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Glucose-6-Phosphate fate in muscle cell

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Glucose-6-Phosphate fate in muscle cell

Postby druid » Fri Oct 20, 2006 5:17 pm

Hi all.

I have a question on Glc6P fate in a muscle cell.
How does a muscle cell decide where to funell the Glc6P: to glycolysis or to
glycogen synthesis?
Raised blood glucose level will cause dephosphorylation of PFK2, PK enabling
glycolysis and glycogen synthase enabling glycogen synthesis. It would be
logical if glycogen synthase were inhibited by AMP/ADP thus giving more chances
to glycolysis before glycogen synthesis at low energy charge. But paradoxally
glycogen synthase is inhibited by ATP!
( http://www.jbc.org/cgi/reprint/268/18/13286 )


What do you say?
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Postby MrMistery » Fri Oct 20, 2006 5:49 pm

well, from what i know, glycogen synthesis in skeletical muscle cells is regulated by hormones.
Insulin causes glycogen synthesis while epinephrin causes glycogen breakdown. i don't know how they act on a cellular level though(my memory sucks). epinephrine, as I remember, functions through a G protein linked receptor on the plasma membrane that initiates a signal transduction pathway. Insulin is a protein hormone, so it also must have a receptor on the plasma membrane. my logic tells me it would also be a G protein(obviously a different one) as it seems the best suited kind of receptor.

But i am sure you can find something about the molecular mechanism of these hormones on the internet easily..
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Postby druid » Fri Oct 20, 2006 7:12 pm

Well, maybe I was not very clear. I know that insuline activates protein phosphatases which dephosphorylates all key enzymes, activating anabolic pathways ;)
My question is how glycolysis overcompetes glycogen synthesis in a muscle cell which is in low energy charge but blood has high glucose level. My logic tells me it would be stupid for the cell to produce glycogen being in low ATP level ;) But I find how this is regulated neither in Mathews nor in Berg biochemistry. The search on the internet has brought anti-sense discovery that glycogen synthase is inhibited by ATP, not by ADP/AMP as i anticipated ( http://www.jbc.org/cgi/reprint/268/18/13286 ).

Thanks in advance for help.
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Postby MrMistery » Sat Oct 21, 2006 7:51 am

ok, sorry for my first totally off-topic post.unfortunately, i can't say i can help much. i've been browsing through lehninger for the last 15 minutes and it offers 10 pages on various control and regulation of glycogen synthesis, but nothing to say that glycogen synthase is inhibited by ATP or ADP. I found that the breakdown of glycogen to glucose-1-phosphate is stimulated when AMP binds to the enzyme, but that's it.

However, i have found something that links to what you need, somehow. THis is probably off-topic too but worth reading.
glycogen synthase can xist in two forms(conventionaly termed a-the active form- and b-the inactive form-). glycogen synthase a has three Ser residues near its carboxyl terminus, which are phosphorilated by glycogen synthase kinase 3, turning it into the b form. GSK3 actually requires a prior phosphorilation stage by casein kinase(priming). So, to turn glycogen synthase from the active to the inactive form, 4 ATP molecules are used up.
insulin triggers activation of glycogen synthase b by blocking the activity of GSK3 and activating a phosphoprotein phosphatase(PP1 in muscle cells). glucose-6-phoaphate, free glucose stimulate the enzyme PP1 alosterically.
But as i said, nothing about ATP...

UUh, hard stuff...
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Postby druid » Sat Oct 21, 2006 2:47 pm

Well, I've asked the question I'll answer it by myself ;)

Glycogen synthase is deactivated at basal intracellular level of Glc6P. When a cell starves and glucose comes from blood, Glc6P is consumed by glycolysis. Because glycogen synthase is inactive, glycogen synthesis doesn't compete with glycolysis. When cellular energy charge is restored to high level, Glc6P begins to accumulate. That's Glc6P that is allosteric activator of the synthase! Not ATP! Thus, at time of plenty, when intracellular ATP level is high, glycolysis slows down, [Glc6P] grows and the synthase becomes activated and starts to produce glycogen.

Thanks for help!
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Postby MrMistery » Sat Oct 21, 2006 3:32 pm

So it was no ATP? Guess my lehninger was right then:lol:
Well, i've learned something new today
out
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Postby druid » Sat Oct 21, 2006 3:58 pm

Well, to make the picture absolutely clear (primarily for me myself ;)) I'll add:

Suppose, marathon runner after 42 km depleted almost all her muscle/liver glycogen. I meet this championgirl at finish line, see she's almost dead and decide to make glucose infusion. Her pancreas, sensing sudden rise in glucose, irresponsibly sends insulin to the blood, not suspecting her organism is out of energy sources. Now, starving muscle will activate its glycogen synthase in response to insulin, but it desperately needs ATP for living. Thus, the competetion between glycogen synthesis and glycolysis begins. But in spite of being dephosphorylated glycogen synthase is inactive at low [Glc6P], so glycolysis wins.
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Postby kiekyon » Mon Oct 23, 2006 6:16 pm

this is from voet & voet
both glycogen phosphorylase and glycogen synthase are regulated by effectors that include ATP, ADP and G6P.
Glycogen synthase is activated by by G6P.
When there is high demand of ATP(low[ATP], low [G6P], high [AMP]), glycogen phosphorylase is stimulated and glycogen synthase is activated.
When [ATP] and [G6P] are high, the reverse is true and glycogen synthesis is favoured.


frankly, i cannot imagine any scenario of high [G6P] and low [ATP] persist for long...
wont the G6P be converted to ATP immediately??
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