Carbohydrate Metabolism Lesson 7 (Gluconeogenesis) PDF

Carbohydrate Metabolism. Lesson 7 (Gluconeogenesis). Dr. Mohamed Khomsi Fb: ‫ محمد الخمسي‬.‫د‬ July / 2024 1  Gluconeogenesis Name: - Gluconeogenesis...

Carbohydrate Metabolism. Lesson 7 (Gluconeogenesis). Dr. Mohamed Khomsi Fb: ‫ محمد الخمسي‬.‫د‬ July / 2024 1  Gluconeogenesis Name: - Gluconeogenesis. Other Name: - Glucose Synthesis. Pathway: - It is a Late Fasting Pathway. - It is a Pathway for Synthesis of Glucose during Late fasting. - During a Late fasting, Hepatic glycogen Stores are Depleted. - Liver Glycogen, an Essential Source of Glucose, Can Meet these Needs Early fasting for 10–18 hours. - Late fasting Includes Overnight & Prolonged Fasting. State: - It Occurs During Fasting, Stimulated by Glucagon. Definition: - It is the Formation of Glucose or Glycogen from Non-Carbohydrate Source. 2  Gluconeogenesis Site (Organ): - It Occurs in Liver & Kidney. Fasting Time Gluconeogenesis Organ - Liver (90%) Overnight Fasting - Kidney (10%) Prolonged Fasting Liver (60%) (Starvation) Kidney (40%) - Gluconeogenesis Occurs Mainly in the Liver. - Kidney becomes Major Glucose-Producing Organs, in Prolonged Starvation. Site (Cell): - It Occurs in Mitochondria & Cytosol. - GNG Requires both Mitochondrial & Cytosolic Enzymes. Substrate: - Glucose is Formed from Gluconeogenic Precursors - 2 Molecules of Non-Carb Containing 3 Carbon. - 2 Pyruvate, 2 Lactate, 2 Glycerol, 2 αketoacids of Glucogenic amino acids. End Product: - 1 Glucose Molecule. Gluconeogenic Precursors are Molecules that Can be Used to Produce a Net Synthesis of Glucose. 3  Gluconeogenesis Biological Importance: (1) It Provides Glucose, for Organs that Require Absolute & Continuous Supply of Glucose. - After Depleted All stored Glycogen is. e.g. The Brain (Nervous System) & Anaerobic Tissue (like RBC) in Starvation. (2) Gluconeogenesis is also Important for clearing Waste Products from Organs. - It Clears Lactate Produced by RBC (Erythrocyte) & Muscle. - It Clears Glycerol Produced by Adipose Tissue. Medical Importance : - Failure in Gluconeogenesis cause Hypoglycemia. - Excessive Gluconeogenesis causes Hyperglycemia. Failure Excessive Gluconeogenesis cause Gluconeogenesis causes Hypoglycemia Hyperglycemia - Type 2 Diabetes Mellitus. - Change Body Fluid Osmolarity. - Impaired Blood Flow. - Brain Dysfunction. - Intracellular Acidosis. - Coma. - Deranged Endothelial cells. - Death (Fatal). - Increase Superoxide Free Radicals. - Decrease Immunity Function. - Impaired blood coagulation. - Hypoglycemia is Fatal, Because Glucose is Important in Maintaining, Adequate Concentrations of Intermediates of the Citric Acid Cycle. ** Excessive Gluconeogenesis Occurs in Critically ill Patients in Response to Infection & Injury ** - Excessive Gluconeogenesis is also a Contributory Factor to Hyperglycemia in Type 2 DM, - Because of Down-Regulation in Response to Insulin. - Hyperglycemia Associated with a Poor Outcome. 