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Carbohydrate Metabolism 2: Glycogen degradation, glycogen synthesis, reciprocal regulation of glycogen metabolism

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Title: Carbohydrate Metabolism 2: Glycogen degradation, glycogen synthesis, reciprocal regulation of glycogen metabolism


1
Carbohydrate Metabolism 2Glycogen degradation,
glycogen synthesis, reciprocal regulation of
glycogen metabolism
Bioc 460 Spring 2008 - Lecture 34 (Miesfeld)
Glycogen phosphorylase enzyme is a dimer that is
regulated by both phosphorylation and allostery
Carbohydrates in pasta are a good way to
replenish muscle glycogen stores
Gerty Cori won the 1947 Nobel Prize for her work
on glycogen metabolism
2
Key Concepts in Glycogen Metabolism
  • Glycogen is a highly-branched polymer of glucose
    that can be quickly degraded to yield glucose-1P
    which is isomerized to glucose-6P.
  • Glycogen phosphorylase removes one glucose at a
    time from the nonreducing ends using inorganic
    phosphate (Pi).
  • Glycogen synthase adds glucose residues to
    nonreducing ends in a reaction involving
    UDP-glucose the cost of glycogen synthesis is 1
    ATP/glucose residue.
  • Net phosphorylation leads to glycogen
    degradation, whereas, net dephosphoryation,
    results in glycogen synthesis.

3
Overview of Glycogen Metabolism
The storage form of glucose in most eukaryotic
cells (except plants) is glycogen, a large highly
branched polysaccharide consisting of glucose
units joined by ?-1,4 and ?-1,6 glycosidic bonds.

The large number of branch points in glycogen
results in the generation of multiple nonreducing
ends that provide a highly efficient mechanism to
quickly release and store glucose.
4
The reducing and nonreducing ends of glycogen
  • The nonreducing end of glycogen molecules refers
    to the carbon that is opposite to the reducing
    end in the ring structure. The reducing end of a
    linear glucose molecule can be oxidized by Cu2
    by definition.

Reducing end
Nonreducing end
Nonreducing end

Reducing end
5
Glycogen Core Complexes
  • Glycogen core complexes consist of glycogenin
    protein and 50,000 glucose molecules with a-1,6
    branches about every 10 residues creating 2,000
    nonreducing ends. Glycogen is stored primarily in
    liver and skeletal muscle cells.

6
Pathway Questions
  • Liver glycogen is used as a short term energy
    source for the organism by providing a means to
    store and release glucose in response to blood
    glucose levels liver cells do not use this
    glucose for their own energy needs.
  • Muscle glycogen provides a readily available
    source of glucose during exercise to support
    anaerobic and aerobic energy conversion pathways
    within muscle cells muscle cells lack the enzyme
    glucose-6-phosphatase and therefore cannot
    release glucose into the blood.

7
Pathway Questions
  • 2. What are the net reactions of glycogen
    degradation and synthesis?
  • Glycogen Degradation
  • Glycogenn units of glucose Pi ? Glycogenn-1
    units of glucose glucose-6-phosphate
  • Glycogen Synthesis
  • Glycogenn units of glucose glucose-6-phosphate
    ATP H2O ? Glycogenn1 units of glucose
    ADP 2Pi

8
Pathway Questions
  • 3. What are the key enzymes in glycogen
    metabolism?
  • Glycogen phosphorylase enzyme catalyzing the
    phosphorylysis reaction that uses Pi to remove
    one glucose at a time from nonreducing ends of
    glycogen resulting in the formation of
    glucose-1P..Glycogen synthase - enzyme
    catalyzing the addition of glucose residues to
    nonreducing ends of glycogen using UDP-glucose as
    the glucose donor.
  • Branching and debranching enzymes - these two
    enzymes are responsible for adding (branching)
    and removing (debranching) glucose residues.

9
Pathway Questions
  • 4. What are examples of glycogen metabolism in
    real life?
  • The performance of elite endurance athletes can
    benefit from a diet regimen of carbohydrate
    "loading" prior to competition.
  • Key is to deplete glycogen before carbo loading
    to get 2x glycogen level.

10
Function of Glycogen Phosphorylase
  • Glycogen degradation is initiated by glycogen
    phosphorylase, a homodimer that catalyzes a
    phosphorolysis cleavage reaction of the a-1,4
    glycosidic bond at the nonreducing ends of the
    glycogen molecule. Inorganic phosphate (Pi)
    attacks the glycosidic oxygen using an acid
    catalysis mechanism that releases glucose-1P as
    the product.

Although the standard free energy change for this
phosphorylysis reaction is positive (?Gº' 3.1
kJ/mol), making the reaction unfavorable, the
actual change in free energy is favorable (?G'
-6 kJ/mol) due to the high concentration of Pi
relative to glucose-1P inside the cell (ratio of
close to 100).
11
Structure of Glycogen Phosphorylase
  • Exists as a dimer and has binding sites for
    glycogen and catalytic sites that contain
    pyridoxal phosphate (derived from vitamin B6).
    The critical Pi substrate is bound to the active
    site by interactions with pyridoxal phosphate and
    active site amino acids.

12
Function of Phosphoglucomutase
  • The the next reaction in the glycogen degradation
    pathway is the conversion of glucose-1P to
    glucose-6P by the enzyme phosphoglucomutase.
  • Where have you seen this type of reaction before
    (a mutase rxn)?

13
Glycogen Debranching Enzyme
  • The glycogen debranching enzyme (also called
    a-1,6-glucosidase) recognizes the partially
    degraded branch structure and remodels the
    substrate in a two step reaction.
  • Since a-1,6 branch points occur about once every
    10 glucose residues in glycogen, complete
    degradation releases 90 glucose-1P and 10
    glucose molecules.

