Glucose and Glycogen Regulation

Glucose and Glycogen Regulation

• Glucose levels in blood (glycemia) are tightly controlled by various processes involving glucose production or consumption.
• Excess glucose is stored as glycogen, a storage form that can be broken down when needed to maintain normal blood glucose levels.

Glucose Dynamics in Living Organisms

• Glycogenolysis breaks down glycogen into glucose.
• Glycogenesis synthesizes glycogen from glucose.
• Glycolysis breaks down glucose to lactate.
• Gluconeogenesis produces glucose from non-carbohydrate sources.
• Glucose is a potent osmolyte and cannot be stored in large amounts in its free form.

Glycogen Degradation

• Glycogen is a branched polymer of glucose, with alpha(1→4) and alpha(1→6) linkages.
• In vertebrates, glycogen is primarily stored in the liver (up to 10% weight) and skeletal muscles (up to 1-2% weight).
• Glucose residues are removed from the non-reducing ends by phosphorolysis.
• Phosphorolysis cleaves the glycosidic bond, releasing glucose 1-phosphate.
• Debranching enzymes are necessary to remove branches in glycogen.
• Debranching 1 results in glucose 1-phosphate output.
• Debranching 2 results in free glucose output.

Glycogen Degradation: Debranching

• The debranching process involves two enzymatic activities of a single debranching enzyme.
• The first part is a transferase activity, which moves a block of oligoglucose from a branch to a linear chain.
• The second is a glucosidase activity, which hydrolyzes the remaining alpha(1→6) linked glucose.

Glycogen Degradation and Regulation of Glucose Level

• Glucose 1-phosphate is converted to glucose 6-phosphate.
• Glucose 6-phosphate can undergo glycolysis, the pentose pathway, or gluconeogenesis to replenish glucose.
• Glucose 6-phosphatase is only found in liver and kidney cells, enabling glucose release into the bloodstream (gluconeogenesis).
• Muscle and adipose cells lack glucose 6-phosphatase.

Glycogen Storage Diseases

• Glycogen storage diseases result from defects in enzymes involved in glycogen metabolism.
• Deficiencies in these enzymes can lead to the accumulation of abnormal amounts of glycogen in tissues or result from a lack of glycogen degradation.
• Examples like McArdle syndrome (muscle glycogen phosphorylase deficiency).

Glucose 6-Phosphatase Deficiency (Von Gierke Disease)

• The most common glycogen storage disease.
• Results in glucose 6-phosphatase deficiency, impairing glucose release from the liver.
• Characterized by fasting hypoglycemia, fatty liver, and other symptoms.

Glycogen Synthesis

• The synthesis of glycogen involves the addition of glucose molecules to an existing glycogen chain.
• The process begins with UDP-glucose, which carries glucose to the growing glycogen chain.
• Glycogen synthase is the enzyme responsible for adding glucose residues to the non-reducing end of the glycogen chain.
• Glycogenin is required to initiate the formation of the glycogen primer.

Regulation of Metabolic Pathways

• Cells and organisms maintain a dynamic steady state of metabolic pathways.
• Factors regulating enzyme activity include association with regulatory proteins, sequestration (compartmentation), transcription/translation, turnover, allosteric regulation, and covalent modification.

Covalent Modifications of Enzymes

• Phosphorylation/dephosphorylation is a common covalent modification that alters enzyme activity.
• Kinases add phosphate groups, while phosphatases remove them. This change can potentially affect the conformation or interaction with other proteins.

Assessment of Individual Enzyme Contribution to a Pathway

• Experimental methods can assess the contribution of individual enzymes to metabolic fluxes in pathways.

Coordinated Regulation of Glycolysis and Gluconeogenesis

• Coordinated regulation of glycolysis and gluconeogenesis is crucial to avoid futile cycles.
• The three irreversible reactions in glycolysis and gluconeogenesis are key regulatory points.
• Key regulatory molecules include ATP, citrate, ADP, AMP among others.

Regulation of Glycolysis at Hexokinase Level

• Four isozymes of hexokinase exist.
• Liver isozyme IV (glucokinase) is responsive to increased blood glucose levels. Muscle isozymes are inhibited by glucose-6-phosphate.

Hexokinase Isozyme Regulation

• Isozymes I-III have low Km and Vmax and are inhibited by product glucose-6-phosphate.
• Glucokinase (isozyme IV) has a high Km and is not inhibited by product, thus allowing continuous glucose processing after meals .

