25 Regulation of glycogen degradation

Dr. Chirantan Rawal

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Regulation of glycogen degradation

 

Objectives

  1. To understand regulation of glycogenolysis by covalent modification of the phosphorylase enzyme.
  2. To understand regulation of glycogenolysis by allosteric control of the phosphorylase enzyme.
  3. Role of hormones in regulation of glycogen breakdown.

   

Introduction

  • Invertebrates and many microorganisms, surplus glucose is converted to glycogen.
  • Many microorganisms gather carbon and energy reserves to manage with the starvation conditions provisionally found in the surroundings. Biological synthesis of glycogen is a major strategy for such metabolic storage. Glycogen is a chief intracellular reserve polymer. Glycogen consists of α-1, 4- linked glucose subunits with α-1, 6-linked glucose at the branching points.
  • Simultaneous synthesis and breakdown of glycogen results in to hydrolysis of UTP glucose. It results in to futile cycle. Due to this reason, it is very important to control these pathways.

Fig: 26.1  Hydrolysis of UTP occurs on simultaneous glycogen synthesis and breakdown.

 

  • Glycogen is stored in muscle and liver. Glycogen is stored as bulky particles. It contain regulatory enzymes. Such particles also contain enzyme that mobilize glycogen.

 

Overview of Glycogen breakdown

  • Glycogen phosphorylase catalyzes phosphorolytic cleavage. It occurs at the non reducing terminal of glycogen chains.
  • Debranching enzyme separates the branch and transfers it to the main chain. It also releases the residue at α 1-6 branch as free glucose.
  • Phosphoglucomutase converts glucose 1-phosphate into glucose 6-phosphate. Glucose -6-phosphate can enter in to glycolysis. In endoplasmic reticulum of liver, Glucose 6 phosphate can be changedin to free glucose by glucose 6-phosphatase. Free glucose is release in to blood.

 

Mechanism of regulation

  • Covalent modification of Glycogen phosphorylase
  • Allosteric control of Phosphorylase b
  • Hormonal control: Stimulation of glycogen breakdown by adrenaline and glucagon
  • Hormonal control : Inactivation of glycogen breakdown by insulin
  • Calcium control of glycogen breakdown

 

Covalent modification of Glycogen phosphorylase

  • Phosphorylase enzyme exists in two forms. They are phosphorylase a andphosphorylase b. Phosphorylase a is an active form of an enzyme while phosphorylase b is normally inactive form of an enzyme. Phosphorylase b is converted in to phosphorylase a by the process of phosphorylation of serine residue. It iscatalysed byphosphorylase kinase.
  • Active Phosphorylase, i.e. phosphorylated phosphorylase, is converted back in to inactive phosphorylase b by the removal of phosphate group from the active phosphorylase a. It is catalyzed by enzyme Protein phosphatase I.

 

Allosteric control of Phosphorylase b

  • Most of the phosphorylase found in the resting muscles is phosphorylase b. Phosphorylase b is inactive form. Phosphorylase b can be controlled allosterically. AMP activates the phosphorylase b while ATP and glucose-6-phosphate inhibits the phosphorylase b.
  • Glycogen breakdown occurs when there is high demand of ATP in the muscles i.e. low concentration of ATP and glucose-6-phosphate and high concentration of AMP. High concentration of AMP stimulates phosphorylase and hence glycogen breakdown. Situation will be reversed in resting muscles.
  • ATP, AMP or glucose 6-phosphate does not affect Phosphorylase a. It remains active under all situations.
  • Liver phosphorylase b is not activated by AMP. It remains inactive all the time. In liver, glycogen degradation is not responsive to the energy status of the cell. Glycogen degradation is responsive to the energy status of the cell in cells of muscles.

