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[BIOCHEM]

2.6 Glycogen
Metabolism
[BIOCHEM] 2.6 Glycogen
Metabolism
Dr. Magat
Dr. M. Magat

August 8, 2013

Ferrer, A (09054793305), Fernandez J, Fernandez M, Ferranco, Ferrer C, Figueroa, Flores

OUTLINE
I. Introduction to Glycogen Metabolism
A. Overview
B. Glycogen structure and function
C. Storage sites
II. Glycogenesis
A. General Overview
B. Enzymes Involved
C. Pathway
III. Glycogenolysis
A. General overview
B. Pathway
IV. Regulation of Glycogen Metabolism
A. Regulation of Glycogen Phosphorylase
B. Regulation of Glycogen
C. Effector Control of Glycogen Metabolism
D. Negative Feedback Control of Glycogen
Synthesis
E. Glucagon Stimulates Glycogen Degradation in
the Liver
F. Phosphorylase a is a Glucose Receptor in
the Liver
V. Hormonal and Neural Control of Glycogen Synthesis and
Degradation
A. Glucagon and Epinephrine Stimulate
Glycogenolysis in Liver
B. Epinephrine Stimulates Glycogenolysis in
Heart and Skeletal Muscle
C. Neural Control of Glycogenolysis in Skeletal
Muscle
D. Insulin Stimulates Glycogenesis in Muscle and
Liver
VI. Glycogen Storage Diseases
VII. Skeletal Muscle Metabolism
A. Overview of Skeletal Muscle Metabolism
B. Enzymes involved in the Regulation of Fatty
Acyl-CoA Entry
C. Steps in Fatty Acyl-CoA regulation
VIII. Summary
IX. Appendix
OBJECTIVES
At the end of the lecture, the student should be able to:
1. Discuss the key role of glycogen in glucose homeostasis
2. Illustrate and explain the glycogen structure
3. Understand the mechanisms behind glycogen
degradation (glycogenolysis) and glycogen synthesis
(glycogenesis)
4. Understand that the opposing processes of
glycogenolysis and glycogenesis are reciprocally regulated
by allosteric interactions and covalent modification of key
enzymes
5. Discuss the significance of glycogen storage diseases

ed.: McGraw-Hill, 2012. Print.


Nelson, David L. Lehninger's Principles of Biochemistry. 5th
ed. 2009.
Stryer, Lubert. Biochemistry Stryer. 6th ed. 2006.
Marks, Allan D. Mark's Basic Medical Biochemistry a Clinical
Approach. 2nd ed., 2005.
Grisham, Charles M. Biochemistry. 4th ed. 2010.
Voet, Donald J. Principles of Biochemistry.: Wiley, 2008.
Harvey, Richard A. Biochemistry (Lippincott's Illustrated
Reviews). 5th ed., 2010.
2016B. Glycogen Metabolism Trans
Legend: Italicized quoted from the lecturer; bold
emphasis, or from references
I. INTRODUCTION TO GLYCOGEN METABOLISM
A.

Glycogen metabolism can occur in two opposing processes:


1. Glycogenesis synthesis and storage of glycogen
during fed state
2. Glycogenolysis degradation of glycogen to form
glucose or glucose-6-phosphate during starvation
or fasting state/vigorous activity (muscle cells)
/in between meals (liver)
B.

GLYCOGEN STRUCTURE AND FUNCTION

GLYCOGEN

Major form of storage polysaccharide in humans

Found mainly in the liver and skeletal muscle


th
[Devlin, 7 Ed.]

Branched chain homopolysaccharide made out of


-D-glucose containing -1,4 glycosidic bonds
(linear) with -1,6 branches occurring every 8-12
glucose units

Contains only one reducing end with the


nonreducing ends on every branch (sites of
phosphorolysis and hydrolysis)

No catalytic activity or cell signaling properties

Readily available source of fuel

Can be tapped for energy source even in anaerobic


conditions

References:
Devlin, Thomas M. Textbook of Biochemistry with Clinical
Correlations. 7th ed.: Wiley, 2010.
Murray, Robert K. Harper's Illustrated Biochemistry. 29th
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OVERVIEW

Structure of glycogen

[BIOCHEM] 2.6 Glycogen Metabolism Dr. Magat


C.

