Glycogenolysis and Glycogenesis

Glycogenesis and Gluconeogenesis


       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


       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


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


       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


       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

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