3.

03
08-18-16

GLYCOGEN METABOLISM
Redario Laygo, M.D.

METABOLISM OF GLYCOGEN
 Remember: All disaccharides will have the alpha
I. FUNCTIONS OF GLYCOGEN type except lactose, it has beta 1,4. Of all the alpha
II. GLYCOGENESIS type, all have alpha 1,4 except sucrose, it has alpha
a. Mature Glycogen 1,2.
b. Synthesis of UDP-Glucose
III. BIOSYNTHESIS OF GLYCOGEN  Formation of branches
IV. STEPS IN GLYCOGENOLYSIS
a. Regulation of Glycogen Synthase Mature glycogen
b. Glycogen Phosphorylase and Glycogen Synthase
V. cAMP ACTIVATES GLYCOGEN PHOSPHORYLASE
 Mature glycogen should have at least 12 layers.
a. Calcium synchronizes activation of Glycogen  Granules are deposited in the cytosol of liver cells and
Phosphorylase with Muscle Contraction muscle cells.
VI. CLINICAL ASPECTS
 Location of enzymes should also be in the cytosol
FUNCTIONS OF GLYCOGEN  Lafora – one who discovered that glycogen heads can
 Glycogen – synthesized and stored in cytosolic be phosphorylated. Lafora disease is when there is
granules in the liver and muscle. something wrong about the phosphorylation of
o Note: The Heart also contains glycogen but only in glycogen.
small amounts.
o If you compare 1 g of liver tissue and 1 g of muscle Synthesis of UDP-glucose
tissue, the liver has more glycogen. But if you take
the whole organ, the muscle will have a high
amount.
 Liver glycogen – maintain blood glucose
concentration within normal range during early
fasting.
o Note: Order of utilization of macromolecules:
Carbohydrates > Lipids (TAGs in adipose tissue) >
Proteins
 Muscle glycogen – fuel reserve for the synthesis of
ATP during muscle contraction. Note: Important amino acid residue: tyrosine 194. Tyrosine
o Note: Cannot maintain normal blood glucose will serve as an attachment of the first glucosyl unit in the
because the muscles do not have the unique enzyme form of UDP glucose. Glycogenin is a protein molecule with
to gluconeogenesis, glucose 6-phosphatase inherent glucosyl units so it also acts as an enzyme.
o Enzymes unique for gluconeogenesis: pyruvate
carboxylase, PEP carboxikinase, fructose 1,6-
bisphophatase, glucose 6-phosphatase

GLYCOGENESIS
 Synthesis of UDP (uridine diphosphate) glucose
 Formation of glycogen primer – Glycogenin
 Note: Glycogenin is a dimer, there are two subunits
that is made up of tyrosine
 Elongation of glycogen chains (amylase chain
formation)
 Note: Glycogen and starch is made up of glucosyl
units. The 2 parts are the amylose chain (straight)
and amylopectin (branched). Glycosidic linkages:
alpha 1,4 and the site of branching is alpha 1,6.

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 1.01 GLYCOGEN METABOLISM

o Glycogen synthase - Most important

 UDP-glucose is TITLE OF LECTURE
synthesized from glucose(NOTE:
1-phosphate
ALL CAPS) enzyme for glycogenesis
and uridine triphosphate (UTP) in a reaction catalyzed  How can the cells now remodel the molecule to
by UDP-glucose pyrophosphorylase. create a mature glycogen?
 Summary: o At least 11 glucosyl units straight chain
needed to activate branching enzyme
o Amylo (14) to (16) glucan transferase
- branching enzyme that will cleave α
(14) bond and subsequently transfer 6
Note: This reaction is readily reversible. However, glucosyl units there
pyrophosphate is rapidly hydrolyzed by an inorganic o At the 5th it will try to create α (16)
pyrophosphatase. The essentially irreversible hydrolysis bond
of pyrophosphate drives the synthesis of UDP-glucose.  Glycogen synthase and branching enzyme will go
on until there are at least 12 layers of glycogen
BIOSYNTHESIS OF GLYCOGEN molecule as a mature glycogen
How much energy is liberated when you hydrolyze 1 mole  What are the ezymes of glycogenesis?
of pyrophosphate to 2 inorganic phosphate? o Glycogenin
o It liberates -6.6 kilocalories per mole and o Glycogen synthase
is enough to complete the reaction and to o Amylo (14) to (16) glucan transferase
make it irreversible – branching enzyme
o If there is no hydrolysis of the
GLYCOGENOLYSIS
pyprophosphate (no liberation of
energy)  reversible reaction ; cells will
have difficulty in synthesizing glycogen
o Catalyzed by inorganic pyrophosphatase

