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Glycogen
- storage form of glucose
- found in skeletal muscle and liver
- readily mobilized fuel source
- branched, held together by a -1,4 and a - 1,6
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Glucose Homeostasis
 - I - immediately after meal
- III - 4 hours post meal
- IV - 16 hours post meal
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Glycogen Storage Diseases - McArdle's Disease
- strenuous activity produces painful cramps and myoglobinuria (myoglobin in urine i.e. breaking down your muscles)
- -->activity produces no increase in blood lactate levels
- biochemical analysis:
- -->high muscle glycogen - patients can make glycogen but cannot mobilize it
- -->decreased levels of muscle glycogen phosphorylase (which breaks glycogen down)
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Glycogen Storage Diseases - Type O Glycogen Storage Disease
- Morning drowsiness, fatigue, convulsions due to hypoglycemia
- -->high levels of blood glucose and lactase after meals
- biochemical analysis:
- -->liver deficient in glycogen
- -->lack of glycogen synthetase
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The glycogen storage diseases indicated what?
- synthesis (anabolic) and degradative (catabolic) pathways are independent
- pathways must be coordinately regulated
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Glycogenolysis
- glycogen degradation
- 3 enzymes
- --> glycogen phosphorylase
- --> glycogen debranching enzyme
- --> phosphoglucomutase
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Glycogen Phosphorylase
- uses phosphate to break a bond
- reaction: glycogen (n) + Pi --> glycogen (n-1) + glucose -1-phosphate
- phosphorylysis: phosphate (not water) breaks glycosidic bond
- rate determining step of glycogenolysis
- removes only glucose with a-1,4 bonds, only within 4-5 glucose units of branch point (if too close to a branch can't access the access site)
- requires pyrodoxial phosphate(PLP) covalently bound to enzyme (prosthetic group)
- -- facilitates acid base catalysis
- -- PLP derived from vitamin B6
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Glycogen debranching enzyme
- one enzyme with 2 activities
- a-1,4 transglycolase: transfer of a-1,4 trisaccharide to non-reducing end of glycogen (move the branch to the chain so phosphorylase can break it down)
- a - 1,6: glycosidase: removes a-1,6 bound glucose at branch point, hydrolysis reaction
- only reaction that directly makes glucose from glycogen
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phosphoglucomutase
- isomerase
- catalyzes reversible conversion of glucose-1-P to glucose-6-P
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glucose-6-phosphatase
- strips phosphate so that you get glucose ready for transport
- glucose-6-P cannot be transported out of cells, glucose can
- also involved in gluconeogenesis
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Glycogenesis
- glycogen synthesis
- reaction: glycogen (n) +UDP-glucose --> glycogen (n+1) +UDP
- 3 enzymes:
- -->UDP - glucose pyrophosphorylase
- -->glycogen synthase
- -->glycogen branching enzyme
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UDP - pyrophosphorylase
- reaction: ????
- substrate is glucose-1-P is NOT glucose
- --same molecule released by glycogen phosphorylase
- transfer of glucose to UDP has delta G ~ 0
- --reaction driven by hydrolysis of PPi: PPi --> 2 Pi (delta G << 0)
- common strategy to drive unfavorable reactions
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Glycogen Synthase
- can only extend an existing glycogen chain
- can only make a-1,4 linkages
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glycogen branching enzyme
- makes a-1,6 bond
- transfers 7 glucose unit chain to C6 hydroxyl every 8-12 glucose molecules
- increases number of reactive ends
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glycogenin
- autoglycosylating enzyme (can stick glucose on itself)
- contains oligosaccharide on Tyr residue
- makes primers for glycogen synthase
- provides scaffold
- also has synthase activity
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Steps to make a new glycogen molecule (5 total)
- 1. attach glucose to glycogenin (Tyr residue)
- 2. glycogenin complexes with glycogen synthase
- 3. glycogenin-synthase adds up to 7 more glucose residues
- 4. glycogen synthase takes over once chain is >= 8 residues long
- 5. glycogenin dissociates from synthase but remains bound to reducing end of glycogen molecule
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Regulation of glycogen metabolism
- challenge to controlling glycogen flux
- allosteric regulation of rate determining step of both pathways
- --glycogen phoshporylase
- --glycogen synthase
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glycogen phosphorylase
- dimer of identical subunits
- --2 catalytic sites
- --2 allosteric sites
- two conformations
- --T (less active) : buried active site, low substrate affinity
- --R (more active): accesible active site, high substrate affinity
- allosteric modulators
- --activator: AMP
- --inhibitor: ATP, glucose-6-P, glucose
- AMP binds to allosteric site in T state (promotes T to R)
- inhibitors bind allosteric site in T state (prevent T to R)
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