GLYCOGEN METABOLISM

Glycogen: a highly branched polymer of glucose. Chains have glycosidic links

14.

Branches are linked 16.

Glucose stored in polymeric form as glycogen mostly in the liver and skeletal muscle.
Glucose can be rapidly delivered to the blood stream when needed upon degradation of glycogen. = glycogenolysis Enough glucose and energy triggers synthesis of glycogen. = glycogenesis

Metabolic Regulation of Mammalian Glycogen Levels

-- Glycogen reserves are the most immediately available large source of metabolic energy for mammals.

-- Storage and utilization are under dietary and hormonal control.

Primary enzyme targets in glycogen metabolism: glycogen synthetase and glycogen phosphorylase . The actions of the hormones are indirect.

Regulatory enzyme of glycogenesis GLYCOGEN SYNTHTEASE. Synthetase D and Synthetase I.

D is dependent upon Glucose -6phosphate where as I is independent of Glucose -6-phosphate. D is converted to I Synthetase phosphatase. This conversion is done by means of basically hosphorylation of I. Initiated by enzyme action synthetase kinase. It is a cAMP dependent protein kinase.

When the enzyme is phosphorylated, it is inactivated.

Active a form to inactive phosphorylated

b form.

Notice that phosphorylation has the opposite effect on glycogen phosphorylase; phosphorylation activates.

 Primary

hormones = -- epinephrine (adrenaline) = fight-or-flight -- glucagon -- insulin

How is Glycogenesis Activated? -- Complex process stimulated by insulin. -- Insulin indirectly activates a phosphoprotein phosphatase:
glycogen synthase(D)glycogen synthase(I) phosphorylated dephosphorylated

less active dependent on G-6-P

active independent of G-6-P

-- dephosphorylation is the major pathway for stimulation of glycogenesis in liver and resting muscles. -- Another way: In active muscle, there may still be highglucose-6-phosphate. The less active phosphorylated glycogen synthase can be activated by high levels of glucose-6-phosphate.

How is Glycogenesis Inhibited? -- epinephrine and glucagon inhibit glycogen synthesis. a) protein kinase A subunit C phosphorylates glycogen synthase, decreasing its activity. b) also phosphorylase kinase can phosphorylate glycogen synthase, inactivating it. [Its called synthase phosphorylase kinase because of its dual function.]

Phosphorylase is the key enzyme for glycogenolysis. In first step hormone increases cAMP level. cAMP activates protein kinase. That stimulates the key enzyme phosphorylase for glycogenolysis.

In liver Phosphorylase exist in both active(phosphorylase a) and inactive (phosphorylase b) form. Phosphorylase a can be inactivated to phosphorylase b by Dephosphorylase. Reactivation can be done by Dephosphorylase kinase in presence of ATP.

In muscle phosphorylase is persent in two forms Phosphorylase a active in absence of 5-AMP . And Phosphorylase b -active in presence of 5 AMP. Interconversion between a to b by phosphorylase kinase b

======== HORMONES ========= Glucagon - low glucose levels -- A polypeptide hormone produced in -cells of the islets of Langerhan of the pancreas. -- Acts primarily on liver cells. -- Receptors on surface of liver cells. -- Stimulates glycogen breakdown & inhibits glycogenesis. -- Glucagon also blocks glycolysis & stimulates gluconeogenesis.

Epinephrine - low glucose levels

-- Acts primarily on skeletal muscle. -- Receptors on surface of cells. -- Stimulates glycogen breakdown & inhibits glycogenesis. Glucagon and epinephrine both stimulate intracellular pathway via increasing levels of cAMP.

Insulin
-- High levels of glucose induce release of insulin from -cells of islets of Langerhan in the pancreas. -- Insulin is polypeptide hormone. -- Detected by receptors at surface of muscle cells. -- Increases glycogenesis in muscle. -- Intracellular signal pathway involves complex sequential phosphorylations and dephosphorylations.

cAMP Cascade
-- A cyclic AMP cascade is used by both epinephrine and glucagon. -- A cascade is a mechanism in which enzymes activate other enzymes sequentially usually leading to an amplification of an initial signal.

Epinephrine/Glucagon Cascade Regulating Glycogen Metabolism

Outside
Epinephrine AC

Inside

Receptor GProtein

PM

ATP

cAMP+PPi
PM = plasma membrane

AC = adenylate cyclase

Glycogen Storage Diseases:

-- A family of serious, although not necessarily fatal, diseases caused by mutations in the enzymes involving in glycogen storage and breakdown.