21: GLYCOGEN METABOLISM Flashcards
1
Q
what is glycogen; where is it stored
A
- storage form of glucose
- easily mobilized (glucose can be quickly released form glycogen)
- in mammals, glycogen is stored in liver and muscle (average well-fed man stores -70g in liver and -200g in all skeletal muscle)
- in liver, glycogen is used to release glu into blood to maintain blood glu levels
- in muscle, glycogen is stored to provide glu for contraction of muscle
2
Q
why also need to store glucose?
A
- some tissues can’t degrade fat
- brain needs glucose; FAs can’t cross blood/brain barrier
- red blood cells need glucose; no mitochondria so can’t degrade FAs
- rapidly contracting muscles; oxidation of fats needs O2 for TCA cycle and ETC but it is anaerobic
3
Q
glycogen structure
A
- glucose @1-4 linked polymer; glycosidic bond
- has @1-6 linked branches (gives molecules lots of ends; important because its where glu is released/added)
- glycogen forms granules in cytoplasm
- if you had such a high [glu] inside cell, then have huge osmotic pressure so better to store more in insoluble form
- protein in centre is glycogenin
4
Q
synthesis of oligosaccharides
A
- needs to use an activated form of the sugar called nucleotide sugars
- in glycogen synthesis, need UDP glucose
5
Q
glycogen synthesis (linear)
A
- UDP glu will be added onto end of glycogen chain that already exists; catalysed by glycogen synthase
- glycogen chain has 2 ends (non reducing C4 and reducing C1); gly. synth catalyses transfer of glu from UDP-glu onto OH of non-reducing C4 end
- UDP is displaced by OH; attack of OH on innermost P on UDP-glu so forms @1-4 glycosidic bond
- glycogen synthase can now act again on new non-red end using another UDP-glu to add another glu
- glycogen synthase requires pre-formed @1-4 linked w/chain with more than 8 residues before it can act
6
Q
glycogen synthesis (branches)
A
- need glycogen branching enzyme glycosyl-4,6-transferase as gly. synth can only catalyse formation of @1-4 linked bonds
- once linear branch is built, can transfer 6/7 terminal residues from non-reducing end of a glycogen chain of 11+ residues to OH of C6 of glu at interior position to form @1-6 glycosidic bond
- creates 2 non-reducing ends for glycogen synthase to act on
7
Q
glycogenin
A
- acts as primer
- has 2 enzyme activities
1. OH of Tyr194 acts as Nu and w/glycosyl transferase activity, glycogenin can react w/UDP-glu (OH attacks it) to form bond between OH and glu, displacing UDP; that gives 1 glu residue attached to Tyr194 on glycogenin
2. chain extending activity; another UDP-glu comes in and forms @1-4 bond to glu on tyr194 - this reaction happens 6x to form 8 residue glu chain before glycogen synthase can act (doesn’t always stop at 8)
8
Q
synthesis of UDP-glucose
A
Glu-1-P + UTP = UDP-glu + Ppi by UDP-glu phosphorylase
-Glu-1-P can be made by:
Glu phosphorylated by hexokinase using ATP; makes Glu-6-P; then have phosphoglucomutase (has phosphorylated ser residue) to convert Glu-1-P
9
Q
glycogen breakdown (linear)
A
- phosphorolytic cleavage using Pi
- glycogen phosphorylase breaks @1-4 glycosidic bond; can remove 1 residue at a time from non-reducing end
- releases a molecule of glu-1-P; conserve some energy of glycosidic bond in formation of phosphate ester
- enzyme uses cofactor called pyridoxal phosphate (from vit B6) where P is involved in acid-base catalysis; promotes attack of Pi on glycosidic bond
- glycogen phosphorylase can act until it gets to 4 residues from branch
10
Q
glycogen breakdown (branches)
A
- need a debranching enzyme; has 2 activities
- with transferase activity it moves block of last 3 residues; breaks @1-4 bond and moves them to new non-reducing end; have remaining glu linked @1-6
- uses @1-6 glucosidase activity to hydrolysed @1-6 bond; adds water to produce free glu
- now have unbranched chain of @1-4 linked residues for further phosphorylation
11
Q
regulation of glycogen phosphorylase by phosphorylation
A
- controls glycogen breakdown
- B form; less active; favours T state
- A form; more active; favours R state
- has key ser residue on each subunit (OH)
- B is phosphorylated by phosphorylase B kinase using ATP to convert to A
- phosphoprotein phosphatase I dephosphorylates =
- phosphorylation stimulated by hormones: activated by glucagon (acts on liver); in muscle, activated by adrenaline; inhibited by insulin in both liver and muscle
12
Q
allosteric regulation of glycogen phosphorylase
A
- signals what happens in individual cell
- muscle responds to ATP; phosphorylase B inhibited by glu-6-P and ATP; only active if AMP is high
- in liver, phosphorylase A acts as a glucose sensor, inhibited by glu (shifts eq. from active R state to less active T state)
13
Q
regulation of glycogen synthase by phosphorylation
A
- responds to hormones (has A and B form)
- dimeric enzyme; has many sites of phosphorylation
- phosphorylated less active B form
- converted to more active A form by dephosphorylation by PPI
- insulin inactivates glycogen synthase kinase 3 (GSK3) which prevents phosphorylation, makes it more active allowing glycogen synthesis to get ride of high blood glucose
- occurs in liver and muscle
-allosteric regulation: glycogen synthase B is activated by glu-6-P
14
Q
how glucagon and adrenaline work
A
- bind to G-protein-coupled receptors
- 7 transmembrane receptor
- glucagon binds in liver
- adrenaline binds in muscle
- G protein is heterotrimeric: @ subunit binds GDP; has ß and y
1. glucagon/adrenaline bind, g protein is activated, exchanges GDP for GTP
2. released to activate adenylate cyclase which converts ATP to cyclic AMP
3. this is second messenger molecule which binds to protein kinase A and activates it (has 4 BS for cAMP)
4. active PKA phosphorylates and activates phosphorylase B kinase
5. starts cascade of phosphorylation
6. phosphorylates/activates glycogen phosphorylase B to A
7. A form acts to convert glycogen to glu-1-P - *active PKA can also phosphorylate glycogen synthase A to less active B form
- at same time glycogen breakdown is on, synthesis is turned off
15
Q
how insulin works in liver and muscle
A
- insulin receptor is a heterodimer joined by disulphide bonds; tyrosine kinase
- when activated, get phosphorylation of intracellular region of receptor; acts on IRS; converted to phosphorylated form and can activate many protein kinases
- some of those, incl. PKA, will act on GSK3 to phosphorylate and inactivate it which in turn activates glycogen synthase
- insulin can activate PPI to dephosphorylate glycogen synthase and make it more active
- insulin does not act through production of cAMP
