26 Regulation of glycogen synthesis

Dr. Chirantan Rawal

Regulation of glycogen synthesis

Objectives

To understand regulation of glycogenesis by covalent modification of the glycogen synthase enzyme.
To understand regulation of glycogenolysis by allosteric control of the glycogen synthase enzyme.
Role of hormones in regulation of glycogen synthesis.

Introduction

In vertebrates and many microorganisms, surplus glucose is converted to glycogen.

A number of microorganisms gather carbon and energy reserves to manage with the starvation conditions provisionally found in the surroundings.

Organisms accumulate carbon in the form of polysaccharides. Such polysaccharides have high molecular weights. Glycogen has little effect on the internal osmotic pressure in the cell.

Synthesis of glycogen is a main policy for such metabolic storage. Glycogen is a main reserve polysaccharide found inside the cellular environment. 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 into hydrolysis of UTP glucose. It results in to futile cycle. Due to this reason, it is very important to control these pathways.

Fig: 27.1 Hydrolysis of UTP occurs on simultaneous glycogen synthesis and breakdown.

Glycogen is stored in muscle and liver. Glycogen is stored as large particles. These large particles contain regulatory enzymes and enzyme that mobilize glycogen.

Overview of Glycogen synthesis

Glycogenesis and glycogenolysis occur by different pathways. Glycogen synthesis involves the use of an activated form of glucose. Mammals, fungi and eukaryotic heterotrophic microorganisms use UDP-Glucose while bacteria and photosynthetic eukaryotes use ADP-Glucose.

Initially glucose is phosphorylated to glucose 6-phosphate. This reaction is catalyzed by hexokinase (muscle) or glucokinase ( liver).

Phosphoglucomutase catalyse the isomerisation of Glucose 6-phosphate to glucose 1-phosphate.

Now UDP-glucose pyrophosphorylase catalyse the formation of UDP-glucose fromUTP and glucose 1-phosphate.

Glycogen synthase transfers the glucosyl residue from UDP-glucose to the non reducing terminal residues of glycogen. It is transferred to hydroxyl terminal of C4 end of glycogen to form an α-1–4 glycosidic bond.

Glycogen synthase catalyzes only α- 1–4 glycosidic bonds. It results in to the formation of α- amylose. Branching is catalysed by separate enzyme called Branching enzyme. It is also known as amylo-(1–4→1–6) transglycosylase.

Mechanism of regulation

Covalent modification of Glycogen synthase

Glycogen synthase enzyme exists in two forms. They are Glycogen synthaseaandGlycogen synthaseb. Glycogen synthase a is an active form of an enzyme while Glycogen synthase b is normally inactive form of an enzyme. Glycogen synthaseb is converted in to Glycogen synthasea by the process of dephosphorylation. It is catalysed by Protein phosphatase.

Active Glycogen synthase, i.e. dephosphorylated glycogen synthase, is converted back in to inactive phosphorylated glycogen synthase by the process of phosphorylation. It is catalyzed by enzyme Protein kinase A.

Allosteric control of Glycogen synthase

High concentration of Glucose 6-phosphate activates glycogen synthase b. Glucose-6-phosphate concentration is low during muscle contraction. Therefore activity of glycogen synthase b is inhibited. During muscular contraction phosphorylase b ismore active (refer glycogen breakdown). Therefore during muscular exercise glycogen degradation promoted while glycogensynthesis is inhibited. This is important for preventing futile cycle.

ATP and glucose 6-phosphate concentration is high during resting stage. This condition inhibits activity of phosphorylase b (refer glycogen breakdown) whereas glycogen synthase is activated to restore the glycogen.

Glucose-6-phosphate does not affect Glycogen synthase a. Therefore Glycogen synthase a form is active and does not affected by the concentration of glucose 6-phosphate.

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

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

Elevated concentration of G6P

Low concentration of glucose-6-phosphate.

Hormonal control: Adrenalin inhibits the glycogen synthesis

Glycogenesis and glycogenolysis is regulated by hormones. When level of blood glucosefalll, α cells of pancreases secretes the glucagon. Glucagon stimulates glycogenolysis inside the liver. Glycogenolysis releases glucose into the bloodstream to improve blood glucose levels again. ‘Flight or fight’ response stimulates the adrenal medulla to releases adrenaline (epinephrine).

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 promotes the glycogenolysis

Active Glycogen synthase, i.e. dephosphorylated glycogen synthase, is converted back in to inactive phosphorylated glycogen synthase by the process of phosphorylation. It is catalyzed by enzyme Protein kinase A.

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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

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)