Download Biochemistry 7/e

Berg • Tymoczko • Stryer
Biochemistry
Seventh Edition
CHAPTER 21
Glygogen Metabolism
Copyright © 2012 by W. H. Freeman and Company
 Glycogen is a polymer of glucose consisting of 104 to 105 glucose monomers linked by a(14) glycoside
bonds, but with frequent branches arising from a(1
units are branched.
6) bonds. In glycogen, about 10% of the glucose
 The molecule has one reducing end (right hand end of chain) but many nonreducing ends (left hand ends)
due to the branches.
 The nonreducing ends are the locations of all glucose additions or removals.
 Branches are added by branching enzyme, and removed by debranching enzyme.
Glycogenolysis
 Degradation of stored glycogen (glycogenolysis) occurs through the
action of glycogen phosphorylase.
 The action of phosphorylase is to phosphorolytically remove single
glucose residues from a-(1,4)-linkages within the glycogen molecules.
 The product of this reaction is glucose-1-phosphate. The advantage of
the reaction proceeding through a phosphorolytic step is that:
1. The glucose is removed from glycogen in an activated state, i.e.
phosphorylated and this occurs without ATP consumption.
2. The concentration of Pi in the cell is high enough to drive the
equilibrium of the reaction the favorable direction since the free energy
change of the standard state reaction is positive.
Glycogenolysis:degradation of glycogen
The active form of Vitamin B-6 is Pyridoxal-5phosphate or P5P, this active form allows for the best
absorption, because it is ready to go to work
immediately.
debranching enzyme (a-(1,6)-glucosidase )
Enzymatic activity of
glycogen phosphorylase
debranching enzyme (also called glucan
transferase) which contains 2 activities:
glucotransferase and glucosidase.
The transferase activity removes the
terminal 3 glucose residues of one branch
and attaches them to a free C-4 end of a
second branch
The glucose in a-(1,6)-linkage at the
branch is then removed by the action
of glucosidase
Glycogen synthesis
A different reaction sequence is required for glycogen
synthesis because the glycogen phosphorylase is not easily
reversed.
A high energy glucose donor is required to make new
glycoside bonds in glycogen.
This is the compound uridine diphosphate glucose
(UDP-Glc), an example of a sugar nucleotide
UDP glucose is made by the action of the enzyme
UDP-glucose pyrophosphorylase.
The incoming glucose-1-phosphate displaces two
units of phosphate from UTP, released as inorganic
3–.
pyrophosphate,
HP
O
2
7
UDP-glucose pyrophosphorylase
Glycogen synthase uses UDG-glucose as glucose donor
Glycogen synthase adds glucose to the non-reducing
ends of glycogen chains.
The 4α-OH of the non reducing terminal glucose acts
as the nucleophile, and displaces UDP from UDP
glucose. The added glucose forms a new a(14)
glycoside bond.
Glycogen synthesis costs ATP energy
Since UTP is required at the UDP-glucose pyrophosphorylase step, and
UDP is released at the glycogen synthase step, these reactions contribute an
energy cost of 1 UTP hydrolysed (equivalent to 1 ATP) for each glucose
unit added with glucose-6-phosphate as starting point.
An additional ATP is needed when glucose is the starting point. The benefit
is that glycogen can be synthesized when cellular energy is in surplus.
Glycogen can deliver glucose-6-phosphate to glycolysis without costing
ATP, which occurs when energy is in demand
PANCREATIC HORMONES
 The primary role of the pancreatic hormones is the regulation of whole body energy
metabolism,
 principally by regulating the concentration and activity of numerous enzymes involved
in catabolism and anabolism of the major cell energy supplies.
 The pancreas has exocrine and endocrine functions.