4  Gluconeogenesis from Pyruvate Substrate: - 2 Pyruvate Molecules. End Product: - 1 Glucose Molecule. Point of Entry: - Oxaloacetate. - Pyruvate Enters the Gluconeogenic Pathway at the Oxaloacetate level. Site (Cell): - It Begins in Mitochondria & Ends in Cytosol. - All the Steps Occur in Cytosol, Except for the First Step, - The Carboxylation of Pyruvate, which Happen in Mitochondria. Energy: - 6 ATP are Required (Lost) for Synthesis of 1 Mole of Glucose. Step Energy Lost Conversion of 2 (Pyruvate) to 2 (Oxaloacetate) Requires 2 ATP by Pyruvate Carboxylase Conversion of 2 (Oxaloacetate) to 2 (PEP) Requires 2 GTP By PEP CarboxyKinase Conversion of 2 (3-PG) to 2 (1,3-BPG) Requires 2 ATP by Phosphoglycerate Kinase - Since 2 Moles of Pyruvate are Required to Form 1 Mole of Glucose, - 6 Moles of High-Energy Phosphate are Required. - 1 GTP is the Equivalent of 1 ATP. 5 Gluconeogenesis from Pyruvate 6  Gluconeogenesis from Pyruvate Steps: (1) Pyruvate is Converted to Oxaloacetate, by Pyruvate Carboxylase, - A Mitochondrial Enzyme that Requires Biotin & ATP. (2) Oxaloacetate Cannot Cross the Mitochondrial Membrane Directly. Oxaloacetate is Converted to Malate or Aspartate, Which Can Cross the Mitochondrial Membrane. (3) Malate or Aspartate are Reconverted to Oxaloacetate in the Cytosol. (4) Oxaloacetate is Decarboxylated to form PEP, by PEP Carboxylkinase. - This Reaction Requires GTP. (5) PEP is Converted to Fructose-1, 6-Bisphosphate, by Reversal of the Glycolytic Reactions. (6) The Conversion of Fructose-1,6-Bisphosphate to Fructose-6-Phosphate, By Fructose 1,6-Bisphosphatase. (7) Conversion of Glucose-6-Phosphate to Glucose By Glucose-6-Phosphatase. - This Enzyme Catalyzes the Release of Free Glucose from Glucose-6-Phosphate. 7  Gluconeogenesis from Pyruvate - Conversion of Oxaloacetate to PEP, by PEP Carboxylkinase. - This Reaction Requires GTP. In Liver and Kidney, GTP is Produced by of Succinate Thiokinase Reaction in CAC, - Thus Providing a Link between CAC & Gluconeogenesis, - To Prevent Excessive Removal of Oxaloacetate for Gluconeogenesis, - Which Would Impair Citric Acid Cycle Activity. - Succinate Thiokinase in Other Tissue Provides ATP Rather than GTP. - Its Presence of Fructose 1,6-Bisphosphatase Determines, - Whether a Tissue is Capable of Synthesizing Glucose (or Glycogen), - F-1,6-BPtase is Present in Liver, Kidney & Skeletal Muscle, - F-1,6-BPtase is Absent from Heart & Smooth Muscle. - Glucose-6-phosphatase Releases Free Glucose from Glucose-6-Phosphate, - Generated from Both Gluconeogenesis and Glycogenolysis. - G-6-Ptase is Present in Liver & Kidney, - G-6-Ptase is Absent from Muscle, which, Cannot Export Glucose into Bloodstream. 8  Gluconeogenesis from Pyruvate Steps: - Conversion of 2 Pyruvate to 1 Glucose. - Gluconeogenesis Involves Several Enzymatic Steps that Do Not Occur in Glycolysis, - Thus Glucose is Not Generated by a Simple Reversal of Glycolysis. - The 3 Irreversible Steps of Glycolysis are Bypassed (Reversed) by 4 Steps (Enzymes) in Gluconeogenesis. Irreversible step in Irreversible step in Glycolysis Gluconeogenesis - Pyruvate Carboxylase - Pyruvate Kinase - PEP Carboxykinase - PFK-1 - Fructose-1,6-Bisphosphatase - Hexokinase - Glucose-6-phosphatase Key Enzymes: (1) Pyruvate Carboxylase. (2) PEP Carboxykinase. (3) F-1,6-Bisphosphatase. (4) G-6-phosphatase. ** F-1,6-Bisphosphatase is the Most Important Key Enzyme ** The formation of glucose does not occur by a simple reversal of glycolysis, because the overall equilibrium of glycolysis strongly favors pyruvate formation. Instead, glucose is synthesized by a special pathway, gluconeogenesis 9  Gluconeogenesis from Pyruvate Regulation: - Glucagon & Epinephrine (Fasting