STORAGE SITES

LIVER

Major storage site of glycogen


Maintains blood glucose levels
During fasting state, glycogen is converted to
glucose-6-phosphate by glycogenolysis and
glucose-6-phosphate is coverted to glucose by
th
glucose-6-phosphatase [Devlin, 7 Ed.]

Stored glycogen is depleted between 12 and 18


hours during fasting

10% of wet weight is due to glycogen stores


MUSCLE

Glycogen serves as a fuel reserve for the synthesis


th
of ATP within muscle tissue only [Devlin, 7 Ed.]

Has twice as much total muscle glycogen as


liver glycogen due to its total mass

Glucose-6-phosphate is not converted to free


glucose due to the absence of glucose-6phosphatase

Exercise mobilizes muscle glycogen for formation


of ATP

Glycogen accounts for 1-2% of its wet weight

Formation of glucose-1-phosphate from glycogen

2.

II. GLYCOGENOLYSIS
A.

GENERAL OVERVIEW

Breakdown of glycogen to glucose or glucose6-phosphate


Takes place in every tissue, but especially in
muscle and liver
In the well-fed state, glycogen granules are
abundant in their liver, and totally depleted after 1218 hrs. of fasting
Three-quarters of total body glycogen is in muscle
and intense exercise causes rapid loss of glycogen
by glucose-1-phosphate release in muscle fibers
B.

1.

PATHWAY

Phosphorylase limit dextrin: a glycogen molecule


that has been degraded to the limit by
phosphorylase because of the branches
Catalyzes phosphorolytic cleavage (yield:
glucose-1-phosphate) as opposed to -amylase
which catalyzes hydrolytic cleavage (yield: glucose)
th
[Stryer, 6 Ed]
Metabolic advantage: product is a sugar-P (a sort
of glycolysis substrate)
Debranching enzyme

Bifunctional enzyme with two distinct catalytic


sites

Composed of glucanotransferase and


amylo--1,6-glucosidase

Glucanotransferase function: transfers 3


glucose residues from a branch to a nearby
nonreducing end

Amylo-1,6-glucosidase function: catalyzes the


hydrolysis of -1,6 glycosidic linkage to yield
a free glucose unit

For every 10 glycosyl units at branch point, 9


will be released as glucose-1-P, only 1 as
glucose.

Action of debranching enzyme allows


phosphorylase to continue its degradation of
glycogen to finally form glucose-1-phosphate
and glucose
o Hydrolysis can be utilized to form
glucose

Glycogen Phosphorylase

Initiates glycogenolysis and is the rate limiting


enzyme/ step

Catalyzes phosphorolysis of glycogen

Cofactor: pyridoxal phosphate (PLP, from Vit.


th
B6) [Lehninger, 5 Ed]

A reaction in which Pi is used to cleave -1,4


glycosidic linkages to yield glucose-1phosphate

This reaction always occurs at terminal,


nonreducing ends of a glycogen molecule

Stops attacking -1,4-glycosidic linkages four


glucosyl residues from an -1,6 branch point
Action of Debranching Enzyme on Glycogen
3.

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Phosphoglucomutase

Converts glucose-1-phosphate to glucose-6phosphate

This reaction is near-equilibrium and is used in


both glycogen degradation and synthesis.
a.) Phosphorylated serine residue transfers a

[BIOCHEM] 2.6 Glycogen Metabolism Dr. Magat


o

phosphate group to C6 of glucose-1phosphate to form a glucose-1,6bisphosphate intermediate.


b.) Phosphate group in C1 is then transferred
to the serine residue to regenerate
enzymatic activity of the residue.

B.
1.

Conversion of glucose-1-phosphate to glucose-6phosphate with the formation of glucose-1,6-bisphosphate


intermediate
4.

