Glycogen Synthesis and Breakdown

Glycogen Structure

-Many non-reducing ends

-The only reducing end is attached to glycogenin "primer"

Glycogenolysis

-Glucose removed from multiple non-reducing ends simultaneously

-Allows rapid mobilization of glucose

Glycogenolysis in Muscle

-Provides glucose 1P

-Converted to Glc 6P for glycolysis

-ATP responds to exercise, epinephrine

Glycogenolysis in liver

-Provides glucose 1P

-Converted to Glc 6P

-Phosphatases hydrolyses it to glucose

-Secreted into blood for other organs

-Responds to low blood glucose, glucagon

Degradation of Glycogen

Does not require energy

D1

Debrancher glycogen phosphorylase hydrolyses a-1,4

D2

Glucose 6 phosphatase removes phosphate for glucose transport

S1

-Glucose phosphorylated by hexokinase (glucokinase)

-Glucose converted to Glucose 1P by phosphoglucomutase

S2

UDP glucose synthesized uses UTP

S3

Glucose added to primer or to non-reducing end of a glycogen molecule branching enzyme

Glycogen Synthesis

-UDP Glucose pyrophosphorylase uses Glucose 1P and UTP to generate UDP-glucose, a high energy intermediate pyrophosphate

-Glucose is then added to non-reducing end of glycogen in an a-1,4 linkage by glycogen synthase

Glycogen Synthesis Steps

1) Glycogen synthase adds straight chains (regulated step)

2) When chains have about 10-12 residues per chain, a 6-8 residue piece is cleaved and reattached to a different glucose unit via an a(1->6) bond

3) Branching enzymeL Amylo 4,6 Transferase removes and relocates 6-8 glucose residues, glycogen primers are also synthesized

Glycogenin protein

Uses UDP glucose to autoglycosylate itself on a serine hydroxyl, extending a glycosyl chain long enough for glycogen synthase to use it as a substrate

Branching

Increases:

-Sites for synthesis and degradation

-Site of solubility

Glycogen phosphorylase

-Cleaves a(1->4) glycosidic bonds between glucose residues at non-reducing ends using phosphate ion as a nucleophile

-Adds phosphate to anomeric carbon of the terminal glycosidic bond

-Releases glucose 1-phosphate

*Cannot act on bonds of the 4 glucose residues closest to the branch point (steric hindrance)*

Release of glucose 1-P

- Muscle: Converted back to glucose 6-phosphate

- Liver: Glucose 1-P is converted to free glucose

Debranching enzyme

1) 4:4 Translocase breaks a 1,4 bond and moves 3 glucosyl residues to main chain

2) a 1,6 glucosidase removes branchpoint residue as free glucose

Pompe Disease, Type II

-Lysosomal a-glucosidase

-All organs with lysosomes

-Infantile form, early-onset progressive muscle hypotonia, cardiac failure, death before 2

-Only lysosomal storage disease

Regulation of Glycogen Stores: Liver

-Glucose to blood

-Insulin

-Glucagon (cAMP)

-Epinephrine (cAMP)

Regulation of Glycogen Stores: Muscle

-Glucose to ATP

-Insulin

-Epinephrine (cAMP)

-AMP

Liver Glycogen

-Glucose is mobilized first from glycogen

-Substantial amount of glycogen is mobilized within first few hours of fast

-First 22 hours of fast: glycogenolysis is fairly constant

-Gluconeogenesis is later

Degradation of Glycogen

a: Phosphorylated form is ACTIVE

b: dephosphorylated is inactive

Synthesis: Glycogen Synthase

D: Phosphorylated form is INACTIVE (b)

I: Dephosphorylated form is active (a)

Glucagon activates glycogen degradation and inhibits synthesis in the liver

1) Glucagon receptor associated G protein activate AC to make cAMP

2) cAMP activates protein kinase A

3) PKA phosphorylates & activates phosphorylase kinase

4) Phosphorylase kinase phosphorylates and activates glycogen phosphorylase

5) PKA phosphorylates and inactivates glycogen synthase

6) Glucose 1-P released from glycogen

**Epinephrine (but not glucagon) acts on muscle through B-receptors in a similar way**

Epinephrine action at a receptors in the hepatocyte

1) G proteins activate Phospholipase C: Cleaves phosphatidyl inositol 2P (PIP2) to DAG and IP3

2) IP3 stimulates Ca release from endoplasmic reticulum (Ca and DAG activate Protein Kinase C (plasma membrane))

3) Ca binds calmodulin to activate phosphorylase kinase

4) Calmodulin-dependent protein kinase, which phosphorylates and inactivates glycogen synthase (PKC and Phosphorylase Kinase do too)

5) Phosphorylase kinase phosphorylates and activates glycogen phosphoryase