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