Branching enzyme promote formation of


-1,6 glycosidic linkages

2.

Following enzyme is dependent on site of


glycogenolysis

In the liver: glucose 6-phosphate is hydrolyzed


by glucose-6-phosphatase to release free
glucose into the blood

In muscle: glucose-6-phosphate immediately


proceeds to glycolysis

An average molecule of glycogen yields about 12


molecules of glucose produced by the debranching
enzyme.

ENZYMES INVOLVED

Glycogenin
Serves as primer on which new chains are
assembled (by glycogen synthase) and enzyme for
catalysis of glycogen assembly. (Serves as both
substrate AND enzyme)
Primer for rate-limiting enzyme.
Polypeptide of 332 amino acids
Self-glucosylating enzyme that uses UDPglucose to link glucose to one of its own Tyrosine
residues via glucosyltransferase.
Glycosidic linkage synthesized: -1,4 glycosidic
linkages
To become active glycogenin, the hydroxyl group
th
nd
of tyrosine [Devlin, 7 Ed] or Serine [Marks, 2 Ed]
must first bind to 8 glycosyl/glucosyl residues
Glycogen synthase
Rate-limiting enzyme
Only active in glycogenesis
Catalyzes the formation of glycosidic bonds
between C1 of the glucose of UDP-glucose and C4
of a terminal glucose residue of glycogen (must be
a non-reducing end)
th
Cannot form a (1,6) glycosidic linkage [Devlin, 7
Ed]
Liberates UDP to be converted back to UTP by 1
ATP and the enzyme nucleoside diphosphokinase
[Stryer, 6th Ed]
UDP + ATP UTP + ADP

relevance: for activation of glucose-1-phosphate again


to UDP-glucose.
3.

Summary of Glycogenolysis
III. GLYCOGENESIS

A. GENERAL OVERVIEW
Occurs in the cytosol
Glycogenesis in muscle plays an important role in
lowering blood glucose levels after a high
carbohydrate intake
Glucose molecules can traverse the plasma
membrane with ease. For storage to be possible,
glucose must be polymerized into glycogen so
that it will not leave the cell.
Process is activated during rest periods
following the Cori cycle (in the liver)
o Glycogen synthase promote formation of
-1,4 glycosidic linkages
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th

1,4--glucan branching enzyme [Devlin, 7 Ed]


Once a straight chain of ~11 glycosyl residues has
formed, around 7 will break off and will form a 1,6glycosidic bond to the glycogen
Glycosidic linkage synthesized: -1,6 glycosidic
linkage
Importance:
a. Increases solubility
b. Creates large number of terminal
residues (sites of glycogen
phosphorylase and glycogen synthase for
increased rate of glycogen breakdown
and synthesis respectively)

Branching of Glycogen

[BIOCHEM] 2.6 Glycogen Metabolism Dr. Magat

C.

PATHWAY

The new branch has to be formed at least 4


glycosyl residues away from an adjacent
branch point

Step 1 Step 3: Activation of Glucose


STEP 1: Phosphorylation
Glucose + ATP glucose-6-phosphate + ADP

Enzyme:
Hexokinase: peripheral tissues
Glucokinase: hepatic tissue

STEP 2: Isomerization
G6P glucose-1-phosphate

Enzyme: Phosphoglucomutase
o Interconverts glucose 1-phosphate and
glucose 6-phosphate. Glucose 6-phosphate
can enter glycolysis, or in liver, can be
converted to free glucose by glucose 6phosphatase in the endoplasmic reticulum,
then released to replenish blood glucose.
(Lehninger)

STEP 3: Transformation to sugar nucleotide


Glucose-1-phosphate + UTP UDP-glucose + PPi

Enzyme: G1P Uridyl Transferase (also called


UDP-glucose pyrophosphorylase)
Generates: UDP-glucose
o Sometimes called activated glucose
because of its large negative free energy
of hydrolysis
o This energy is used to build the glycogen
molecule
o UDP glucose is made energetically
favorable and irreversible by hydrolysis of
pyrophosphate to inorganic phosphate by
th
pyrophosphate. [Devlin, 7 Ed]
Activated C-1 will attach itself to end of the
glycogen chain at the non-reducing end
4-

