Glycogenolysis and Glycogenesis

Glycogenesis and Gluconeogenesis

Objective

•       At the end of this lecture, student will be able to

–      Explain the reactions of glycogenesis

–      Explain the reactions of glycogenolysis

–      Discuss the regulation of glycogenesis & glycogenolysis

–      Describe glycogen storage diseases

Glycogenesis

•       Glycogen is the storage form of glucose in animals, as starch in plants

•       Quantity of glycogen in muscle (250g) is 3 times higher than liver (75g)

•       Glycogen is stored as granules in the cytosol, where enzymes of glycogen synthesis and break down are present

•       Prime function of glycogen (liver) is to maintain the blood glucose levels, particularly and glycogen (muscle) serves as a fuel reserve for the supply of ATP during muscle contraction

•       synthesis of glycogen from glucose

•       Takes place in the cytosol and requires ATP and UTP, besides glucose

Reactions of Glycogenesis

1. Synthesis of UDP-glucose:

•       Hexokinase (muscle) & glucokinase (liver) convert glucose to glucose 6-phosphate

•       Phosphoglucomutase catalyses the conversion of glucose 6-phosphate to glucose 1-phosphate

•       glucose 1-phosphate reacts with UTP(Uridine triphosphate) to form uridine diphosphate glucose-UDPG catalysed by the enzyme

•       UDPG-pyrophosphorylase

2. Requirement of primer to initiate glycogenesis

•       A small fragment of pre-existing glycogen act as a 'prime  to initiate glycogen synthesis

•       In absence of glycogen primer, a specific protein namely 'glycogenin‘ can accept glucose from UDPG

•       Hydroxyl group of amino acid tyrosine of glycogenin is the site at which the initial glucose unit is attached

•       Enzyme glycogen initiator synthase transfers the first molecule of glucose to glycogenin. Then glycogenin itself takes up a few glucose residues to form a fragment of primer which serves as an acceptor for the rest of the glucose molecules

3. Glycogen synthesis by glycogen synthase:

•       Glycogen synthase is responsible for formation of 1,4-glycosidic linkages, this enzyme transfers the glucose from UDP-glucose to the non-reducing end of glycogen to form α-1,4 linkages

4. Formation of branches in glycogen:

•       Glycogen synthase can catalyse the synthesis of a linear unbranched molecule with 1,4 α-glycosidic linkages

•       Glycogen is a branched tree-like structure

•       Formation of branches is brought about by the action of a branching enzyme, namely amylo 1,4-1,6 transglycolase

•       This enzyme transfers a small fragment of 5 to 8 glucose residues from the non-reducing end of glycogen chain (by breaking α-1,4 linkages) to another glucose residue where it is linked by α-1,6 bond

•       This leads to the formation of a new non-reducing end, besides the existing one

•       Glycogen is further elongated and branched, respectively by the enzymes glycogen synthase and glucosyl 4-6 transferase

The overall reaction of the glycogen synthesis:

                (Glucose)n + Glucose + 2ATP →(Glucose)_n+1+ 2ADP+Pi

Out of 2 ATP, 1 is required for the phosphorylation of glucose while the other is needed for conversion of UDP to UTP

Glycogenolysis

•       Degradation of stored glycogen in liver and muscle constitutes glycogenolysis

•       It is a irreversible process and enzymes for this are present in cytosol

•       Glycogen is degraded by breaking α-1,4- & α-1,6-glycosidic bonds

1. Action of glycogen phosphorylase: α-1,4-glycosidic bonds are cleaved sequentially by the enzyme glycogen phosphorylase to yield glucose 1-phosphate

•       This process - phosphorolysis, continues until four glucose residues remain on either side of branching point (α-1,6-glycosidic link)

•       Glycogen so formed is known as limit dextrin which cannot be further degraded by phosphorylase

2. Action of debranching enzyme:

•       The branches of glycogen are cleaved by two enzyme activities present on a single polypeptide called debranching enzyme, hence it is a bifunctional enzyme

•       Clycosyl 4 : 4 translerase activity removes a fragment of three or four glucose residues attached at a branch and transfers them to another chain

•       Here, one α-1,4-bond is cleaved and the same α-1,4 bond is made attached

•       Amylo α-1,6-glucosidase breaks the α-1,6 bond at the branch with a single glucose residue and releases a free glucose

•       The remaining molecule of glycogen is again available for the action of phosphorylase and debranching enzyme to repeat the reactions stated above

3. Formation of glucose 6-phosphate and glucose:

•       Combined action of glycogen phosphorylase and debranching enzyme, glucose 1-phosphate and free glucose in a ratio of 8:1 are produced

•       G-1-phosphate is converted to G-6-phosphate by the enzyme phosphoglucomutase

•       G-6-P is converted to glucose in the liver by the enzyme glucose -6- phosphatase

Regulation of glycogenesis and glycogenolysis

•       The regulation is essential to maintain the blood glucose levels

•       Glycogenesis and glycogenolysis are controlled by the enzymes glycogen synthase and glycogen phosphorylase

Regulation of these enzymes is accomplished by 3 mechanisms

                                1. Allosteric regulation

                                2. Hormonal regulation

                                3. lnfluence of calcium

1. Allosteric regulation of glycogen metabolism

•       Certain metabolites that allosterically regulate the activities of glycogen synthase and glycogen phosphorylase

•       Control is carried out in such a way that glycogen synthesis is increased when substrate availability and energy levels are high

•       On the other hand, glycogen breakdown is enhanced when glucose concentration and energy levels are low

 

2. Hormonal regulation of glycogen metabolism:

•       Hormones are also regulate glycogen synthesis ad degradation

3. Regulation of glycogen synthesis by cAMP:

•       The glycogenesis is regulated by glycogen synthase

•       Enzyme exists in two forms glycogen synthase-a, which is not phosphorylated and the active form and secondly glycogen synthase-b, which is phosphoryIated and inactive form

•       Glycogen synthase-a can be converted to b form by phosophorylation

•       Process of phosphorylation is catalysed by a cAMP dependent protein kinase

•       Inhibition of glycogen synthesis brought by epinephrine and glucagon through cAMP by converting active glycogen synthase 'a' to inactive synthase-b

Regulation of glycogen degradation by cAMP:

•       Hormones like epinephrine and glucagon bring about glycogenolysis by their action on glycogen phosphorylase through cAMP

•       Glycogen phosphorylase exists in two forms, active 'a’ form and inactive 'b‘ form

Effect of Ca2+ ions on glycogenolysis:

•       When the muscle contracts, Ca²⁺ ions are released from sarcoplasmic reticulum

•       Ca²⁺ binds to calmodulin- calcium modulating protein and directly activates phosphorylase kinase without the involvement of cAMP dependent protein kinase

•       Therefore, insulin increased glycogen synthesis and glucogon increase glycogen degradation

Glycogen storage diseases

Summary

•       Glycogenesis is synthesis of glycogen from glucose

•       Degradation of stored glycogen constitutes glycogenolysis

•       Regulation of glycogen synthesis and its degradation is accomplished by, Allosteric regulation, Hormonal regulation & lnfluence of calcium

•       Glycogen storage diseases are Von’s Gierke’s diseases, Pompe’s diseases, Cori’s diseases, Anderson’s diseases, Mc Ardle’s diseases, Her’s diseases and Tarui’s diseases

 For detailed PDF Notes Click on Download Button