State), Inhibit glycolysis & Stimulate Gluconeogenesis. - Insulin (Superfluity of Glucose) Stimulates glycolysis & inhibits Gluconeogenesis. Because Insulin Antagonizes the effect of Glucocorticoids & Glucagon-Stimulated cAMP, Stimulated by - Anti-insulin. - ATP & Acetyl CoA. Inhibited by - Insulin. - ADP - Glucagon: Stimulates F2,6 bisphosphatase) & (Inhibits PFK-2) - Acetyl CoA & ATP: Stimulate Pyruvate carboxylase 11  Gluconeogenesis from Lactate Substrate: - 2 Lactate Molecules. - Lactate is Released into the Blood by, - Exercising Skeletal Muscle & Anaerobic Cells that Lack Mitochondria (e.g. RBCs). End Product: - 1 Glucose Molecule. Point of Entry: - Oxaloacetate. Energy: - It Loses 6 ATP. Site (Cell): - It Begins in Mitochondria & Ends in Cytosol. Steps: - The Liver Coverts 2 Lactate into 2 Pyruvate by Lactate Dehydrogenase, - Then 2 Pyruvate Enters Gluconeogenesis. Cori Cycle: - Blood Glucose is Converted to Lactate by RBCs & Exercising Muscle, - Lactate Diffuses into the Blood & Reaches Liver. - In Liver, Lactate is Oxidized by NAD+ & Lactate Dehydrogenase to Form Pyruvate, - Pyruvate is Converted to Glucose, - Which is Released Back into the Circulation. 11  Gluconeogenesis from Glycerol Substrate: - 2 Glycerol Molecules. - Glycerol is Derived From the Backbone of Triacylglycerols by TAG Hydrolysis. - Glycerol is Delivered by the Blood to the Liver. End Product: - 1 Glucose Molecule. Point of Entry: - DHAP. - Glycerol Enters the Gluconeogenic Pathway at the DHAP Level. Energy: - It Loses 2 ATP. - Since 2 Moles of Glycerol are Required to Form 1 Mole of Glucose, - 2 Moles of High-Energy Phosphate are Required. Site (Cell): - It occurs in Cytosol. Steps: - Glycerol is Phosphorylated to Glycerol-3-Phosphate by Glycerol Kinase, - Glycerol-3-Phosphate is Oxidized to DHAP by Glycerol Phosphate Dehydrogenase. - Adipocytes Cannot Phosphorylate Glycerol, Because They Lack Glycerol kinase. - In the Fed State, Glycerol is Used for: Re-esterification of Free FAs to TAG, or a Substrate for Gluconeogenesis in the liver. - In the Fasting State, Glycerol Released from Lipolysis of TAG in Adipose tissue for: - Substrate for Gluconeogenesis in the Liver & Kidneys. 12  Gluconeogenesis from Glucogenic Amino Acids - Glucogenic Amino Acids Derived from Hydrolysis of Tissue Proteins, - Are the Major Sources of Glucose During a Fast. Glucogenic Amino Acids are Metabolized to (1) α-keto Acids, (2) Intermediates of Glycolysis, (3) Intermediates of TCA. - These α-KA & Intermediates Can be used in Glucose synthesis. - These α-KA & Intermediates include: - Pyruvate. - Oxaloacetate. - α-ketoglutarate. - Succinyl CoA. - Fumarate. Amino acid Intermediate Glycine, Alanine, Serine, Cysteine, Pyruvate Tryptophan Aspartate, Asparagine Oxaloacetate Histidine, Arginine, Proline, Glutamine, α-ketoglutarate Glutamate Isoleucine, Methionin, Threonine, Valine Succinyl CoA Tyrosine Fumarate Phenylalanine ** α-ketoglutarate, Succinyl CoA, Fumarate enter Krebs cycle to form Oxaloacetate which is a Direct precursor of PEP & Gluconeogenesis Alanine - Glucose cycle: - In Muscle, Glycolysis occurs & converts Glucose to Pyruvate then to Alanine. - Alanine enters bloodstream to reach Liver. - In Liver, Gluconeogensis occurs to converts Pyruvate to Glucose. 13 Regulation of GNG 14 Regulation of GNG 15 Regulation of GNG 16