PPi + H2O 2 Pi

2-

Enzyme: Inorganic Pyrophosphatase


makes the formation of UDP-glucose
energetically favourable and reversible

STEP 4: Elongation

Glucose molecules are assembled in a straightchain (unbranched) with -1,4 glycosidic bonds
Enzyme: Glycogen synthase
Key enzyme in glycogenesis

STEP 5: Branching

Formation of -1,6 glycosidic bonds


Enzyme: Branching Enzyme

IV. REGULATION OF GLYCOGEN METABOLISM


th
[Devlin, 7 ed, pp. 635-643], see appendix for figures
Glycogen synthase and regulatory enzyme of glycogen
synthesis
Glycogen phosphorylase: regulatory enzyme of
glycogen degradation
Both are subject to control by allosteric effectors and
covalent modification.
A. REGULATION OF GLYCOGEN PHOSPHORYLASE
Glycogen Phosphorylase
o Activated by AMP, inhibited by glucose and ATP
o Exists in two interconvertible forms:
Phosphorylase a
phosphorylated, active (R or Relaxed
state)
Phosphorylase b
dephosphorylated, inactive (T or Tense
state)
low activity but greatly stimulated by
AMP (R state)
Ultimate control of glycogen phosphorylase involves
reciprocal regulation of phosphoprotein phosphatase
and phosphorylase kinase activities.
Phosphorylase kinase
o Two forms:
Phosphorylase kinase a: active
Phosphorylase kinase b: inactive
o Phosphorylates and activates phosphorylase
o Subject to regulation by phosphorylationdephosphorylation
o Phosphorylated and activated by protein kinase A
o Dephosphorylated
and
inactivated
by
phosphoprotein phosphatase
o Complex composed of 4 different subunits with
copies of each subunit in the complex (4444)
-subunit: catalytic activity
-, -, -subunit: regulatory control
-, -subunit
phosphorylated in the transition from
inactive b form to active a form
-subunit
2+
Ca -binding
regulatory
protein
calmodulin
2+
Functions as a Ca receptor in cells
2+
Binding of Ca to calmodulin ->
phosphorylase kinase becomes more
active -> inc. glycogenolysis

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[BIOCHEM] 2.6 Glycogen Metabolism Dr. Magat


o Maximum activation requires:
Phosphorylation of specific serine residues
2+
Interaction of Ca with calmodulin
Phosphoprotein phosphatase
o Regulation involves cAMP
o Inc. cAMP levels promotes activation of glycogen
phosphorylase
by
signaling
activation
of
phosphorylase kinase and
inactivation
of
phosphoprotein phosphatase
o Epinephrine and glucagon: cAMP levels
o Activation promoted by insulin

B. REGULATION OF GLYCOGEN SYNTHASE


Glycogen synthase
o Active for glycogenesis and inactive for
glycogenolysis
o Inhibited when glycogen phosphorylase is active
o Can be phosphorylated on at least 9 different
serine residues and by 11 identified protein kinases
(in contrast to glycogen phosphorylase which is
regulated by phosphorylation at 1 site by 1 specific
kinase )
o Exist in two forms:
Phosphorylated D form
Dependent on G6P for activity
Corresponds to b or inactive form of the
enzyme
Nonphosphorylated I form
Independent of G6P
a or active form of the enzyme
Phosphorylation of glycogen synthase
o Catalyzed by several protein kinases, which in turn
are regulated by second messengers of hormone
2+
action, including cAMP, Ca and diacylglycerol
Cyclic AMP
o Inc level signals inactivation of glycogen
synthase via activation of protein kinase A and
inhibition of phosphoprotein phosphatase
Calcium
o Influences phosphorylation states of glycogen
synthase and glycogen phosphorylase
Calmodulin-dependent kinase & Protein kinase C
2+
o cAMP-independent, Ca -activated protein kinases
o both phosphorylate glycogen synthase
o cannot phosphorylate glycogen phosphorylase
o For full activity, protein kinase C requires:
Phospholipid
Diacylglycerol
Calcium
Glycogen synthase kinase-3, casein kinase I, casein
kinase II also phosphorylates glycogen synthase
Insulin-sinalling cascade results in:
o Activation of protein kinase B -> inactivates
glycogen synthase kinase-3 by phosphorylation ->
activates
glycogen
synthase
via
dephosphorylation by phosphoprotein phosphatase

