown is activated by

• low blood glucose (glucagon) or

• a result of fight-or-flight response (epinephrine) by posttranslational modification of glycogen phosphorylase
  (think rapid muscle movements = rapid ATP use)

When blood glucose levels are __ (insulin signaling) glycogen phosphorylase a is

high
both allosterically inhibited by glucose and dephosphorylated by PP1 (protein phosphorylase 1)

Phosphorylase b (T state)

The less active form (default), transferring phosphoryl group Ser on each subunit triggers conformation change

Phosphorylated glycogen phosphorylase a (R state)

the enzyme glycogen phosphorylase’s active form (Serine chain with P group inside)
Phosphoprotein phosphatase 1 (PP1) removes P groups from Phosphorylase a, converting to less active state

Glycogen synthase is reciprocally regulated by both __ and __ signaling

insulin and glucagon;
Insulin can inhibit, glucagon can enhance, glycogen synthase b is inactive and phosphorylated, PP1 is enhanced by insulin and G6P but inhibited by glucagon and epi.

Glycogen synthase kinase 3 (GSK3)

adds phosphoryl group to three ser residues on glycogen synthase a, converting to synthase b, inactivates unless G6P or insulin is present; Insulin stimulates glycogen synthesis by activating PP1 and by inactivating GSK3.

High blood glucose leads to (cascade effect down)

Inc insulin, inc insulin-sensitiive protein kinase or synthesis of HKII, PFK-1m pryuvate kinase, inc PP1 decreased glycogen phosphorylase for glycogen breakdown. From synthesis of HKII, Inc glycolysis.

Low blood glucose leads to (cascade)

inc glucagon, inc [cAMP], inc PKA, inc FBPase-2, dec F2,6BP, dec PFK-1, dec glycolysis

dec pyrutvate kinase, dec glycolysis

Inc PKA, inc glycogen synthase

Inc PKA, inc phosphorylase kinase, inc glycogen phosphorylase, inc glycogen breakdown