How Glycogen Metabolism Is Controlled In The Liver And Muscle Notes

Control of glycogen metabolism in the liver and muscle

Glycogen catabolism:

• Glycogen is broken down by the following enzymes:

• Glycogen phosphorylase removes one glucosyl residue at A time from the non-reducing ends of glycogen, catalysing the following reaction:

  • Glycogen(n) + Pi glucose-1-phosphate + glycogen(n-1)

• Glycogen phosphorylase can only act on α-1,4 glycosidic linkages until 4 residues away from a branching α-1-6 linkage

• The bifunctional debranching enzyme moves the next 3 residues to another branch (transferase site) and cleaves the α-1,4 linkage to release the last glucose (α-1,6 glucosidase site)

• This leaves one unbranched elongated chain for glycogen phosphorylase

• The glucose-1-phosphate released is converted to glucose-6-phosphate by phosphoglucomutase

Muscle and liver differences are reflected in glycogen catabolism control:

• Glucose-6-phosphate enters glycolysis in most tissues inc. muscle, but the liver expresses glucose-6-phosphatase (in the lumen of ER) so the glucose-6-phosphate can be converted to glucose and released

• Muscle uses glucose to produce ATP for its own energy use whereas liver provides glucose for peripheral tissues; this necessitates different regulation in these tissues

• Control is primarily of glycogen phosphorylase, which is the rate-limiting process of glycogen catabolism and is expressed as different isozymes in liver and muscle

• Both isozymes have a phosphorylase A and a phosphorylase B isoform; phosphorylase A is phosphorylated

• Both isoforms have an active, relaxed (R) and inactive, tense (T) state

• Phosphorylase B’s equilibrium strongly favours the T state; phosphorylase A’s equilibrium strongly favours the R state

In muscle:

• Most phosphorylase is in the B isoform at rest

• High AMP ratios (signalling exercise) allosterically stabilises the R state of phosphorylase B

• ATP competes with AMP for this binding site, so abundant energy promotes the T state

• Glucose-6-phosphate, phosphorylase B’s product, also favours the T state

• Phosphorylase A is active independent of AMP, ATP or G6P, so phosphorylase B is converted to phosphorylase A via phosphorylase kinase upon hormonal stimulation

• Adrenaline (signalling impending exercise) initiates a cascade via β-adrenoreceptors:

  • G_s activated adenylate cyclase activated [cAMP] increases PKA activated phosphorylase kinase phosphorylated glycogen phosphorylase B phosphorylated [glycogen phosphorylase A] increases

• Phosphorylase kinase is also stimulated upon electrical excitation of the cell and upon [Ca²⁺] increasing (both of which signal contraction)

• Ca²⁺activates phosphorylase kinase because one of its units is calmodulin

• Maximum activity of phosphorylase kinase is only achieved with both high calcium levels and phosphorylation

In the liver:

• In liver, phosphorylase is not responsive to AMP as the liver’s energy charge never dramatically falls

• Glucose binds to phosphorylase A,...

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