Allosteric regulation and covalent modification of glycogen


phosphorylase (*Noncovalent control = allosteric control)
Insulin activation of glycogen synthase
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[BIOCHEM] 2.6 Glycogen Metabolism Dr. Magat


and inactivate glycogen synthase
Inhibits glycolysis at the level of glucose-6phosphofructo-1-kinase and pyruvate kinase
Net effect: very rapid increase in normal blood
glucose levels
As blood glucose level increase, less glucagon is
released preventing hyperglycemia.

Allosteric regulation and covalent modification of glycogen


synthase
C.

EFFECTOR CONTROL OF GLYCOGEN


METABOLISM
Enables muscle to keep working for at least a short
period
Dec
ATP levels less inhibition of glycogen
phosphorylase
Dec G6P levels less activation of glycogen synthase
Inc AMP levels activation of glycogen phosphorylase

D.

NEGATIVE FEEDBACK CONTROL OF GLYCOGEN


SYNTHESIS
As glycogen accumulates in a tissue, portion of the
glycogen synthase in the active a form decreases.
PHOSPHORYLASE A IS A GLUCOSE RECEPTOR
IN LIVER
Binding of glucose to phosphorylase A
o promotes inactivation of phosphorylase A
inhibits glycogenolysis
o glycogen is synthesized rather than degraded
Phosphorylase A
o can function as a glucose receptor because the
concentration of glucose in liver reflects that in
blood (which is not true for extrahepatic tissues)
o Liver cells have a very high capacity transporter
for glucose (GLUT2)

EPINEPHRINE
Released into blood from chromaffin cells of adrenal
medulla in response to stress
Binding of epinephrine with -adrenergic receptor on
liver cells:
o Activate adenylate cyclase
o Activate
glycogenolysis
and
inactivate
glycogenesis and glycolysis to maximize release
of glucose
Binding of epinephrine with -adrenergic receptor on
liver cells:
o Signals formation of inositol 1,4,5-triphosphate
(IP3) and diacylglycerol
o IP3
Stimulate
release
of
calcium
from
endoplasmic
reticulum

activate
phosphorylase kinase activate glycogen
phosphorylase
Contribute to inactivation of glycogen
synthase through:
2+
Ca -mediated
activation
of
phosphorylase
kinase
and
calmodulin-dependent
protein
kinase
Diacylglycerol-mediated activation
of protein kinase C
Major consequence of epinephrine action on liver:
increased rate of glucose release into blood
B.

EPINEPHRINE STIMULATES GLYCOGENOLYSIS IN


HEART AND SKELETAL MUSCLE
Epinephrine binds to -adrenergic receptor
stimulates adenylate cyclase to produce cAMP
Lack of glucose-6-phosphatase stimulate glycolysis
rather than release of glucose into blood
Effect: make more glucose-6-phosphate available for
glycolysis
ATP generated from glycolysis can meet the need for
energy imposed on these muscles by the stress that
triggered epinephrine release.

E.

C.

