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Important

The2ndMidTermExam
IsOn
th
November17 (Monday),2014
InRemsen017at5.00PM

CHAPTER 15
Glycogen Metabolism
&
Metabolic Regulation

Glycogen Granules in a Hepatocyte.


- Glycogen, a storage form of carbohydrate

2-D cross-sectional view of glycogen.


A view of the atomic structure of a
A core protein of glycogenin is surrounded
single branched strand of glucose
by branches of glucose units. The entire
units in a glycogen molecule.
globular granule may contain ~30,000
glucose units

Metabolism of Tissue Glycogen is


Regulated
Digestive breakdown is Unregulated - nearly 100%
of ingested food is absorbed and metabolized
But tissue glycogen is an important energy
reservoir - its breakdown is carefully controlled
Glycogen consists of "granules" of high MW
Glycogen phosphorylase cleaves glucose from the
nonreducing ends of glycogen molecules
This is a phosphorolysis, not a hydrolysis
Metabolic advantage: product is a sugar-P - a
potential glycolysis substrate

Removal of a glucose residue from the nonreducing end


of a glycogen chain by glycogen phosphorylase.
This process is repetitive; the enzyme removes successive
glucose residues until it reaches the fourth glucose unit
from a branch point

(Pyridoxalphosphateisacofactor)

Glycogen Breakdown Near An (16) Branch Point

Oligo(1>6to(1>4)GlucanTransferase

Glucose-1-Phosphate Can Enter


Glycolysis or, In Liver Replenish
Blood Glucose

In Liver and Kidneys ER Exists Glucose-6-Phosphatase..


SkeletalmuscleandadiposetissueslackthisG6Phosphatasesystem

How Is Glycogen Synthesized?


Glycogen synthesis takes place in virtually
all animal tissues to some extent, but is
especially PROMINENT in the liver and
skeletal muscles.
Glucose units are activated for transfer by
formation of sugar nucleotides
Luis Leloir showed in the 1950s that glycogen
synthesis depends on Sugar Nucleotides
UDP-Glucose Pyrophosphorylase catalyzes
a phosphoanhydride exchange driven by
pyrophosphate hydrolysis

How Is Glycogen Synthesized?

UDP-glucose is one of the sugar nucleotides. Discovered by


Luis Leloir in the 1950s, they are activated forms of sugar.

The mechanism of the UDPGlucose Pyrophosphorylase


reaction. Attack by a
phosphate oxygen of glucose1-P on the -phosphorus of
UTP is followed by departure
of the pyrophosphate anion.

Glycogen Synthase Catalyzes Formation


of (14) Glycosidic Bonds in Glycogen

Forms -(1 4) glycosidic bonds in glycogen


The very large glycogen particle is built around a
single protein, glycogenin, at the core
The first (and 7 more) glucose is linked to a
tyrosine -OH on the protein (by Glycogenins
Glucosyl-transferase activity)
Sugar units are then added by the action of
glycogen synthase
Glycogen synthase transfers glucosyl units from
UDP-glucose to C-4 hydroxyl at a nonreducing
end of a glycogen strand.
Note the oxonium ion intermediate

Figure. The
Glycogen
Synthase
Reaction.

Advanced Glycation End Products A


Serious Complication of Diabetes
Sugars can react nonenzymatically with proteins
The C-1 carbonyl groups of glucose form Schiff
bases linkages with lysine side chains of proteins
These Schiff base adducts undergo Amadori
rearrangements and subsequent oxidations to form
irreversible glycation end products (AGEs)
AGEs are implicated in circulation, joint, and vision
problems in diabetics
Measurement of glycated hemoglobin is a better
diagnostic yardstick for type-2 diabetes than serum
glucose levels

Glycogen Synthesis Requires Primed


Initial Sugar Made By Glycogenin

How Is Glycogen Metabolism Controlled?


