KUO101
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Q: what happens to glycogen phosphorylase when insulin levels are high? How exactly does insulin exert its action on the enzyme and how is this action facilitated by high glucose levels in the hepatocyte?

I’m very confused by this question. Glycogen phosphorylase breaks down glycogen into Glucose-1-phosphate, which is the first step of glycogenolysis. Glycogenolysis happens in response to low blood glucose levels. I don’t understand how insulin/high glucose levels are relevant? Please help!
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macpatgh-Sheldon
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Hi,
I am not a biochemist, but I would expect that insulin, its eventual action being to reduce blood glucose levels, inhibits glycogen phosphorylase in some way, or at least changes something that tends to drive the reaction in the opposite direction to the enzyme action of glycogenolysis.

On researching the mechanism of this putative inhibition of glycogen phosphorylase, I located the following research paper for you, followed by an excerpt from it (save you going through 23 pages!).

https://www.ncbi.nlm.nih.gov/pmc/art...9/pdf/4070.pdf


"In liver, elevated intracellular glucose levels have been proposed to stimulate GYS2 by a mechanism involving a liver-specific glycogen-targeting subunit, GL(2). GYS2 is dephosphorylated and activated by protein phosphatase-1 (PP1) complexed with GL. GL also interacts with the activated form of glycogen phosphorylase (GPa), which antagonizes activation of GS through PP1-GL. When blood glucose levels are elevated, glucose binds to hepatic GPa and stabilizes the enzyme in the inactive conformation (GPb). Glycogenolysis is switched off, and inhibition of PP1-GL is blocked, allowing PP1-GL to dephosphorylate and activate GS and promote glycogen deposition in the liver. Kelsall et al. (15) reported that binding between GL and GP could be disrupted by a single point mutation (GLY284→F) and generated a knockin mouse model carrying this mutation to examine the physiological role of this allosteric interaction in hepatic glycogen metabolism in vivo"

Trust this will get you full marks!

NB: (1) GYS2 is hepatic glycogen synthase (GYS1 being the muscle equivalent)
(2) The actions in bold are probably also mediated by insulin (??)
M (ex-medic)
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KUO101
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(Original post by macpatelgh)
Hi,
I am not a biochemist, but I would expect that insulin, its eventual action being to reduce blood glucose levels, inhibits glycogen phosphorylase in some way, or at least changes something that tends to drive the reaction in the opposite direction to the enzyme action of glycogenolysis.

On researching the mechanism of this putative inhibition of glycogen phosphorylase, I located the following research paper for you, followed by an excerpt from it (save you going through 23 pages!).

https://www.ncbi.nlm.nih.gov/pmc/art...9/pdf/4070.pdf


"In liver, elevated intracellular glucose levels have been proposed to stimulate GYS2 by a mechanism involving a liver-specific glycogen-targeting subunit, GL(2). GYS2 is dephosphorylated and activated by protein phosphatase-1 (PP1) complexed with GL. GL also interacts with the activated form of glycogen phosphorylase (GPa), which antagonizes activation of GS through PP1-GL. When blood glucose levels are elevated, glucose binds to hepatic GPa and stabilizes the enzyme in the inactive conformation (GPb). Glycogenolysis is switched off, and inhibition of PP1-GL is blocked, allowing PP1-GL to dephosphorylate and activate GS and promote glycogen deposition in the liver. Kelsall et al. (15) reported that binding between GL and GP could be disrupted by a single point mutation (GLY284→F) and generated a knockin mouse model carrying this mutation to examine the physiological role of this allosteric interaction in hepatic glycogen metabolism in vivo"

Trust this will get you full marks!

NB: (1) GYS2 is hepatic glycogen synthase (GYS1 being the muscle equivalent)
(2) The actions in bold are probably also mediated by insulin (??)
M (ex-medic)
Thank you so much you really helped me out
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