o Glycogen phosphorylase – most

Synthesis Of Glycogen important enzyme for breakdown of
o Glycogenin – primer; having the activity glycogen
of a glucosyl transferase o Phosphorylitic cleavage of the terminal α
o Tyrosine 194 – most important residue of (14) glycosidic bond at the non-
glycogenin reducing end of glycogen
o What happens through the inherent o Carbon 5 - non-reducing end
glucosyl transferase activity of o Carbon 1 – reducing end
glycogenin? - Formation of O-Glycosidic o β – D- glucopyranose – the major anomer
bond in physiological milieu
o Glycogen molecules will continue adding
glucosyl units until there are 8 glucosyl
units
o At least 8 glucosyl units are needed until
glycogen synthase takes over the process

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 1.01 GLYCOGEN METABOLISM

Glycogen Phsphorylase And Glycogen Synthase

TITLE OF LECTURE (NOTE: ALL CAPS)  2 principal enzymes that control Glycogen
metabolism:
o Glycogen phosphorylase - allosterically
activated by AMP and inhibited by ATP,
glucose-6-P and caffeine
o Glycogen synthase - stimulated by
glucose-6-P and activated by insulin
 Both enzymes are regulated by covalent
modification (phosphorylation and
dephosphorylation)

Steps in the Hormonal Activation of GLYCOGENOLYSIS

o Glycogen phosphorylase – cleaves one STEP 1:
glucosyl unit at a time in the form of
glucose-1-phosphate (Phosphorylitic  Hormones GLUCAGON (act on liver only),
cleavage) EPINEPHRINE, or NOREPINEPHRINE activate
o Epimers of Glucose: Mannose and adenylyl cyclase which activates cyclic AMP.
Galactose STEP 2:
o Is very beneficial to cells of the muscles  cAMP activates cAMP DEPENDENT PROTEIN
o Glucose-1-phosphate isomerized to KINASE.
Glucose-6-phosphate STEP 3:
o Activity of glycogen phosporylase will  cAMP DEPENDENT PROTEIN KINASE
stop at 4 glucosyl units away from the phosphorylates PHOSPHORYLASE KINASE B
branching point (inactive) into PHOSPHORYLASE KINASE A
o Debranching enzyme activities (active) which leads to glycogenolysis activation.
 Amylo (14) to α(14) glucan STEP 4:
transferase – cleaved α(14)  cAMP DEPENDENT PROTEIN KINASE also
removing 3 glucosyl units phosphorylates GLYCOGEN SYNTHASE A (active)
creating another α(14) bond into GLYCOGEN SYNTHASE B (inactive) thereby
 α(16) glucosidase – cleaving deactivating glycogenesis
glucose as free glucose STEP 5:
What are the products of a glycogen breakdown?  cAMP DEPENDENT PROTEIN KINASE also
1. glucose-1-phosphate phosphorylates the INHIBITOR-1 (inactive) to
2. free glucose INHIBITOR-1-PHOSPHATE (active) which leads to
These are the things you have to remember: glycogenolysis activation
 For glycogen breakdown what is the most
important enzyme? THEREFORE, HIGH cAMP CONCENTRATIONS ARE
Glycogen phosphorylase ASSOCIATED WITH GLYCOGENOLYSIS ACTIVATION AND
GLYCOGENESIS DEACTIVATION.
 And then the name of your debranching enzyme,
what is the name of the first activity?
Steps in the Hormonal Activation of GLYCOGENESIS
 Amylo α(14) to α(14) glucan transferase
 The second activity is STEP 1:
α(16) glucosidase  At low levels of GLUCAGON (act on liver only),
EPINEPHRINE, or NOREPINEPHRINE, adenylyl
Regulation Of Glycogen Synthase cyclaseactivity will decrease
Reciprocal regulation (when glycogenolysis is on,
glycogenesis is off and vice versa) STEP 2:
 Low blood sugar activates glycogenolysis  cAMP concentration decreases and cAMP
 After carbohydrate consumption -inactive DEPENDENT PROTEIN KINASE activity also
glycogenolysis decreases

