Carbohydrate Metabolism Lecture 3

Carbohydrate Metabolism Lecture 3: Glycogen & Hexose Monophosphate Shunt

• Glycogen metabolism involves the synthesis and degradation. These processes are carefully regulated to maintain sufficient glucose for energy needs. Insulin, glucagon, and epinephrine are the primary hormones that control these processes.
• Glycogenesis (glycogen synthesis) occurs in the liver after a meal when blood glucose levels are high.
  • Glucose-6-phosphate is converted to glucose-1-phosphate by phosphoglucomutase. This enzyme contains a phosphoryl group attached to a reactive serine residue.
  • UDP-glucose formation is followed by glycogen synthesis from UDP-glucose, catalyzed by two enzymes.
  • Glycogen synthase catalyzes the transfer of the glucosyl group of UDP-glucose to the non-reducing ends of glycogen.
  • Amylo-α(1,4 to 1,6)-glucosyl transferase (Branching enzyme) creates the α(1,6) linkages for branches.
  • Glycogen synthesis is believed to be instigated by the transfer of glucose from UDP-glucose to a specific tyrosine residue called glycogenin on a "primer" protein.
• Glycogenolysis (glycogen degradation) involves two key reactions.
  • Removal of glucose from non-reducing ends: Glycogen phosphorylase breaks down α(1,4) linkages releasing glucose-1-phosphate. Glycogen phosphorylase stops when it reaches four glucose residues from a branch point.
  • Hydrolysis of α(1,6) glycosidic bonds at branch points: Amylo-α(1,6)-glucosidase (also called Debranching enzyme) transfers outer three of four glucose units to a nearby non-reducing end, and then removes the single glucose residue at each branch point. The product is free glucose.
• Cori's disease is a glycogen storage disease. It's caused by a deficiency in the debranching enzyme. Patients exhibit enlarged livers (hepatomegaly) and low blood sugar (early fasting hypoglycemia).

Regulation of Glycogen Metabolism

• Glycogen synthesis and degradation are regulated through a complex mechanism involving insulin, glucagon, and epinephrine.
• Glucagon stimulates glycogenolysis and inhibits glycogenesis. It activates a reaction cascade involving cAMP.
• Insulin inhibits glycogenolysis and stimulates glycogenesis. It activates a phosphorylation cascade to inhibit enzymes in glycogenolysis and activate enzymes for glycogenesis.
• Epinephrine is released during stress and promotes glycogenolysis, inhibiting glycogenesis. Increased amounts are released in emergency situations, providing energy for managing the situation.
• Glycogen synthase and glycogen phosphorylase exist in active and inactive conformation, interconverted by covalent modification.
• Phosphorylating enzymes (e.g., phosphorylase kinase) are activated by cAMP, leading to activation of glycogen phosphorylase and inactivation of glycogen synthase.
• Deactivation occurs when phosphoprotein phosphatase reverses these effects, converting the enzymes back to their inactive states.

Hexose Monophosphate Shunt

• The pentose phosphate pathway is an alternative pathway for glucose oxidation. It produces NADPH and ribose-5-phosphate, both essential for various metabolic processes.
• The pathway occurs in the cytoplasm and has two phases: Oxidative and Non-oxidative.
• The oxidative phase is responsible for NADPH production through three key reactions (using glucose-6-phosphate dehydrogenase, gluconolactonase, and 6-phosphogluconate dehydrogenase).
• The non-oxidative phase involves isomerization and condensation of numerous sugar molecules. These reactions utilize transketolase and transaldolase to convert the sugars into intermediates that can enter the glycolytic pathway, producing ribose-5-phosphate and crucial glycolytic intermediates. This phase facilitates the synthesis of aromatic amino acids in some organisms.

Pentose Phosphate Pathway

• An alternative metabolic pathway for glucose oxidation.
• This pathway produces NADPH (reducing agent) and ribose-5-phosphate (component of nucleotides).
• The pathway occurs in two phases (oxidative and non-oxidative).
  • The oxidative phase generates NADPH and converts glucose-6-phosphate into ribulose-5-phosphate.
  • The non-oxidative phase does not generate ATP but does interconvert sugars (e.g. ribose-5-phosphate, fructose-6-phosphate, and glyceraldehyde-3-phosphate), useful for other pathways.

Regulation of the HMP Shunt

• The pentose phosphate pathway is regulated to meet cellular needs for NADPH and ribose-5-phosphate. It is highly active in cells needing large amounts of NADPH (like red blood cells).
• The oxidative phase is primarily absent in cells that synthesize little lipid (e.g., muscle cells), as these cells have little demand for NADPH.
• G6PD (glucose-6-phosphate dehydrogenase) is a key regulatory enzyme whose activity is affected by NADPH, GSSG, and glucose-6-phosphate.
• Insulin and high-carbohydrate diets stimulate HMP shunt activity by increasing the synthesis of G6PD and 6-phosphogluconate dehydrogenase.

NADPH & Red Blood Cells

• NADPH is important for antioxidant activity in protecting cells from oxidative damage.
• Red blood cells are heavily reliant on the pentose phosphate pathway for NADPH.
• Glutathione peroxidase and glutathione reductase use NADPH to regenerate reduced glutathione, reducing oxidative damage.
• Deficiency of NADPH can lead to increased oxidative stress, resulting in fragile red blood cells and hemolytic anemia. Favism is an example.

Explore the intricate processes of glycogen metabolism in this comprehensive quiz. Learn how glycogenesis occurs after meals and the role of key hormones like insulin and glucagon in regulating glucose levels. Test your knowledge on the enzymes involved in glycogen synthesis and their functions.