Biochem Muscle Weakness Glycogen
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descriptive name for glycogen
structure of glycogen (bonds) -
branched chain homopolysaccharide made from alpha-D-gluc
alpha 1,4 glycosidic linkages
alpha 1,6 about every 8-10 glucose units - where is glycogen stored
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cytoplasm in large hydrated granules, each containing ~100,000 gluc units
primarily in liver and muscles - is more glycogen stored in muscle or liver
- total glycogen stored in muscle (because there is so much more muscle) is three times that of liver, even though liver has higher concentrations of glycogen
- why not store glucose in fat? or as free glucose?
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cannot convrt fat back to glucose, only glucose to fat
free glucose is osmotically active so need glycogen - how does the function of glycogen differ in liver and muscle?
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liver maintains blod glu
muscles supply fuel reserve - where is glycogen utilized
- 75% brain, the rest is erythrocytes skeletal and heart muscles
- how long does the glycogen supply last in the liver
- less than 24 hours
- what is gluconeogenesis and why would you need glycogen if you have this pathway?
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- the synthesis of glu from small molecules like aa (happens in liver)
is much SLOWER, need fast release hence glycogen - muscles and glycogen, why doesnt glucose diffuse out of muscles when it is made from muscle glycogen?
- muscles lack Glucose-6-phosphatase and therefore glucose found in muscles is in the G-6-P form that doesnt diffuse out of cells.
- Four broad steps of glycogen synthesis
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synthesis if UDP glucose
adding of primer
elongation
branching - explain biochemical process of glycogen synthesis
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glucose is taken up into the cell and phosphorylated by hexokinase (glucokinase in liver)
G-6-P is then mutated to G-1-P via phosphoglucomutase
G-1-P is converted to UDP-gluc using UTP
via uridylyltransferase or UDPGLc pyrophosphorylase -
explain biochemical process of glycogen synthesis continued
use specific aa sites -
UDP-glucose is attached to glycogenin at OH of tyr 194 via autoglucosylation
glycogenin has a glucosyltransferase activity (note: udp is kicked out in the reaction) - explain biochemical process of glycogen synthesis continued
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elongation
new glycosidic bond formed between incoming(activated) C1 OH and the accepting C4
via glycogen synthase
adds three at a time
alpha 1,4 glycosidic linkage - what is special about glycogen synthase?
- it is rate limiting and regulated
- is glycogen synthase's Km for small glycogen molecules large or small
- it's large(ie low affinity)
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glycogen branching
enz? - glucosyl 4:6 transferase
- how does glucosyl 4:6 transferase work
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transfers 6-8 gluc residues from end of chain to another residue forming an alpha 1,6 bond
hence its 4:6 b/c it breaks an alpha 1,4 bond and makes an alpha 1,6 bond - is glucose added to the reducing or nonreducing end of a chain?
- non reducing
- why branch?
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increases glycogen solubility
increases nonreducing ends to which glucosyl residues can be added - describe glycogenolysis
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glycogen phosphorylase uses Pi to cleave alpha 1,4, requires PLP (B6 derivative)as coenz
debranching enzyme: 4-alpha-D-glucotransferase, removes outer 3 of limit dextrin and attaches to a nonreducing end, amylo-alpha1,6,glucosidase cleaves last glucose - decribe the debranching enzyme and the two catalytic sites (bifunctional)
- debranching enzyme: 4-alpha-D-glucotransferase, removes outer 3 of limit dextrin and attaches to a nonreducing end, amylo-alpha1,6,glucosidase cleaves last glucose usig water
- whats the ratio of glucoses released from phosphorylase to debranching enz
- 12:1
- how else can you degrade glycogen?
- lysosomal glycogen degradation 1-3%
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REGULATION
glycogen phosphorylase is active or inactive when phosphorylated -
active when phosphorylated
a form active
b form inactive -
what activates glycogen phosphorylase
what inactivates it -
activated via phosphorylase kinase using ATP
inactivated using phosphoprotein phosphatase -
REGULATION of phosphorylase kinase
what regulates the regulator -
phosphorylated is active
phos'd by protein kinase A
dephos'd by phosphoprotein phosphatase - glycogen phosphorylase chemical characteristics
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allosteric
T and R states,
a is active b/c P shifts equilibrium to R state - how is PKA . . released from regulatory sites
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H activates Gprotein receptor causes formation of cAMP
cAMP binds regulatory sites on PKA and releases catalytic portion - what does PKA inhibit and how
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phosphoprotein phostphatase
it P's protein phosphatase inhibitor activating it so that protein phosphatase cant change things back into their inactive forms - PKA activates phosphorylase kinase which activates glycogen phosphatase releasing glucose
- jkh
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PKA inhibits phosphoprotein phosphatase by activating it's inhibitor(protein phosphatase inhibitor) so that
glycogen phosphorylase isnt turned off - lkb
- summary of cAMP activation
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inhibits synyhesis (glycogenesis)
increases catabolism (glycogenolysis) - cAMP
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activates glycogen phosphorylase kinase and therefore glycogen phosphorylase
inactivates glycogen synthase (because glycogen phosphorylase kinase is activated)
activates protein phosphatase inhibitor - is glycogen synthase active or inactive when p'd
- inactive
- synthesis vs catabolism and phosphorylation
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synthesis is inactive when p'd
catab is active when p'd - Insulin and glycogen synthesis
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maybe:
inhibition of protein kinases,
activation of phosphoprotein phosphatase
glycogen synthase is de P'd (active)
phosphorylase kinase and phosphorylase are de P'd (inactive) - what are allosteric effectors?
- bind enz regulatory site to promote R or T state
- what is the effector of phophorylase kinase b (catab)
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Ca, will activate this even though it's dephosed
binds delta subunit, conf change activates gamma - what is the effector of phosphorylase b
- AMP, activates it, in muscles
- effector of phosphorylase a
- glucose, inhibits it , only hepatic
- effector of synthase b
- G-6-P, activates, in both liver and muscle
- how does Ca activate glycogenolysis in liver?
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Ca increased in liver due to epi binding alpha-adrenergic receptors
this activates phospholipase C generating IP3 and DAG
IP3 causes Ca release in cytosol which activates glycogenolysis - AMP to ATP ratio, if increased reflects what?
- low energy
- AMP is an allosteric effector of?
- phosphorylase b, activates
- high amp to atp ratio means what
- activation of catabolism