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
- 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
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