V. HORMONAL AND NEURAL CONTROL OF


GLYCOGEN SYNTHESIS AND DEGRADATION
A. GLUCAGON AND EPINEPHRINE STIMULATE
GLYCOGENOLYSIS IN LIVER
GLUCAGON
Released from cells of pancreas in response to low
blood glucose levels
During fasting, glucagon stimulates glycogenolysis:
o Binding of glucagon to its receptor on liver cells
activate adenylate cyclase triggers the
cascades that activate glycogen phosphorylase
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NEURAL CONTROL OF GLYCOGENOLYSIS IN


SKELETAL MUSCLE
2+
Nerve impulse membrane depolarization Ca
release from sarcoplasmic reticulum into sarcoplasm
of muscle cells muscle contraction
2+
Reaccumulation of Ca by sarcoplasmic reticulum
relaxation
2+
Increase in Ca concentration:
o activates phosphorylase kinase and glycogen
phosphorylase
o inactivates glycogen synthase
o more glycogen converted to glucose-6phosphate more ATP produced to meet
greater energy demand of muscle contraction

[BIOCHEM] 2.6 Glycogen Metabolism Dr. Magat

Glycogenolysis in response to nerve impulse


D.

IIIa

Limit
dextrinosis,
Forbes or
Coris
disease

Liver and
muscle
debranching
enzyme

IIIb

Limit
dextrinosis

IV

Amylopectino
sis,
Andersens
disease

Limit
debranching
enzyme
Branching
enzyme

Myophospho
rylase
deficiency,
McArdles
syndrome

Muscle
phosphorylase

VI

Hers
disease

Liver
phosphorylase

Taruis
disease

Muscle and
phosphofructoki
nase 1

INSULINSTIMULATES GLYCOGENESIS IN MUSCLE


AND LIVER

INSULIN
released from cells of pancreas in response to
increased blood glucose levels
increases glucose utilization in part by promoting
glycogenesis and inhibiting glycogenolysis in muscle
and liver
stimulation of glucose transport essential in muscle
but not liver:
o Hepatocytes: high-capacity, insulin-insensitive
glucose transporter (GLUT2)
o Skeletal muscle cells and adipocytes: insulinsensitive glucose transporter (GLUT4)

VI. GLYCOGEN STORAGE DISEASES


th
[Harper, 29 ed., p. 181]
Type
Name
Enzyme
Clinical
Deficiency
Features
0
Glycogen
Hypoglycemia;
VII
synthase
hyperketonemia;
early death
Ia
Von Gierkes
Glucose-6Glycogen
disease
phosphatase
accumulation in
liver and renal
tubule cells;
hypoglycemia;
lactic academia;
ketosis;
VIII
hyperlipemia
Ib
Endoplasmic
As type 1a;
reticulum
neutropenia and
glucose-6impaired
phosphate
neutrophil
transporter
function leading
to recurrent
IX
infections
II
Pompes
Lysosomal
Accumulation of
disease
14 and 16 glycogen in
glucosidase
lysosome:
(acid maltase)
juvenile onset
variant, muscle
hypotonia, death
X
from heart failure
by age 2; adult
onset variant,
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Liver
phosphorylase
kinase

Liver and
muscle
phosphorylase
kinase

cAMPdependent
protein kinase A

muscle
dystrophy
Fasting
hypoglycemia;
hepatomegaly in
infancy;
accumulation of
characteristic
branched
polysaccharide
(limit dextrin);
muscle
weakness
As type IIIa, but
no muscle
weakness
Hepatosplenome
galy;
accumulation of
polysaccharide
with few branch
points; death
from heart or
liver failure
before age 5
Poor exercise
tolerance;
muscle glycogen
abnormally high
(2.5-4%); blood
lactate very low
after exercise
Hepatomegaly;
accumulation of
glycogen in liver;
mild
hypoglycemia;
generally good
prognosis
Poor exercise
tolerance;
muscle glycogen
abnormally high
(2.5-4%); blood
lactate very low
after exercise;
also hemolytic
anemia
Hepatomegaly;
accumulation of
glycogen in liver;
mild
hypoglycemia;
generally good
prognosis
Hepatomegaly;
accumulation of
glycogen in liver
and muscle; mild
hypoglycemia;
generally good
prognosis
Hepatomegaly;
accumulation of
glycogen in liver

