Out line for Lect 34 Glycogen Metabolism
I used the “suggested study points” that Dr Peffley sent out to sort of frame this outline
Introduction: Why Glycogen?
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Humans consume about 160 g of glucose per day, but the blood carries only about 20 g
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75% of glucose is used by the brain
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Most tissues, including liver and muscle, preferentially use fatty acids as their energy source
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After a meal, excess glucose is stored as glycogen in muscle (340g) and liver
(120g). Further glucose is converted to FAT in the liver and stored as TG in adipose tissue
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Between meals, liver glycogen is hydrolyzed to glucose to be released into the bloodstream to maintain blood
glucose.
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Only liver can do this because it contains glucose 6-phosphatase
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Cleaves the phosphate group off of G-6-P to make free glucose
Glycogen versus Fatty Acids
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liver contains about an 18-24 hour supply of glucose
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By 30 hours it’s totally gone.
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muscle glycogen is hydrolyzed to provide glucose 6-phosphate for anaerobic glycolysis
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Why is glycogen used as a store in addition to TGs?
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Muscle metabolizes glycogen much more rapidly than fatty acids
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Fatty acids are not metabolized under anaerobic conditions
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Acetyl CoA (produced by FA breakdown) cannot be converted to glucose
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free energy of reaction of Acetyl CoA to Pyruvate too largely positive
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High acetyl CoA negative modulator for PDH
Know the general structure of glycogen
Structure of glycogen
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Branched glucose polysaccharide
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glucosyl units linked by α-1,4 glycosidic bonds with α-1,6 branches every 8-10 residues
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present in all tissues as very high molecular weight polymers (107 – 108 g/mol)
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collected together in glycogen particles
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One glucose unit, located at the reducing end of each glycogen molecule, is attached to glycogenin protein
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Other ends of chains are non-reducing ends – where addition and release of glucose residues occur
Branched structure allows for:
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tight packing of glucose
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rapid degradation and rapid synthesis
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enzymes can work on several branches at the same time
enzymes involved in synthesis and degradation and some regulatory enzymes are bound to surface of glycogen
particles
Describe steps in synthesis of glycogen and degradation of glycogen (glycogenolysis)
Glycogen Synthesis
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Glucose is phosphorylated to glucose 6-phosphate by hexokinase
(glucokinase in liver) as it enters the cell
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Glucose 6-phosphate is converted to glucose 1-phosphate
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Traps glucose inside cell
in preparation for attachment to glycogen
Glucose 1-phosphate must be activated first: UTP is utilized
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Phosphate on glucose position 1 attaches to the α phosphate on
UTP, displacing PPi, results in UDP-glucose = activated glucose
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Energy for UDP-glucose formation from hydrolysis of PPi
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UDP-glucose is also a precursor for other pathways
Attaching Glucose
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The anomeric carbon of glucose on UDP-glucose forms an α-1,4
linkage with carbon C-4 on the glucose at the non-reducing end of
the glycogen chain,
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displaces UDP and increases the chain length.
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When the chain is about 11 residues long, a 6-8 residue piece is cleaved from the end of the chain and
reattached to a glucosyl unit by an α-1,6 bond, forming a branch point.
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Each branch is lengthened until they are cleaved to form new branches, etc.
Know differences between glycogen break down in liver and muscle
Glycogen: a reservoir of glucosyl units for ATP generation from glycolysis
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Glycogen is degraded to glucose 1-phosphate, which is converted to
glucose 6-phosphate
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Liver: dephosphorylates glucose 6-phosphate to free glucose and
sends the free glucose out into the blood – blood sugar regulation
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Skeletal muscle: glycogen important fuel source when ATP demands
are high and when glucose 6-phosphate levels are low due to
anaerobic glycolysis
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Other tissues: low amount of glycogen makes it an emergency reserve
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E.g., Absence of oxygen or restricted blood flow
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Liver and Muscle are the two big users of glycogen
Glycogen Breakdown in Liver - Degradation
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Key players: Glycogen phosphorylase and the debrancher enzyme
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Glycogen phosphorylase cleaves a single glucose units by
transferring a phosphate from ATP to the anomeric carbon of the
glucose, breaking the α-1,4 glycosidic linkage.
