Glycogen Metabolism I Flashcards
What is the structure of glycogen?
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
What does glycogenin do?
it make a primer to start the formation of glycogen
it utilizes Manganese in its complex
Where is glycogen stored?
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
True or false, the brain is very dependent on glucose.
True
_____ is used to _______ blood ______ levels.
Liver, maintain, glucose
_____ is used to generate ______ in _____.
Glucose, energy, muscles
What are the functions of glycogen?
–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
Explain glycogen metabolism.
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
List the steps in glycogenolysis.
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
List the four key enzymes of glycogenolysis.
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
Chain shortening
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.
Branch transfer and release of glucose
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
phosphoglucomutase
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.
glucose 6-phosphatase
Gluc-6-phosphate cannot get out of the cell
Only the liver has glucose 6-phosphatase
Converts it to glucose
Regulation of GP
GP regulated by:
several allosteric effectors (signal energy state of the cell)
reversible phosphorylation (responsive to hormones)
What forms does GP exist in?
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
Allosteric Regulation of Liver GP
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)
Allosteric Regulation of Muscle GP
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
What role does phosphorylation play?
Phosphorylation of a single serine residue converts b to a.
Conversion initiated by hormones
Phosphorylation carried out by phosphorylase kinase
(PK)
Hormonal Control of GP
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
What is the off-switch?
Shuts down when secretion of hormone stops
PK and GP are dephosphorylated and inactivated
Breakdown of glycogen stops
Synthesis of glycogen promoted
Liver vs Muscle Glycogen Phosphorylase
• 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
GPCR-mediated cascade
Glucagon and Epinephrine work through GPCR - do not cross membrane like steroid hormones
Glucagon and Epinephrine signal glycogen breakdown