Glycogenesis and Glycogenolysis

biochem ex#2

Describe the structure of glycogen.

• Glycogen is the storage form of glucose in animals

• It’s a branched polymer composed of multiple α–D-glucose units linked by α-(1,4) glycosidic bonds in a linear chain.

• Approximately every 12 to 14 glucose residues, an α-(1,6) bond is created, forming a branch point on the linear chain.

• This branching allows for more glucose units to be packed into glycogen's structure and prevents crystallization of glucose

• Glycogen has one reducing end and multiple non-reducing ends where glucose units can be added or removed.

Describe the role of glycogen in the liver and muscle.

Liver glycogen: Its primary function is to maintain blood glucose concentration. Liver glycogen increases in the well-fed state and decreases in the starvation state. Glucose stored as glycogen in the liver can be released into the bloodstream when needed.

Muscle glycogen: Its function is to serve as a fuel reserve for ATP synthesis during exercise. Muscle glycogen levels are decreased by strenuous muscle activity and are synthesized when glycogen stores are depleted4 . Muscle glycogen is primarily used within the muscle cells and is not directly released into the bloodstream as free glucose (due to lack of glucose 6-phosphatase)

Define glycogenesis

Glycogenesis is the synthesis of glycogen from α-D-glucose. It is an anabolic process

Explain the process of glycogenesis

Glycogenesis involves several steps:

1. Conversion of glucose 6-phosphate to glucose 1-phosphate: Catalyzed by the enzyme phosphoglucomutase

2. Synthesis of UDP-glucose: Glucose 1-phosphate reacts with UTP, catalyzed by UDP-glucose pyrophosphorylase, to form UDP-glucose and pyrophosphate (PPi)

3. Synthesis of an initiating primer: The protein glycogenin, a priming glucosyltransferase, acts as an acceptor of glucose residues. A glucose unit from UDP-glucose is attached to glycogenin

4. Chain elongation: Glycogen synthase catalyzes the transfer of glucose units from UDP-glucose to the non-reducing end of the growing glycogen chain, forming α-(1,4) glycosidic bonds

5. Formation of branches: The 4:6 transferase (branching enzyme), also known as amylo-α-(1,4),α-(1,6) transglucosidase, transfers a block of 5-8 residues from a non-reducing end (with α-(1,4) linkages) to another glucose residue on the chain, creating an α-(1,6) branch point

Explain the process of glycogenolysis.

Glycogenolysis is the breakdown of glycogen to release glucose 1-phosphate and α-D-glucose. It’s a catabolic pathway. The steps are:

1. Shortening of glycosidic chains: Glycogen phosphorylase, using pyridoxal phosphate as a prosthetic group, cleaves the α-(1,4)-linkages of glycogen from the non-reducing ends by phosphorolysis, releasing glucose 1-phosphate. This continues until four glucosyl units remain from a branch point, forming a limit dextrin

2. De-branching (move 3 residues): The 4:4 transferase activity of the debranching enzyme moves three of the four remaining glucose residues from the branch to the non-reducing end of another chain, breaking one α-(1,4) bond and forming a new one

3. De-branching (remove 1 glucose): The 1:6 glucosidase activity of the debranching enzyme hydrolyzes the remaining single glucose residue attached by an α-(1,6)-glycosidic bond, releasing free glucose

4. Conversion of glucose 1-phosphate to glucose 6-phosphate: Phosphoglucomutase catalyzes this interconversion. In the liver, glucose 6-phosphate is further dephosphorylated by glucose 6-phosphatase in the ER to release glucose into the bloodstream. In the muscle, which lacks glucose 6-phosphatase, glucose 6-phosphate enters glycolysis

Identify the enzyme(s) and intermediates of glycogenesis and glycogenolysis.

Glycogenesis:

• Enzymes: Hexokinase (converts glucose to glucose 6-phosphate), phosphoglucomutase, UDP-glucose pyrophosphorylase, glycogenin, glycogen synthase, 4:6 transferase (branching enzyme)

• Intermediates: Glucose 6-phosphate, glucose 1-phosphate, UDP-glucose, glycogen (with increasing chain length and branches)

Glycogenolysis:

• Enzymes: Glycogen phosphorylase, 4:4 transferase (debranching enzyme), 1:6 glucosidase (debranching enzyme), phosphoglucomutase, (in liver) glucose 6-phosphatase

• Intermediates: Glycogen (with shortening chains and limit dextrins), glucose 1-phosphate, glucose (from debranching), glucose 6-phosphate

Explain the action of the enzymes involved in glycogen metabolism.