A highly regulated process, involving Reciprocal
Control of Glycogen Phosphorylase (GP) and
Glycogen Synthase (GS)
GP allosterically activated by AMP, Glucogon
(Liver), Epinephrine (Muscle), Ca++, and inhibited
by ATP, glucose-6-P and caffeine
GS is stimulated by glucose-6-P
Both enzymes are regulated by covalent
modifications - phosphorylation

RegulationofMuscleGlycogenPhosphorylase
(GP)byCovalentModification
PP1InactivatesGlycogenPhosphorylase

Phosphoprotein
phosphatase 1 (PP1)

Glycogen Synthase is Regulated by


Covalent Modification
Glycogen Synthase exists in two distinct forms
Active, Dephosphorylated GS-I
LESS active, Phosphorylated GS-D
The phosphorylated form is allosterically
activated by glucose-6-P
At least 9 serine residues are phosphorylated
4 different protein kinases are involved
Dephosphorylation is carried out by
phosphoprotein phosphatase-1 (PP1)
PP1 Activates Glycogen Synthase

Insulin Modulates the Action of Glycogen


Synthase in Several Ways
Binding of insulin to plasma membrane receptors in
the liver and muscles triggers protein kinase
cascades that stimulate glycogen synthesis
Insulins effect include stimulation of lipid synthesis,
glycogen synthesis, protein synthesis, glycolysis,
and active transport, AND Inhibition of
gluconeogenesis and lipid breakdown
Glucose uptake provides substrate for Glycogen
Synthesis and Glucose-6-P, which allosterically
activates the otherwise inactive form of glycogen
synthase

Insulin Modulates the Action of Glycogen


Synthase in Several Ways

Figure. Insulin
triggers protein
kinases that
stimulate
glycogen
synthesis

Again The Path from Insulin to GSK3 and


Glycogen Synthase

The Actions of Insulin on Metabolism

Figure. The metabolic effects of insulin are mediated through


protein phosphorylation and second messenger modulation.

So Hormones Regulate Glycogen


Synthesis and Degradation
Storage and utilization of tissue glycogen and
other aspects of metabolism are regulated by
hormones, including glucagon, epinephrine, and
the glucocorticoids (steroid hormone)
Insulin is a response to increased blood glucose
Insulin triggers Glycogen Synthesis when blood
glucose rises
Between meals, blood glucose is 70-90 mg/dL
Glucose rises to 150 mg/dL after a meal and
then returns to normal within 2-3 hours
Glucagon and Epinephrine stimulate Glycogen
Breakdown

Hormones Regulate Glycogen Synthesis


and Degradation

Figure. The portal


vein system
carries pancreatic
secretions such
as INSULIN and
GLUCAGON to
the liver.

Glucagon and Epinephrine Stimulate Glycogen


Breakdown and Inhibit Glycogen Synthesis

Glucagon and epinephrine stimulate glycogen


breakdown the opposite effect of insulin
Glucagon (a 29-residue peptide), is secreted by
pancreas alpha cells
Glucagon acts in LIVER and ADIPOSE tissue only
Epinephrine (adrenaline) is released from adrenal
glands
Epinephrine acts on LIVER and MUSCLES
When either hormone binds to its receptor on the
outside surface of the cell membrane, a
phosphorylase cascade amplifies the signal

Glucagon and Epinephrine


Activate a cascade of
reactions that Stimulate
Glycogen Breakdown and
Inhibit Glycogen Synthesis
in liver and muscles,
respectively.

Epinephrine and Glucagon


The difference:
Both are Glycogenolytic in Liver, but for different
reasons
Epinephrine is the fight or flight hormone
It rapidly mobilizes large amounts of energy
Glucagon is for long-term maintenance of steadystate levels of glucose in the blood
It activates glycogen breakdown
It activates liver gluconeogenesis

Regulation of
Carbohydrate
Metabolism in
the Liver:

Difference in the Regulation of Carbohydrate


Metabolism in Liver and Muscle

Suggested Problems
3,4,5,6,7,8,10,12,13

Hormones Regulate Glycogen Synthesis


and Degradation
Insulin is secreted from the pancreas (to liver) in
response to an increase in blood glucose
Note that the portal vein is the only vein in the body
that feeds an organ
Insulin acts to lower blood glucose rapidly in several
ways, stimulating Glycogen Synthesis and
Inhibiting Glycogen Breakdown

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