Term
| benefit of glycogen as fuel versus more reduced fatty acid |
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Definition
- readily mobilizable glucose units for sudden, strenuous activity
- can be used as fuel in anaerobic conditions |
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Term
| major sites of glycogen storage |
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Definition
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Term
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Definition
| cytoplasmic glycogen storage unit |
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Term
| fate of Glucose 6-phosphate in the muscle and brain |
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Definition
| undergo glycolysis followed by either lactic acid fermentation or ox phos |
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Term
| fate of Glucose 6-phosphate in the liver |
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Definition
- glycogen is not major fuel source
- converted into glucose and released into bloodstream for other tissues
- pentose phosphate pathway released Ribose and NADPH |
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Term
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Definition
key point of control of glycogen breakdown
- performs phosphorolysis on nonreducing end until fourth glycosyl from branch point
- converts α-1,4 glycosidic bond into and G1P α phosphoryl ester
- phosphate source is orthophosphate
- coenzyme is pyridoxial phosphate |
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Term
| structure of glycogen phosphorylase |
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Definition
- homodimer
- amino terminal = glycogen binding site
- active site = deep crevice
- coenzyme = PLP, pyridoxal phosphate
- PLP has Schiff-base linkage with the ε-amino of an active site Lys residue |
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Term
| mechanism of glycogen phosphorylase action |
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Definition
- phosphorolysis NOT hydrolysis: water is blocked from the active site
- 2 step (retained steriochemistry at C1) with C+ (carbocation intermediate)
- pyridoxal phospahate acts as acid-base catalyst donating-taking proton from orthophosphate
- Processive: enzyme bound to glycogen can perform multiple reactions without release of glycogen |
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Term
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Definition
| shifts block of 3 glycosyl residues from one outer branch to another outer branch leaving only a residue with a C6 glycosidic bond |
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Term
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Definition
"debranching enzyme"
- hydrolyzes α-1,6- glycosidic bonds
- reactants = glycogen and H20
- product = free glucose and glycogen (n-1) |
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Term
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Definition
- phosphoenzyme: has phosphorylated Ser residue at active site
- converts G1P to G6P in two steps
- intermediate = Glucose-1,6-bisphosphate
- reminiscent of phosphoglycerate mutase
- used in galactose metabolism |
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Term
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Definition
- enzyme of liver, absent in muscle
- hydrolyzes G6P to free glucose and orthophosphate
- transmembrane protein of ER and catalyzes on lumenal side of ER
- associated with 3 transport proteins and a stabilizing protein |
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Term
| Default conformation of Muscle Phosphorylase |
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Definition
| - usually inactive phosphorylase b (equilibrium favors T state) |
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Term
| Allosteric effectors of Muscle phosphorylase b |
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Definition
Energy Charge:
- activated by AMP (low energy charge)
- AMP competitively inhibited by ATP (high energy charge)
Feedback Inhibition
- G6P stabilizes T state |
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Term
| Allosteric effectors of Muscle phosphorylase a |
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Definition
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Term
| Reversible covalent modification of Muscle phosphorylase a |
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Definition
Hormonal control
- Epi leads to phosphorylated Ser in each phosphorylase subunit |
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Term
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Definition
- covalently modifies glycogen phosphorylase b to turn it into phosphorylase a
- modification triggers conformational changes that move blocking loops out of each active site |
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Term
| Default conformation of Liver Phosphorylase |
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Definition
usually active phosphorylase A
- equilibrium favors R state
- phosphorylase A = very sensitive glucose sensor of liver; can rapidly promote R/T shifts |
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Term
| Allosteric effectors of Liver phosphorylase a |
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Definition
Glucose
- binds to each subunit and stabilizes T state of A
- Glucose binding and T state stabilization trigger release PP1 that was bound to R state of A
- Free PP1 then promotes conversion of phosphorylase A to phosyphorylase B (ie stops breakdown and starts synthesis)
Energy Charge?
