8P2-1

10-10-11 Glycogen Metabolism

Glycogen metabolism is carefully regulated so that sufficient glucose is available for the body’s energy needs.

Insulin, glucagon and epinephrine control glycogenesis and glycogenolysis.

8P2-3

Glycogen BreakdownGlycogen phosphorylase removes glucose

units from the nonreducing end until four are left approaching a branch point. The glucose is produced as glucose-1-P.

G-1-P is isomerized to G-6-P.Note: this saves one ATP molecule when

glucose from glycogen goes through glycolysis! A net of three ATP are produced.

When the four glucose units next to a branch remain, another enzyme is needed.

The phosphorylase reaction

8P2-6

Glycogen BreakdownWhen four glucose units remain, two

additional enzymes are requiredTransferase removes three (“limit branc

h”) of the four units and transfers them to the end of another chain.

The glucose 1,6 bond is cleaved by -1,6-glucosidase. Glucose is the product, not phosphorylated glucose.

Transferase and -1,6-glucosidase are requiredfor the complete breakdown of glycogen

The phosphoglucomutase reaction

Liver contains glucose-6-phosphatase(also used for gluconeogenesis)

Regulation of glycogen breakdown

Glycogen phosphorylase is regulated by:

1. Allosteric interactions – signal theenergy state of the cell

2. Reversible phosphorylation – inresponse to hormones such asinsulin, glucagon, epinephrine

3. Regulation differs in muscle andliver

Muscle phosphorylase is regulated bythe intracellular energy charge

Muscle phosphorylase exists in two forms:

1. phosphorylase a (usually active)2. phosphorylase b (usually inactive)

phosphorylase b exists primarily in the inactive T state, active only when bound to AMP which stabilizes the active R state

3. ATP inhibits stimulation by AMP bycompeting for AMP binding; thus energycharge regulates muscle phosphorylase b

Inactive muscle phosphorylase b is converted to active phosphorylase a by hormone-regulated phosphorylation

active

inactive

Liver phosphorylase produces glucose for use by other tissues when blood glucose is low

Liver phosphorylase a is inhibited by glucose

Phosphorylase kinase converts inactive phosphorylase b to active phosphorylase a

Phosphorylase kinase is activated by calcium ionsand phosphorylation; responsive to hormonallyregulated Protein Kinase A (phosphorylation)and muscle contraction (calcium)

Protein Kinase A phosphorylates phosphorylase kinase whichphosphorylates phosphorylaseactivating glycogen breakdown.

Epinephrine and glucagon signal the need for glycogen breakdown

Hormonal signals activate G-proteins that initiate glycogen breakdown

Epinephrine primarily targets muscle (anticipated or actual muscle activity)

Glucagon primarily targets liver(low blood sugar)

The regulatory cascade for glycogen breakdown

Glycogen SynthesisSynthesis of glycogen, the storage form of

glucose, occurs after a meal

Requires a set of three reactions (1 and 2 are preparatory and 3 is for chain elongation):

1. Synthesis of glucose-1-phosphate (G-1-P) from glucose-6-phosphate by

phosphoglucomutase

2. Synthesis of UDP-glucose from G-1-P by UDP-glucose phosphorylase

8P2-22

Glycogenesis – synthesis of G-1-P

Final product v

ia 1,6-bisphosphate

hexokinase

ATP, Mg2+

OCH2

OHOH

OHOPO3

2-

OHPhosphogluco-mutase

8P2-23

Glycogenesis – synthesis of UDP-G

Pyrophosphate hydrolyzes

UDP glucose-phosphorylase

H2O

2 Pi

UDP-G

Glycogen Synthesis

3. Synthesis of Glycogen from UDP-glucose requires two enzymes:

i. Glycogen synthase grows chainii. Branching enzyme (amylo-(1,41,6)-glucosyl transferase) creates (1,6) linkages for branches

Coordinate control of glycogen metabolism

Increase breakdownDecrease synthesis

Speeding glycogen synthesis

Slowing glycogen synthesis

Insulin stimulates glycogen synthesis byactivating glycogen synthase kinase

Glycogen synthase kinase maintainsglycogen synthase in its inactivephosphorylated form

Insulin induces glycogen synthesis

Hexokinase = tissuesnonallosteric vs [glucose](with respectto glucose)high glucose affinityinhibited by G6P

Glucokinase = liver“allosteric” vs [glucose](with respect to glucose)low glucose affinitynot inhibited by G6P

Therefore, glucokinase activity increases rapidlyat high [glucose] = ~6mM, liver takes up glucose

At low [glucose], liver does not compete, tissues take upglucose in proportion to their needs

The liver acts as a blood glucose buffer

Glycogen metabolism in the liver regulates blood-glucose levels

Two signals stimulate glycogen synthesis:

1. insulin2. high blood glucose concentrations

Liver phosphorylase a is the glucose sensor in liver cells