Is there a difference in the amount of energy
that can be recovered from glucose-1P and glucose?
14
Regulation of Glycogen Phosphorylase Activity
  • Activity is regulated by both covalent
    modification (phosphorylation) and by allosteric
    control (energy charge).
  • Glycogen phosphorylase is found in cells in two
    conformations
  • active conformation, R form
  • inactive conformation, T form
  • Phosphorylation of serine 14 (Ser 14) shifts the
    equilibrium in favor of the active R state.
  • This phosphorylated form of glycogen
    phosphorylase is called phosphorylase a (active),
    and the unphosphorylated form is called
    phosphorylase b. It is the same polypeptide, just
    a different name.

15
Regulation of Glycogen Phosphorylase Activity
  • The enzyme responsible for phosphorylating
    glycogen phosphorylase b to activate it, is
    phosphorylase kinase which is a downstream target
    of glucagon and epinephrine signaling, as well
    as, insulin signaling.

16
Tissue-specific isozymes of glycogen phosphorylase
  • The activity of glycogen phosphorylase can also
    be controlled by allosteric regulators, which
    binds to the T state and shifts the equilibrium
    to the R state.
  • Liver and muscle isozymes of glycogen
    phosphorylase are allosterically-regulated in
    different ways, which reflects the unique
    functions glycogen in these two tissues.

17
Tissue-specific isozymes of glycogen phosphorylase
  • Liver glycogen phosphorylase a, but not muscle
    glycogen phosphorylase a is subject to allosteric
    inhibition by glucose binding which shifts the
    equilibrium from the R to T state.
  • When liver glycogen phosphorylase a
    (phosphorylated form) is shifted to the T state,
    it is a better substrate for dephosphorylation by
    PP-1 than is the R state.
  • Why does it make sense that muscle glycogen
    phosphorylase b, but not liver glycogen
    phosphorylase b, would be allosterically
    activated by AMP in the absence of hormone
    signaling?
  • Hint what does the liver do with the glucose-6P
    that is produced?

18
Glycogen synthase catalyzes glycogen synthesis
  • The addition of glucose units to the nonreducing
    ends of glycogen by the enzyme glycogen synthase
    requires the synthesis of an activated form of
    glucose called uridine diphosphate glucose
    (UDP-glucose).
  • The rapid hydrolysis of PPi by the abundant
    cellular enzyme pyrophosphatase results in a
    highly favorable coupled reaction.

Why does rapid conversion of PPi --gt 2 Pi result
in a more favorable reaction?
19
Glycogen Synthase Reaction
  • Glycogen synthase transfers the glucose unit of
    UDP-glucose to the C-4 carbon of the terminal
    glucose at the nonreducing end of a glycogen
    chain.
  • The UDP moiety is released and UTP is regenerated
    in a reaction involving ATP and the enzyme
    nucleoside diphosphate kinase.

20
Glycogen Branching Enzyme
  • Once the chain reaches a length of 11 glucose
    residues, the glycogen branching enzyme transfers
    seven glucose units from the end of the chain to
    an internal position using a a-1,6 branchpoint.

21
Growing Glycogen Tree - Starting with Glycogenin
Protein
22
Regulation of Glycogen Synthase Activity
  • The activity of glycogen synthase is also
    primarily controlled by reversible
    phosphorylation.
  • Dephosphorylation activates glycogen synthase,
    whereas, glycogen phosphorylase is activated by
    phosphorylation.
  • In this case, the active glycogen synthase a
    (active) form is dephosphorylated and favors the
    R state, whereas, the inactive glycogen synthase
    b form is phosphorylated and favors the T state.
  • The a form is always the active form glycogen
    phosphorylase a is phosphorylated, whereas,
    glycogen synthase a is dephosphorylated.

23
Regulation of Glycogen Synthase Activity
  • Hormone activation of glycogen synthase activity
    is mediated by insulin, which promotes the
    activation of glycogen synthase by stimulating
    PP-1 activity. Epinephrine and glucagon signaling
    leads to inactivation of glycogen synthase.

24
Reciprocal regulation of glycogen metabolism
Since glycogen phosphorylase and glycogen
synthase have opposing effects on glycogen
metabolism, it is critical that their activities
be reciprocally regulated to avoid futile cycling
and to efficiently control glucose-6P
concentrations within the cell.
What is the metabolic logic of glucose inhibition
of glycogen phosphorylase activity and activation
of glycogen synthase?
25
Hormone signaling in liver cells
  • Net phosphorylation drives glycogen degradation,
    and net dephosphorylation drives glycogen
    synthesis.

26
Glucagon signaling
  • cAMP triggers two types of phosphorylation
    circuits in muscle cells one that stimulates
    glycogen degradation and a second that inhibits
    glycogen synthesis.

27
Insulin signaling
  • Insulin signaling results in dephosphorylation of
    glycogen metabolizing enzymes and elevated rates
    of glycogen synthesis.

28
Human glycogen storage diseases
A number of human diseases have been identified
that affect glycogen metabolism. Disease symptoms
in many cases include liver dysfunction due to
excess glycogen fasting-induced hypoglycemia (low
blood glucose levels) in the most severe
diseases, death at an early age.
29
Human glycogen storage diseases
von Gierke's disease is due to a deficiency in
the enzyme glucose-6-phosphatase which causes a
build-up of glycogen in the liver because
glucose-6P accumulates and activates glycogen
synthase. McArdle's disease harbor defects in
muscle glycogen phosphorylase. These individuals
suffer from exercise-induced muscle pain due to
their inability to degrade muscle glycogen.
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