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Glycogen breakdown is a phosphorhylase reaction where
breaking of a bond uses a phosphate ion as a nucleophile)
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Releases glucose 1-phosphate, which is converted to glucose 6phosphate by phosphoglucosemutase: this then enters a
variety of pathways
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In liver, glucose 6-phosphate is dephosphorylated by glucose 6phosphatase and transported out of the cell by Glucose is
transported out of a cell by a bi-directional GLUT transporter
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Note: only happens in the liver, which regulates blood
glucose levels
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Glycogen phosphorylase can’t act on glycosidic bonds of the four
glucoses adjacent to a branch – the branch does not fit properly into
the active site.
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Debrancher enzyme has two activities to handle branch points:
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4:4 transferase activity - a three glucose unit is removed from the 4 glucoses at the branch point, and it
is attached to the end of a longer straight chain by an α-1,4 glycosidic bond (glycogen phosphorylase
operates on this)
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1,6-glucosidase activity – the single remaining glucose residue of the branch attached by the α-1,6
linkage is cleaved forming free
glucose.
Yield of glucose at the branch point:
1 glucose and 7-9 glucose 1phosphate residues
Glycogen breakdown in Muscles: Exercise
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Muscles use lots of ATP, need lots of energy
to keep ATP production going.
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ATP  ADP which is converted to AMP by
adenlyate kinase. AMP is the signal for
mobilization of glycogen stores.
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Regulation of Glycogen Phosphorylase in Muscle
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Two major signals control glycogen phosphorylase activity:
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AMP, which is produced by muscle metabolism
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Phosphorylation, which is stimulated by hormone binding
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The presence of AMP makes the inactive form of glycogen phosphorylase (phosphorylase b) more
active w/o phosphorylation.
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phopshorylation of phosphorylase to “a” form increases activity even more.
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The muscle isoform of glycogen phosphorylase is unique in that AMP is it’s an allosteric activator.
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Both AMP and phosphorylation affect glycogen phosphorylase during exercise.
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Calmodulin activates phosphorylase kinase, which activates glycogen phosphorylase itself.
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As AMP levels rise, this signals the need for more ATP, hence glucose, resulting in increased enzyme
activity.
Calmodulin is activated by high Ca2+ levels in the cell.
Muscle: Glycogen to Glycolysis
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Glycogen is broken down to glucose 1-phosphate by (glycogen phosphorylase) which is converted to glucose
6-phosphate
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Skeletal muscle does not have glucose 6-phosphatase, so it can’t generate free glucose that can enter the
blood stream
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Rather, glucose 6-phosphate enters the glycolytic pathway to make ATP within the muscle cell.
Lysosomal Degradation of Glycogen
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Glycogen particles can become trapped in transport vesicles that fuse with lysosomes
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break down substances to base units – does not to make metabolic intermediates that intersect key
pathways
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Specific enzyme, lysosomal glucosidase, hydrolyzes glycogen to glucose
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type II glycogen storage disease: genetic defect in lysosomal glucosidase
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prevents it from functioning
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glycogen particles build up in vesicles
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disrupts heart and liver function.
Explain the consequences of defects in glycogen metabolism
Disorders of Glycogen Metabolism
Explain the regulation of glycogen degradation and synthese– hormonal regulation
Regulation of Glycogen Breakdown and Synthesis
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Glycogen Metabolism is Regulated by Insulin and Glucagon
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Glucagon signals the fasting state – stimulates glycogen breakdown
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Glycogen phosphorylase is phosphorylated by cAMP-dependent PKA
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Glucagon (only acts on liver cells) stimulates PKA, which phosphorylates both enzymes.
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Glycogen phosphorylase turns “ON”
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Glycogen synthase turns “OFF”
Insulin signals the high glucose state – stimulates glycogen synthesis
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Insulin activates phosphatases, which reverse the phosphorylation effects.
Regulation of Liver and Muscle Glycogen Stores
Explain epinephrine-mediated regulation of glycogen degradation
Epinephrine also Binds to α-Receptors in the Liver(and muscles too): Fight or Flight
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Epinephrine binding to the a-receptors transmits a signal via G proteins to phospholipase c, which hydrolyzes
PIP2 to DAG and IP3
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IP3 stimulates release of Ca2+ from the ER
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Ca2+ binds to the modifier protein calmodulin, which activates calmodulin-dependent protein kinase and
phosphorylase kinase – Both Ca2+ and DAG activate protein kinase C
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These three kinases phosphorylate glycogen synthsase at different sites and decrease its activity
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Phosphorylase kinase phosphorylates glycogen phosphorylase b to the active form and thus activates
glycogenolysis as well as inhibiting glycogen synthesis.
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Turns off glycogen synthesis, so glucose stays in a free form for tissue utilization