- NO: liver isozyme insensitive to AMP |
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Term
| Phosphorylase Kinase composition |
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Definition
(αβγδ)₄
γ = catalytic
all others = regulatory; δ = Calmodulin
PKA = phosphorylates αβ (uses 4 ATP) to make it partially active
Ca++ = binds δ (uses 4 Ca++) to make it partially active
PKA + Ca++ = Fully active phosphorylase kinase |
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Term
| Protein Kinase A activation |
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Definition
Epi - acts on β-adrenergic 7 TM Receptor
Glucagon - acts on glucagon 7 TM Receptor
Muscle: stimulated by Epi
Liver: stimulated by Glucagon (mostly) and Epi |
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Term
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Definition
"fight or flight" state
- stimulated by (anticipated) muscle activity
- secreted by adrenal medulla
- tyrosine-derivative |
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Term
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Definition
"starvation" state
- stimulated by low blood glucose
- secreted by α-cells of pancreas |
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Term
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Definition
Epi binding α-adrenergic 7 TM receptor
- initiation of phosphoinositide cascade |
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Term
| how to rapidly shut off glycogen breakdown |
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Definition
- removal of hormone
- GTPase
- phosphodiesterase
- PP1: protein phosphatase 1 |
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Term
| Protein Phosphatase 1/PP1 |
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Definition
Stabilize Glycogen Phosphorylase B
- hydrolyze 2 P's from glycogen phosphorylase a
Decrease acitivity of phosphorylase kinase
- hydrolyze 4 P's from phosphorylase kinase
Structure
- catalytic subunit
- regulatory subunit: 3 domains act as scoffolding to bring reactants together (catalytic subunit-binding, glycogen-binding, and target enzyme-binding subunits)
- GM and GL are tissue-specific isozymes of the regulatory subunit |
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Term
| Active glucose form in glycogen synthesis |
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Definition
UDP-Glucose
- α phosphoester linkage at C1
- formed by UDP-Glucose Pyrophosphorylase (G1P + UTP -> UDP-Glc + PPi)
- PPi hydrolysis drive reaction to the right |
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Term
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Definition
- Key control point in glycogen synthesis
- adds glycosyl to nonreducing end
- requires Glycogenin primer of at least 5 units |
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Term
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Definition
- a glycosyltransferase homodimer
- core of glycogen granule
- each subunit adds α-1,4 glucose polymers to the other subnit (autoglycosylation)
- site of initial attachment is Tyr phenol
- uses activated UDP-glucose |
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Term
| Branching enzyme of glycogen synthesis |
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Definition
- form α-1,6 glycosidic bond
- cleaves about 7 terminal residues from linear polymer at least 11 units long
- branch points at least 4 units from each other |
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Term
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Definition
- increased glycogen solubility
- increased rate of glycogen metabolism: lots terminal residues = lots of sites of activity for glycogen phosphorylase and glycogen synthase |
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Term
| Covalent Modification of Glycogen Synthase |
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Definition
PKA and GSK (glycogen synthase kinase)
- phosphorylation stabilizes glycogen synthase B (turns OFF glycogen synthesis!)
- effect of Epi and glucagon
PP1
- dephosphorylation stabilizes glycogen synthase A (turns ON glycogen synthesis!)
- effect of increased blood glucose
(Ins doesn't covalently modify glycogen synthase but DOES covalently modify GSK to shut it off thereby helping PP1) |
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Term
| Allosteric effectors of Glycogen Synthase B |
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Definition
| - it takes HIGH levels of G6P to stabilize the R state of glycogen synthase B |
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Term
| Allosteric effectors of Glycogen Synthase A |
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Definition
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Term
| Reciprocal regulation of glycogen degradation and synthesis |
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Definition
PKA is common to both pathways
- Active PKA is signal for glycogen breakdown (stabilize phorphorylase A = ON, stabilize glycogen synthase B = OFF)
PP1 is common to both pathways
- active PP1 is signal for glycogen synthesis (stabilize phosphorylase B = OFF, stabilize gycogen synthase A = ON) |
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Term
| what happens when exercise is over |
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Definition
- Must switch from glycogen breakdown to synthesis
- PP1 first inactivates glycogen phosphorylase a and phosphorylase kinase
do slow breakdown
- PP1 then inactivates glycogen synthase b to increase synthesis |
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Term
| what happens during exercise |
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Definition
- must maintain glycogen breakdown
- Epi and Glucagon activate PKA
- PKA inhibits PP1: First phosphorylate regulatory subunit GM (catalytic subunit is released making it less active), Second phosphorylate inhibitors of catalytic subunit(bind to catalytic subunit making it inactive) |
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Term
| what happens after eating |
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Definition
elevated blood glucose triggers Ins release
- promote glycogen synthesis by inactivating GSK (ie phosphorylating it through some protein kinase)
liver phosphorylase A senses increased blood glucose
- glucose stabilizes T state
- PP1 released from T state and becomes active
- PP1 first slows down glycogen breakdown (through stabilizing phosphorylase B = inactive)
- PP1 then increases glycogen synthesis (through stabilizing glycogen synthase A = active)
- "Lag" is how long between phosphorylase A inactivation and synthase A activation. Prevents pathways from running at the same time.
(muscle phosphorylase A is insensitive to blood glucose) |
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Term
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Definition
- stabilizes glycogen synthase B (phosphorylated inactive form) and promotes glycogen breakdown
- activated by Epi and Glucagon
- inactivated by Ins through protein kinases
- counteracted by PP1 which stabilizes glycogen phosphorylase B (inactive) and glycogen synthase A (active) |
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Term
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Definition
glycogen storage dz
- mutated glucose 6-phosphatase or glucose 6 phosphate transporter
- excess liver glycogen, huge abdomen
- increase liver glycolysis, high blood pyruvate and lactate
- increase fat metabolism |
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Term
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Definition
glycogen storage dz
- mutated α-1,4-glucosidase from lysosome
- engorged lysosome |
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Term
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Definition
glycogen storage dz
- mutated α-1,6-glucosidase debranching enzyme
- stuck with short outer branches = poor glycogen mobilization
- looks like von Gierke |
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Term
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Definition
glycogen storage dz
- mutated Muscle phosphorylase = can't mobilize glycogen
- high level ADP = painful cramps
- reliance on creatine phosphate = alkaline pH
- no lactate accumulation |
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