Transcript Glycolysis

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.
8P2-1
Glycogen Breakdown
Glycogen 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.
8P2-3
The phosphorylase reaction
Glycogen Breakdown
When four glucose units remain, two
additional enzymes are required
Transferase removes three (“limit
branch”) of the four units and transfers
them to the end of another chain.
The glucose 1,6 bond is cleaved by a1,6-glucosidase. Glucose is the
product, not phosphorylated glucose.
8P2-6
Transferase and a-1,6-glucosidase are required
for 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 the
energy state of the cell
2. Reversible phosphorylation – in
response to hormones such as
insulin, glucagon, epinephrine
3. Regulation differs in muscle and
liver
Muscle phosphorylase is regulated by
the 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 by
competing for AMP binding; thus energy
charge regulates muscle phosphorylase b
active
inactive
Inactive muscle phosphorylase b is converted to
active phosphorylase a by hormoneregulated phosphorylation
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 ions
and phosphorylation; responsive to hormonally
regulated Protein Kinase A (phosphorylation)
and muscle contraction (calcium)
Protein Kinase A phosphorylates
phosphorylase kinase which
phosphorylates phosphorylase
activating 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 Synthesis
Synthesis 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
Glycogenesis – synthesis of G-1-P
hexokinase
ATP, Mg2+
CH2OH
O
Phosphogluc
mutase
OH
HO
2OPO3
OH
8P2-22
Glycogenesis – synthesis of UDP-G
UDP glucosephosphorylase
Pyrophosphate
hydrolyzes
2 Pi
H2O
UDP-G
8P2-23
Glycogen Synthesis
3. Synthesis of Glycogen from UDPglucose requires two enzymes:
i. Glycogen synthase grows chain
ii. Branching enzyme (amyloa(1,41,6)-glucosyl transferase)
creates a(1,6) linkages for branches
Increase breakdown
Decrease synthesis
Coordinate control of glycogen metabolism
Speeding glycogen synthesis
Slowing glycogen synthesis
Insulin stimulates glycogen synthesis by
activating glycogen synthase kinase
Glycogen synthase kinase maintains
glycogen synthase in its inactive
phosphorylated form
Insulin induces glycogen synthesis
Hexokinase = tissues
nonallosteric vs [glucose]
(with respectto glucose)
high glucose affinity
inhibited by G6P
Glucokinase = liver
“allosteric” vs [glucose]
(with respect to glucose)
low glucose affinity
not inhibited by G6P
Therefore, glucokinase activity increases rapidly
at high [glucose] = ~6mM, liver takes up glucose
At low [glucose], liver does not compete, tissues take up
glucose 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. insulin
2. high blood glucose concentrations
Liver phosphorylase a is the glucose sensor
in liver cells