[BIOCHEM] 2.6 Glycogen Metabolism Dr. Magat


VII. SKELETAL MUSCLE METABOLISM
A.

OVERVIEW OF SKELETAL MUSCLE METABOLISM


Muscle State
Fed state
Starved state
Prolonged Starvation

Fuel Source
Muscle glycogen
Fatty acids
Proteins (through
proteolysis)

RED MUSCLE FIBERS


Contain large amount of myoglobin and
mitochondria
Can convert glycogen pyruvate CO2 + H2O
(glycogenolysis+ glycolysis + TCA)

Mechanism of Fatty Acyl-CoA regulation


-

WHITE MUSCLE FIBERS

Contain less myoglobin and mitochondria

Can only supply substrates for glycolysis, with the


end product being lactate

Have enormous capacity for glycogenolysis and


glycolysis as compared to red muscle fibers, but
can only function at full capacity for short periods of
time
Type I
Glycogen
content
Aerobic
metabolism
capacity

Type IIb
fibers
High

High

Intermediate

Low

VIII. SUMMARY OF GLYCOGEN METABOLISM


1.

2.

3.
4.

5.

During exercise, the skeletal muscle obtains fuel


from anaerobic glycolysis.
For high-intensity exercises, Type IIb fibers are
used, resulting in lactic acidosis, NAD+, and the
activation of the Cori cycle

B.

Low

Type IIa
fibers
Intermediate

Citrate from TCA will stimulate the action of acetyl


CoA carboxylase. Acetyl CoA will be stored as malonyl
CoA, thus inhibiting the entry of FA by inhibiting CPT-1

6.

ENZYMES INVOLVED IN REGULATION OF FATTY


ACYL-CoA ENTRY
1.

2.

3.

Carnitine palmitoyltransferase 1 (CPT-1)

Transport of fatty acid (FA) into the


mitochondria
Acetyl CoA carboxylase (ACC-2)

Carboxylation of acetyl CoA into malonyl


CoA (for storage)

Active during fed state


Malonyl CoA decarboxylase (MCoADC)

Degrades malonyl-CoA to acetyl CoA

C.

STEPS IN FATTY ACYL-CoA REGULATION

1.

ACC-2 converts acetyl-CoA to malonyl-CoA,


inhibiting CPT-1 (fatty acyl-CoA cannot enter)
energy, AMP, activating AMP-activated
protein kinase (AMP-PK)
Phosphorylation of ACC-2 (gets inactivated) and
MCoADC (gets activated) by AMP-PK
MCoADC decarboxylates malonyl-CoA to acetylCoA, allowing fatty-acyl-CoA to enter mitochondria
and the muscle to generate more ATP via oxidation of FAs

7.

8.

2.
3.
4.

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9.

Glycogen is a homopolysaccharide linked via 1,4 glycosidic linkage with branching -1,6
glycosidic bonds occurring every 8-12 glucose
units
It contains only ONE reducing end and the
nonreducing ends are located on each of the
branches
It is stored mainly in the liver, but can also be
found in muscles
The liver uses glycogen to maintain blood
glucose concentration while the muscle uses it
as a source of ATP for increased muscular activity
Glycogenolysis is the process of degradation of
glycogen to glucose units (liver) or to glucose6-phosphate.
The key enzymes of glycogenolysis are as follows:

Glycogen phosphorylase catalyzes


glycogen phosphorolysis to yield glucose1-phosphate

Glycogen debranching enzymes


o Glucanotransferase transfers
3 glucose residues to a nearby
glycogen branch
o Amylo--1,6-glucosidase
catalyzes the hydrolysis of -1,6
glycosidic linkage to form free
glucose

Phosphoglucomutase converts
glucose-1-phosphate to glucose-6phosphate
Glucose-6-phosphate from glycogenolysis can be
converted to glucose by glucose-6-phosphatase;
however, this only occurs in liver as it is absent in
the muscle. Glucose-6-phosphate in the muscle
can readily enter glycolysis.
Glycogenesis is the process by which glycogen is
synthesized from glucose units.
The key enzymes of glycogenesis are as follows:

