Ferchmin 2017
Sugar nucleotides and glycogen metabolism
In this handout we will discuss:
Sugar nucleotides synthesis and its varied role in monosaccharide
metabolism.
Glycogen metabolism and the complex regulation of its synthesis and
breakdown. Regulation by hormones and metabolites.
These are the scientists that discovered the metabolism of sugar
activated nucleotides, glycogen metabolism and other polysaccharides.
The three were directly or indirectly my mentors.
Bernardo A Houssey Luis Federico Leloir
Ranwell Caputto
1
Sugar nucleotides and glycogen metabolism
Several nucleotides can
activate sugars. In the case
of glucose for glycogen
synthesis it is UTP. See next
page
The first reaction a), is reversible but it is
coupled to b) that releases -5 kcal/mol and
favors reaction a).
2
Sugar nucleotides of glucose or of any other carbohydrate are called
activated because sugars bound to nucleotides can be transferred by
specific enzymes to proteins and other molecules or can be subjected to
enzymatic modifications possible only with activated sugars.
UDP-glucuronic is important for detoxification of many drugs and
metabolites. Below is shown the formula of conjugated bilirubin:
We, primates, lost the ability
to make ascorbate. Therefore
we are genetically deficient.
3
Galactose metabolism
Fructose is an ketose, therefore it
is not a substrate of aldose
reductase and causes no cataracts.
Glucose and galactose are aldoses
and they do cause cataracts
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Deficiency of galactokinase causes a mild form of galactosemia (galactose deficiency) that causes
cataracts.
Deficiency of hexose-1-phosphate-uridylyl transferase causes the sever type of galactosemia with
liver failure, mental retardation and cataracts.
The name galactose-1-phosphate-uridylyl transferase is simply wrong but commonly used
including in the NBE. The correct name is hexose-1-phosphate uridylyl transferase. This is so
because it transfers equally well glucose as it does galactose. So, the name in the fig is not in
agreement with the commission for enzyme nomenclature but it is used in most books and in the
NBE.
The 4 epimerase uses NAD+ as cofactor and the transition state is 4 keto hexose.
Why a deficiency of the 4 epimerase was never reported (as far as I know)?
Unrelated to this topic, in glycosaminoglycans a 5 epimerase transforms beta-D- glucuronyl into 5
alpha-L-iduronic. Do you remember that, actually it is “cute” but not too important for medical practice.
Synthesis of Glycogen
Synthesis of uridinediphosphoglucose or UDPGlu
Do you remember
phosphoglyceromutase?
Any similarities with
phosphoglucomutase?
PPi is hydrolyzed by a pyrophosphorylase in a reaction coupled with the pyrophosphorylase
to dissipate energy as heat thus making the synthesis of UDP-Glu thermodynamically favorable.
6
Why do we need to
waste 2 ATPs and
make glycogen?
Deficiency of
branching enzyme
gives long branches.
Causes death at about
to years of age.
Andersen’s disease
The content
of glycogen is
about 10 % of
the wet
weight of the
liver and 2%
of muscle.
7
Glycogen synthase only adds glucoses to an existing chain of at least 4
glucose residues. Glycogenin acts by catalyzing the addition of glucose
to itself (autocatalysis) by first binding glucose from UDP-glucose to the
hydroxyl of Tyr-194 from UDP-glucose, by glycogenin's
glucosyltransferase. Once sufficient residues have been added, glycogen
synthase takes over extending the chain. Glycogenin remains covalently
attached to the reducing end of glycogen.
8
Glycogen degradation
The breakdown of glycogen and entry into
glycolysis as glucose-6-P is achieved by
three enzymes: glycogen phosphorylase,
debranching enzyme and
phosphoglucomutase.
Glycogen phosphorylase produces
glucose-1-P plus limit dextrin.
The debranching enzyme has a
transferase and glycosidase (hydrolase)
activities.
Hexokinase is bypassed when glucose
comes from glycogen!
Deficiency of phosphorylase
(Mc Adler’s) causes muscle
cramps and no lactate
formation during exercise.
Deficiency of debranching
enzyme causes accumulation
of limit dextrin
In the next slide we will address the regulatory mechanisms involved in glycogen metabolism
9
After this hasty and nasty introduction to cell signaling we will study the regulation
of glycogen synthase and glycogen phosphorylase and a regulatory enzyme called
phosphorylase b kinase. For the three enzymes we will use the diagram shown below.
Please, understand the diagram. Later we will integrate all this in a graph.
The granule of glycogen contains the three enzymes mentioned above plus other
regulatory enzymes.
Glycogen synthase can be D, or dependent on glucose-6-P, or I, independent of the presence
of glucose -6-P. Please, remember that the immediate precursor of glycogen is UDP-glucose
not glucose-6-P. The latter is only an allosteric regulator of glycogen synthase.
10
11
Glycogen phosphorylase b kinase also phosphorylates the synthase and should actually be
called synthase phosphorylase b kinase. The phosphorylation of the alpha subunit regulates
the dephosphorylation of the beta subunit. The delta subunit is calmodulin. The direct
interaction of Ca2+ with calmodulin activates this enzyme. This effect is specially relevant in
muscle.
12
Integration of the regulation of glycogen synthesis and breakdown
Adenylyl Cyclase
Glucagon
Epinephrine
Receptors
cAMP
ATP
AMP
R2C2
R2(cAMP)4
Phosphodiesterase
2C
ACTIVE PKA
Glycogen synthase
Phosphorylase b
Kinase
Glycogen Phosphorylase
activation
inhibition
13
Integration of the regulation of glycogen synthesis and breakdown
Adenylyl Cyclase
Glucagon
Epinephrine
Receptors
cAMP
ATP
AMP
R2C2
R2(cAMP)4
Phosphodiesterase
2C
ACTIVE PKA
Phosphorylase b
Kinase
Glycogen synthase
Glycogen Phosphorylase
Protein Phosphatase
activation
Protein Phosphatase Inhibitor
inhibition
14
Integration of the regulation of glycogen synthesis and breakdown
Adenylyl Cyclase
Glucagon
Epinephrine
Receptors
cAMP
ATP
AMP
R2C2
R2(cAMP)4
Phosphodiesterase
Ca2
2C
ACTIVE PKA
+
Phosphorylase b
Kinase
Glycogen synthase
Glycogen Phosphorylase
Protein Phosphatase
activation
Protein Phosphatase Inhibitor
inhibition
15
Insulin activates glycogen synthesis
16
17
Insulin stimulates glucose transport in muscle and adipose cells by stimulating
translocation of glucose transporter 4 (GLUT4) to the plasma membrane.
18
Integration of the regulation of glycogen synthesis and breakdown
Insulin-R
PI3-K
Adenylyl
Cyclase
Remember
that
ATP
(-1) x (-1)=+1
or inhibition of
cAMP is as
inhibition
good as activation
PKB/Akt
R2C2
R2(cAMP)4
Glucagon
Epinephrine
Receptors
Heart,
muscle and
other
AMP
Phosphodiesterase
GSK-3
Ca2
2C
ACTIVE PKA
+
Phosphorylase b
Kinase
Glycogen synthase
Glycogen Phosphorylase
Protein Phosphatase
activation
Protein Phosphatase Inhibitor
inhibition
19
Akt inhibits glycogen synthase kinase 3 (GSK-3) which then stops inhibiting the glycogen synthase