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STEP 3: Insulin is a peptide hormone which is made up of

 Since cAMP TITLEDEPENDENT
OF LECTUREPROTEIN
(NOTE: KINASE
ALL CAPS) alpha and beta chains that are made up of amino
activity is low, PHOSPHORYLASE KINASE B acids.
(inactive) will not be phosphorylated into o What are the amino acids involved in the
PHOSPHORYLASE KINASE A (active) leads to formation of disulfide bridges? Cysteine.
glycogenolysis deactivation
STEP 4: o 2 cysteine residues through oxidation will form
 Since cAMP DEPENDENT PROTEIN KINASE disulfide bonds
activity is low, GLYCOGEN SYNTHASE A (active) o Insulin being a protein and a peptide hormone
will not be phosphorylated into GLYCOGEN cannot just pass thrthe membrane hthefore
SYNTHASE B (inactive) thereby activating needing a receptor, the receptor would be
glycogenesis. Glycogen Synthase A is the enzyme receptor tyrosine kinase.
used to add UDPGlc to a glycogen primer.
STEP 5: o Some of the actions of insulin are: it will stimulate
 Since cAMP DEPENDENT PROTEIN KINASE activity of PDE (phosphodiesterase), so therefore
ACTIVITY is low, INHIBITOR-1 (inactive) will not it will act on cAMP. It being an esterase, it will try
be phosphorylated into INHIBITOR-1- to give the bond that you find – transforming it to
PHOSPHATE (active) 5’ AMP. Therefore, resulting to 0 levels of cAMP.

cAMP ACTIVATES GLYCOGEN PHOSPHORYLASE o So, subsequent activation of protein kinase A can
o When we have the active protein kinase A, the no longer occur. So the levels of this will be
glycogen synthase and the glycogen decreasing.
phosphorylase will receive a phosphate H.
o What is the activity of glycogen phosphorylase o Another action of insulin hormones is to stimulate
when it receives a phosphate? It therefore a phosphatase – the one that will remove attached
becomes active. phosphate groups. – this would add to enzymes
that receive phosphate group. Glycogen
o What about nitrogen synthase when it receives a
Phosphorylase will now be dephosphorylated as
phosphate? It becomes inactive.
well as the glycogen synthase at the same time.
NOTE: THIS IS FOUND IN THE LIVER. o If your Glycogen Phosphorylase is devoid of a
phosphate – it is now inhibited.
Calcium Synchronizes Activation Of Glycogen
Phosphorylase With Muscle Contraction o What abut your Glycogen Synthase with
So, what about in the muscle? phosphate – it is now active.

o Our muscle needs ATP for muscle contraction, o Therefore, with the predominance of insulin –
therefore what else is needed? Calcium ion. glycogenesis is predominant through stimulation
of glycogen synthase
o Protein Kinase A will also affect another enzyme
that will affect glycogen synthase to be able to o Through the action of protein phosphates,
integrate a coupling or integrate the need for phosphates will be removed in muscles.
energy or as well as the need for calcium ions
o Can there be now breaking down of glycogen? No
when talking about contraction.
because Glycogen Phosphorylase is inactive.
o Initially, before active Protein Kinase A activates
glycogen phosphorylase there should be o Gpk transforms to the inactive form. Why?
interfering kinases. Glycogen phosphorylase will Because we have to no cAMP to activate.
then becpme glycogen phosphorylase kinase
which again, is activated by phosphates.
o By the way, phosphates will come from ATP
through its hydrolysis.
o After eating lunch, insulin will be the
predominating hormone in our system. Insulin
will be secreted and will now introduce glucose.

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 1.01 GLYCOGEN METABOLISM

CLINICAL ASPECTS
TITLE OF LECTURE (NOTE: ALL CAPS)

TRANSER’S MESSAGE

biochem
me

LABAN DAI
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