 Endocrine function involves Islets of Langerhans
Four hormones are secreted:
Hormone
Origin
Composition
Function
Insulin
β cells (central)
disulfide bonded
dipeptide of 21 and
30 amino acids
Glucagon
α cells (peripheral)
polypeptide of 29
amino acids
increases glycogenolysis in order to
increase blood glucose levels
(Secreted when blood glucose levels
are low)
Pancreatic
Polypeptide
F cells
polypeptide of 36
amino acids
increases glycogenolysis, regulation
of gastrointestinal activity
Somatostatin
 cells
14 amino acid
version
increases glucose uptake and
utilization, increases lipogenesis,
and general anabolic
effects.(secreated when blood
glucose levels are high)
inhibition of glucagon and
somatotropin release
How does glucagon work?
Glucagon is an endocrine hormone that mobilizes the body’s
energy stores.
It affects liver cells, muscle cells, adipocytes and kidney cells
Glucagon has a major role in maintaining normal
concentrations of glucose in blood, and is often described as
having the opposite effect of insulin.
Glucagon is a linear peptide of 29 amino acids. Glucagon is
synthesized as proglucagon and proteolytically processed to
yield glucagon within  cells of he pancreatic islets.
.
Physiologic Effects of Glucagon
 The major effect of glucagon is to stimulate an increase in blood concentration of
glucose.
 The brain in particular has an absolute dependence on glucose as a fuel, because
neurons cannot utilize alternative energy sources like fatty acids.
 When blood levels of glucose begin to fall below the normal range, it is imperative
to find and pump additional glucose into blood.
 Glucagon exerts control over two pivotal metabolic pathways within the liver,
leading that organ to dispense glucose to the rest of the body:
 Glucagon stimulates breakdown of glycogen stored in the liver.
 Glucagon activates hepatic gluconeogenesis.
 Glucagon also appears to have a minor effect of enhancing lipolysis of triglyceride
 It stimulates glycogenolysis, gluconeogenesis, lipolysis, protein degradation, amino
acid catabolism and ketogenesis
Regulation of glycogenolysis
Glucagon
Glucagon is hyperglycemic - promotes mobilization of glucose
from glycogen (glycogenolysis) and mobilization of free fatty
acids from adipose tissue (lipolysis). It is also gluconeogenic.
Actions of Glucagon:
1. Glycogenolysis
2. Lipolysis
3. Gluconeogenesis
Secretion from pancreatic alpha cells
Regulation of phosphorylase by glucagon
Regulation through beta-adrenergic receptor
glucagon
Glucagon receptor on the cellular membrane
(Glycogne)n
(Glycogne)n-1
+
Glucose-1-p
Muscle phosphorylase is regulated by phosphorylation
phosphorylase kinase is fully activated upon phosphorylation and
calcium binding
glucagon
Regulation of phosphorylase by glucagon
Regulation through beta-adrenergic receptor
Glucagon receptor on
the cellular membrane
Protein phosphatase is inactivated during exercise or fasting by
Epinephrine or glucagon
Glycogen metabolism in the liver regulates the blood glucose level
After meal
1.
2.
3.
4.
5.
Blood glucose levels 
Insulin secretion 
Uptake of glucose by the liver 
Glycogen synthase activities 
Phosphorylase activities 
 Lagging period of glycogen synthase
activation occurs.
 Activation of synthase takes place
only after inactivation of
phosphorlase
 Why?
Suppression of PP1 by liver glycogen phosphorylase a
is relieved upon glucose infusion
 Binding of glucose to phosphorylase a leads
phsophorylase a from R (relaxed) to T
(Taut) state
 While phosphorylase a is bound to PP1 and
GL, PP1 is inactive and thus nonfunctional.
 Upon glucose binding, conformation of
phosphorylase a is changed to T state.
 This causes detachment of PP1 and GL from
phosphorylase a.
 Upon conformational change to T state,
serine 14 on phosphorylase a is exposed.
 PP1 dephosphorylase this exposed serine of
phosphorylase a.
 There are about 10 phosphorylase a to 1
PP1. PP1 is not fully functional until all the
R phosphorylase a turns into T state.
 Upon depletion of phosphorylase a (R state)
, PP1 becomes fully activated and begins to
dephosphorylate glycogen synthase b
turning it into glycogen synthase a.
Insulin induces dephosphorylation of glycogen synthase
via inactivation of glycogen synthase kinase