Glycogenin only gets activated when it


already sees 8 glucose residues linked
on the Tyr/Ser residue

Glycogen synthase rate-limiting


enzyme which catalyzes the formation of
glycosidic bonds between C1 of the
glucose of UDP-glucose and C4 of a
terminal glucose residue of glycogen

[BIOCHEM] 2.6 Glycogen Metabolism Dr. Magat


(must be a non-reducing end)
Glycogen branching enzyme or 1,4-glucan branching enzyme removes an
-1,4 linked 7 residue segment and
reattaches it through an -1,6 linkage to
form a branched chain
10. Glycogen metabolism is controlled by allosteric
effectors and by covalent modification. Covalent
modification of glycogen phosphorylase and
glycogen synthase shifts their TR equilibria
and therefore alters their sensitivity to allosteric
effectors
11. Hormone signals that generate cAMP as a second
2+
messenger or that elevates intracellular Ca , which
bind to the calmodulin subunit of phosphorylase
kinase, promote glycogenolysis.
12. Allosteric effectors/ hormones include the following:

13. Covalent modification


enzymes:

Activation

Deactivation

Allosteric
Glycogenolysis
Glycogenesis
effectors/Hormones
cAMP
+
Insulin
+
Epinephrine
+
Glucagon
+
ATP
+
AMP
+
Free glucose (liver)
+
2+
Ca
+
Caffeine
+
Glucose-6+
Phosphate
Diacylglycerol
+
(-) deactivation; (+) activation

[BIOCHEM]

Glycogen
Synthase
Dephosphorylation
- Phosphoprotein
phosphatase 1
(PP1)
Phosphorylation
- CKII, GSK3, PKA,
PKC,
Phosphorylase
kinase, calmodulin
dependent kinase

the

following

Glycogen
Phosphorylase
Phosphorylation
- Phosphorylase
kinase A
Dephosphorylation
Phosphoprotein
phosphatase

IX. STUDY GUIDE


1.

Which of the following is a bifunctional enzyme?


A. Glycogen phosphorylase
B. Phosphoglucomutase
C. Phosphoglucokinase
D. Debranching enzyme

2.

Epinephrine and glucagon have the following


effects on glycogen metabolism in the liver:
A. The net synthesis of glycogen is increased
B. Glycogen phosphorylase is activated while
glycogen synthase is inactivated
C. Both glycogen phosphorylase and
glycogen synthase are activated but
marked
D. Glycogen phosphorylase is inactivated
which glycogen synthase is activated
E. cAMP-dependent protein kinase is
activated while phosphorylase kinase is
inactivated

3.

Muscle glycogen cannot contribute directly to blood


glucose levels because:
A. Muscle glycogen cannot be converted to
glucose-6-phosphate
B. Muscle lacks glucose-6-phosphatase
C. Muscle contains no glucokinase
D. Muscle contains no glycogen
phosphorylase
E. Muscle lacks phosphoglucomutase

4.

What enzyme catalyzes the phosphorolysis of


glycogen
A. Debranching enzyme
B. Branching enzyme
C. Phosphoglucokinase
D. Glycogen synthase
E. Glycogen phosphorylase

5.

Phosphorylation activates all of the following


except:
A. Glycogen phosphorylase
B. Inhibitor-1
C. Phosphorylase kinase
D. Protein Kinase A

Hormonal control of glycogen metabolism

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include

[BIOCHEM] 2.6 Glycogen Metabolism Dr. Magat


6.

In the skeletal muscle, a sudden elevation of Ca2+


concentration will cause:
A. Activation of cyclic AMP-dependent
protein kinase
B. Dissociation of cyclic AMP-dependent
protein
C. Inactivation of phosphorylase kinase due
to the action of a protein phosphatase
D. Conversion of glycogen phosphorylase b
to phosphorylase a
E. Conversion of cAMP to AMP by
phosphodiesterase

Answers: D, B, B, E, D, D

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[BIOCHEM]