• Phosphoglucomutase: Catalyzes the reversible transfer of a phosphate group between the C1 and C6 hydroxyl groups of glucose

• UDP-glucose pyrophosphorylase: Catalyzes the synthesis of UDP-glucose from glucose 1-phosphate and UTP

• Glycogenin: Acts as a primer by attaching the first few glucose units to itself

• Glycogen synthase: Extends the glycogen chain by forming α-(1,4) glycosidic bonds, transferring glucose from UDP-glucose to the non-reducing end of the glycogen molecule

• 4:6 transferase (branching enzyme): Creates branches in glycogen by transferring a segment of glucose residues from an α-(1,4) linked chain to form an α-(1,6) linkage

• Glycogen phosphorylase: Breaks down glycogen by phosphorolysis of α-(1,4) glycosidic bonds, releasing glucose 1-phosphate

• 4:4 transferase (debranching enzyme): Transfers a block of three glucose residues from a branch point to another non-reducing end

• 1:6 glucosidase (debranching enzyme): Hydrolyzes the α-(1,6) glycosidic bond at the branch point, releasing free glucose

• Glucose 6-phosphatase: (in liver and kidney) Removes the phosphate group from glucose 6-phosphate, forming free glucose

List the co-factors, carriers, and other participants involved in glycogen metabolism.

Glycogenesis:

• UTP (Uridine Triphosphate): Provides the energy for UDP-glucose synthesis and is a precursor to UDP-glucose

• UDP (Uridine Diphosphate): Released after glucose transfer by glycogen synthase

Glycogenolysis:

• Pyridoxal phosphate: A prosthetic group for glycogen phosphorylase

• Inorganic phosphate (Pi): Used by glycogen phosphorylase in phosphorolysis

• Water (H2O): Used by 1:6 glucosidase for hydrolysis

Describe the process of regulation of glycogen metabolism.

The synthesis (glycogenesis) and breakdown (glycogenolysis) of glycogen are tightly regulated to maintain blood glucose levels in the liver and provide energy for muscle contraction in the muscle. Regulation occurs at receptor level and through allosteric control and hormonal level

• In the liver, glycogenesis is accelerated in the well-fed state, and glycogenolysis is accelerated in the fasting state

• In the muscle, glycogenolysis is accelerated during active exercise, and glycogenesis is accelerated at rest

• Glycogen phosphorylase and glycogen synthase are key regulatory enzymes that are controlled by allosteric effectors and hormonal signals17 . The active and inactive forms of these enzymes are interconverted through phosphorylation and dephosphorylation

Explain the influence of different hormones in regulating glycogen metabolism.

• Insulin: Generally opposes the effects of glucagon and epinephrine and favors glycogen synthesis

  • Insulin binding leads to the activation of protein phosphatase-1 (PP-1), which dephosphorylates and activates glycogen synthase and dephosphorylates and inactivates phosphorylase kinase (indirectly inhibiting glycogen breakdown)

• Glucagon: Promotes glycogen breakdown and stops glycogen synthesis in the liver. Glucagon activates adenylyl cyclase, increasing cAMP levels, which activate cAMP-dependent protein kinase.

  • This kinase phosphorylates and inactivates glycogen synthase and phosphorylates and activates glycogen phosphorylase, leading to glycogenolysis

• Epinephrine (adrenaline): Similar to glucagon, promotes glycogen breakdown and inhibits glycogen synthesis in both the liver and muscle17.

  • It also acts through the cAMP pathway to activate protein kinase, leading to the phosphorylation of glycogen synthase (inactivation) and glycogen phosphorylase (activation) The effects of phosphorylation have opposing effects on glycogen synthase and glycogen phosphorylase, ensuring reciprocal regulation of glycogenesis and glycogenolysis