Regulation of Glycolysis at PFK Level

• PFK-1 is allosterically regulated by ATP and citrate.
• ATP inhibits PFK 1

Regulation of Glycolysis at Pyruvate Kinase Level

• The enzyme is allosterically inhibited by ATP, acetyl-CoA, fatty acids and alanine.
• It is activated by F-1,6-BP .

Coordinated Regulation of Gluconeogenesis

• Regulatory molecules such as acetyl-CoA regulate the first enzyme in gluconeogenesis.
• The fate of pyruvate is determined by the energy requirements of the cell.

Coordinated Regulation of Glycolysis and Gluconeogenesis (III)

• ATP and citrate inhibit glycolysis and activate gluconeogenesis.
• ADP and AMP activate glycolysis and inhibit gluconeogenesis.
• Fructose 2,6-bisphosphate is a key regulator influencing both pathways.

Fructose 2,6-bisphosphate

• A potent allosteric regulator of PFK-1 and FBPase-1.
• Activates PFK-1 (glycolysis).
• Inhibits FBPase-1 (gluconeogenesis).

PFK-2/FBPase-2

• A bifunctional enzyme with PFK-2 and FBPase-2 activities, crucial for regulating glycolysis and gluconeogenesis.
• Activity is controlled by hormones like insulin and glucagon.

Coordinated Regulation of Glycolysis and Gluconeogenesis (IV)

• Glucose levels regulate both glycolysis and gluconeogenesis through complex interactions among hormones, intermediates and enzymes.

Coordinated Regulation of Glycogen Synthesis and Breakdown

• Glycogen synthesis is regulated by glycogen synthase.
• Glycogen breakdown is regulated by glycogen phosphorylase.
• Hormones like insulin and glucagon impact the activity of these enzymes.
• Hormones like, epinephrine also impact the regulation.

Control of Glycogen Synthesis

• Activation of glycogen synthase is crucial for glycogen synthesis. Inactivation of this enzyme can be achieved by mechanisms including phosphorylation.
• Insulin generally promotes glycogen synthesis

Control of Glycogen Synthesis

• Control of glycogen synthesis involves activation by protein phosphatase 1 (PP1) and activation by a casein kinase and/or a glycogen synthase kinase.

Control of Glycogen Breakdown

• Activation of glycogen phosphorylase involves phosphorylation. This will occur when blood glucose is low/ glucagon or epinephrine are present.

Coordination of Glycogen Synthesis and Breakdown

• Glycogen synthesis and glycogen breakdown are reciprocally regulated to prevent futile cycles.
• Insulin activation will favor glycogen synthesis and glucagon activation will favor glycogen breakdown

Hormones and Glycogen Metabolism

• Insulin promotes glycogen synthesis while glucagon, epinephrine stimulate glycogen breakdown.
• Hormones play a crucial role in regulating the rate of glycogen synthesis and breakdown to maintain blood glucose homeostasis.

Control of Glycogen Synthesis from Blood Glucose in Myocytes

• Insulin promotes GLUT4 translocation to the plasma membrane.
• This allows more glucose to enter the cell.

Carbohydrate Regulation in Liver Cells (Overview)

• Insulin and glucagon have antagonistic effects on glycolysis and gluconeogenesis.
• Insulin stimulates glycolysis and inhibits gluconeogenesis.
• Glucagon stimulates gluconeogenesis and inhibits glycolysis.

Hormones in Carbohydrate Regulation

• Glucagon, epinephrine, and insulin interplay to regulate glucose metabolism homeostasis.

Differences in Carbohydrate Metabolism in Liver and Muscles

• Muscles lack glucose-6-phosphatase and are not involved in maintaining blood glucose levels.
• Glucose metabolism in muscles is primarily for energy production associated with contraction.

Effects of Insulin

• Insulin inhibits glycogen degradation.
• Insulin stimulates Glycogen Synthase and phosphoprotein phosphatase.
• Insulin inhibits cAMP-dependent protein kinase.

Effects of Glucagon and Epinephrine

• Glucagon promotes gluconeogenesis.
• Epinephrine also promotes gluconeogenesis.
• Ephinephrine promotes glycogen breakdown (muscle).

Drugs and Diseases

• Drugs and diseases associated with glycogen metabolism and glucose homeostasis are mentioned.