Glycogen Metabolism I Flashcards

1
Q

What is the structure of glycogen?

A

Osmotically inactive and readily mobilized form of glucose
 Branched long chain homopolymer of glucose molecules
 12 layers of glucose with approx. 55,000 glucose residues
 Linked together via α-1,4 glycosidic bonds
 Branch points every 12 residues formed via α-1,6
glycosidic bonds between glucose monomers of
separate chains
 Non-reducing ends each contain a terminal glucose
with a free hydroxyl group at C4
 Reducing end has glucose monomer connected to a
protein called glycogenin
 Glycogenin helps to make a primer which is crucial for glycogen synthesis

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2
Q

What does glycogenin do?

A

it make a primer to start the formation of glycogen

it utilizes Manganese in its complex

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3
Q

Where is glycogen stored?

A

Stored in liver, muscle, and other tissues
• Present as granules which not only contain glycogen
but also the enzymes needed for its metabolism
• Defects in these enzymes can lead to disorders

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4
Q

True or false, the brain is very dependent on glucose.

A

True

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5
Q

_____ is used to _______ blood ______ levels.

A

Liver, maintain, glucose

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6
Q

_____ is used to generate ______ in _____.

A

Glucose, energy, muscles

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7
Q

What are the functions of glycogen?

A
–Liver glycogen regulates overall blood
glucose levels
–Maintains blood glucose levels for
brain
–Muscle glycogen provides reservoir of
fuel (glucose) for physical activity for
muscles
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8
Q

Explain glycogen metabolism.

A
Regulated storage and release of glucose
 Synthesis and degradation of glycogen involve
different pathways
 Both pathways regulated independently
 Regulation
 Allosteric control
 Covalent modification through reversible
phosphorylation of key enzymes
 Hormonal control
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9
Q

List the steps in glycogenolysis.

A

Release of glucose-1-phosphate from glycogen
 Remodeling of glycogen remnant to permit further
degradation
 Conversion of glucose -1-phosphate to glucose -6-
phosphate
 Glycolysis
 Free glucose for release into blood stream
 Pentose phosphate pathway – NADPH and ribose derivative

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10
Q

List the four key enzymes of glycogenolysis.

A
 one to degrade glycogen (chain
shortening)
       - glycogen phosphorylase
 two to remodel glycogen remnants
        - transferase
        - alpha-1,6-glucosidase
 one to convert glycogen breakdown
product suitable for further metabolism
        - phosphoglucomutase
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11
Q

Chain shortening

A

Glycogen phosphorylase (GP) (rate limiting enzyme)
catalyzes the cleavage of glycogen.
 Chain shortening occurs at the non-reducing end of the
polymer
 GP adds an orthophosphate and releases a glucose residue as glucose-1-phosphate
 Uses pyridoxal phosphate (vitamin B6) as a cofactor
 Phosphorolysis of glucose residues continues till the GP gets within 4 residues of the α-1,6 linkage of a branch point.

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12
Q

Branch transfer and release of glucose

A

Transferase transfers a block of 3 of the remaining 4
glucose to the non-reducing end of the main chain forming an α-1,4 bond.
 Debranching enzyme or α-1,6 glucosidase cleaves the α-1,6 bond of the single remaining glucose residue to release the free glucose.
 Glucose phosphorylated by hexokinase
 Transferase and α-1,6 glucosidase convert branched
glycogen into a linear structure for further action by GP

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13
Q

phosphoglucomutase

A

Converts Gluc-1-phosphate to Gluc-6-phosphate
 A phosphoryl group is transferred from the enzyme to the substrate, and a different phosphoryl group is transferred back to restore the enzyme to its initial state.

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14
Q

glucose 6-phosphatase

A

Gluc-6-phosphate cannot get out of the cell
 Only the liver has glucose 6-phosphatase
 Converts it to glucose

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15
Q

Regulation of GP

A

GP regulated by:
 several allosteric effectors (signal energy state of the cell)
 reversible phosphorylation (responsive to hormones)

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16
Q

What forms does GP exist in?

A

 Exists in 2 forms:
 Active “a” form (R relaxed state) – in liver
 Inactive “b” form (T tense state) – in muscle
 Both isozymes exist in equilibrium between R and T

17
Q

Allosteric Regulation of Liver GP

A

 Default “a” form or active form
 Inactivated by glucose
 Glucose binds to active site and stabilizes conformation in the inactive T state
 When glucose levels high, no need for glycogen
breakdown (which will make more glucose)

18
Q

Allosteric Regulation of Muscle GP

A

Default “b” form or inactive form
 Activated by AMP
 Binds to active site and stabilizes conformation of b in the active R state
 During muscle contraction ATP converted to AMP by
myosin and adenylate kinase signaling the GP to
breakdown glycogen
 ATP and Gluc-6-phosphate are negative allosteric
regulators
 Under normal physiological conditions GP inactive
because of inhibitory effect of ATP and Gluc-6-phosphate

19
Q

What role does phosphorylation play?

A

Phosphorylation of a single serine residue converts b to a.
 Conversion initiated by hormones
 Phosphorylation carried out by phosphorylase kinase
(PK)

20
Q

Hormonal Control of GP

A

 Muscle activity releases epinephrine (effects are on
muscle)
 Low blood sugar levels release glucagon (acts on liver)
 Effects of both hormones mediated via G protein coupled receptors (GPCR)
 Epinephrine and glucagon signal glycogen
breakdown

21
Q

What is the off-switch?

A

 Shuts down when secretion of hormone stops
 PK and GP are dephosphorylated and inactivated
 Breakdown of glycogen stops
 Synthesis of glycogen promoted

22
Q

Liver vs Muscle Glycogen Phosphorylase

A

• Liver and muscle forms of GP are products of separate
genes. Called isozymes.
• Differ in their sensitivities to regulatory molecules.
• Both forms activated by phosphorylation by PK and
inhibited by ATP and G6P.
• Muscle form is allosterically activated by AMP
(measure of low energy status of cell)
• Liver enzyme is inactivated by free glucose (indicator of
blood sugar levels). Unaffected by AMP.
• Mutation in liver GP results in Hers disease
• Mutation in muscle GP causes McArdle syndrome

23
Q

GPCR-mediated cascade

A

Glucagon and Epinephrine work through GPCR - do not cross membrane like steroid hormones

Glucagon and Epinephrine signal glycogen breakdown