 

High concentration of AMP, low concentration of ATP and Glucose-6-phosphate

 

High concentration of ATP and glucose-6-phosphate. Low concentration of AMP

Fig. 26.3 Regulation of Muscle glycogen phosphorylase b activity

 

 

Hormonal control: Stimulation of glycogen breakdown by adrenaline and glucagon

  • Glycogen metabolism is strongly controlled by hormones. When level of blood glucosedrops, α cells of pancreases secretes the glucagon. Glucagon stimulates glycogenolysis inside the liver. Glycogenolysis releases glucose into the blood to improve level of blood glucose.‘Flight or fight’ response stimulates the adrenal medulla to releases adrenaline (epinephrine).
  • Adrenaline promotes the glycogenolysis, which in turn fulfill the energy requirement of the cells. Adrenaline acts on both muscles and liver cells. Muscle cells do not contain the receptor of glucagon.
  • Earl Sutherland confirmed that phosphorylase b dominate in resting muscle. During muscle contraction, the hormoneepinephrine activates phosphorylation of a serine residue in phosphorylase b, whichconverts it into phosphorylase a, which is a more active form.
  • Adrenaline binds to the β-adrenergic receptor on theplasma membrane of the target cell. It causes a conformational change in the protein. It activates a G-protein, which in turn activates the adenylate cyclase enzyme. Activated adenylate cyclase convertsATP to 3’5’ cyclic AMP (cAMP).
  • Cyclic AMP acts as a second messenger. The cAMP binds to cAMP-dependent protein kinase (PKA).The active protein kinase A phosphorylates phosphorylase kinase. Phosphorylated phosphorylase kinase is active form of phosphorylase kinase. It phosphorylates serine residue in phosphorylase b, whichconverts it into phosphorylase a, that is a more active form.
  • This set of reactions is called a cascade. Cascade response amplifiesthe response generated by a very minute quantity of hormones.

Fig. 26.4 Mechanism of action of epinephrine.

 

Hormonal control : Inactivation of glycogen breakdown by insulin

  • The effect of insulin is opposite to the effect of glucagon and epinephrine. Insulin binds to a receptor on a cell surface and activates a pathway that direct to activation of protein phosphatase-1.
  • Insulin is released in the blood by pancreases when blood glucose level is high. Insulin binds to the receptor on plasma membrane. Binding results in to the activation of the receptor. Activated receptor has tyrosine kinase activity. It will activate insulin responsive protein kinase. Activated insulin responsive protein kinase phosphorylates protein phosphatase -1. It will activate protein phosphatase-1.
  • Protein phosphatase-1 ensures dephosphorylation of phosphorylase kinase. Dephosphorylation makes it inactive.
  • Dephospho phosphorylase kinase (Inactive) is unable to phosphorylate glycogen phosphorylase b. It results in to the decreases in the glycogen breakdown.

     

Calcium control of glycogen breakdown

  • High concentration of calcium ions partially activates the Dephosphorylated phosphorylase kinase. During muscle contraction, sarcoplasmic reticulum release calcium ions. A calcium ion thus stimulates the glycogen breakdown.

Fig.26.5 Regulation of glycogen breakdown by insulin

 

 

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References

  • Peter J. Roach, Anna A. Depaoli-Roach, Thomas D. Hurley, Vincent S. Tagliabracci (2012) Glycogen and its metabolism: some new developments and old themes . Biochemical Journal, 441 (3) 763-787; DOI: 10.1042/BJ20111416
  • Roach PJ, Depaoli-Roach AA, Hurley TD, Tagliabracci VS (2012) Glycogen and its metabolism: some new developments and old themes. Biochem J 441: 763–787. doi: 10.1042/BJ20111416
  • Wilson WA, Roach PJ, Montero M, Baroja-Fernandez E, Munoz FJ, Eydallin G, et al. Regulation of glycogen metabolism in yeast and bacteria. Fems Microbiol Rev. 2010;34(6):952–985.

 

Web site

  • http://www.wiley.com/college/fob/quiz/quiz15/15-20.swf
  • https://www.tamu.edu/faculty/bmiles/lectures/Glycogen%20Metabolism.pdf
  • http://themedicalbiochemistrypage.org/glycogen.php
  • https://en.wikibooks.org/wiki/Principles_of_Biochemistry/Gluconeogenesis_and_Gly cogenesis

 

Books

 

  • Harper’sIllustrated Biochemistry by Robert K.. Murray, Daryl K. Granner, Peter A. Mayes, 26th Edition (2003)
  • Lehninger’S Principle of Biochemistry David L. Nelson and Michael M. Cox,5th Edition (2008)
  • Instant Notes: Biochemistry, 2nd Edition, B.D. Hames & N. M. Hooper (2005)
  • Textbook of Biochemistry, 4th Edition Donald Voet, Judith G. Voet (2011)