Gluconeogenesis_Presentation22.pptxhhhhhh
- 1. GLUCONEOGENESIS: THE PATHWAY OF SURVIVAL WHEN THE BODY TURNS CRISIS INTO OPPORTUNITY 200L MBBS/BDS - GROUP 3
- 2. Gluconeogenesis is a metabolic pathway that synthesizes glucose from non-carbohydrate precursors. These include Lactate, Amino acids, Glycerol part of fat and Propionyl CoA derived from odd chain fatty acids. It is essential during fasting, prolonged exercise, and starvation to maintain blood glucose levels for brain and red blood cell function. INTRODUCTION
- 3. Fasting/Starvation (Hypoglycemia) Intense exercise Low carbohydrate diets Diabetes (Insulin) ORGANS: Primarily in the Liver and Kidney. CELLULAR LOCATION: Cytosol & Mitochondria. INTRODUCTION SITE
- 4. Energy requiring steps (1,3) Energy yielding steps (6,9) Irreversible steps (1,3,9) GLYCOLYSIS
- 5. • Gluconeogenesis closely resembles the reversed pathway of glycolysis, although it is not the complete reversal of glycolysis. • Glycolysis occurs in the Cytoplasm which yields either pyruvate (aerobically) or Lactate (anaerobically) via 10 steps. • Ideally, Pyruvate is converted to Acetyl CoA that enters TCA Cycle but in this case, it cannot. • Pyruvate(3C) enters the Mitochondria where it is converted to Oxaloacetate (4C) by Pyruvate Carboxylase. • Oxaloacetate cannot leave the Mitochondria, it has to be converted to Malate • Malate exits and gets reconverted to Oxaloacetate • Finally Oxaloacetate gets converted to the glycolytic intermediate Phosphoenol Pyruvate by Phosphoenol Pyruvate Carboxykinase (PEPCK) • PEP reverses the glycolytic steps. • The irreversible steps are being circumvented by key gluconeogenic enzymes (i) PEPCK (i) Fructose-1,6-bisphosphatase (iii) Glucose-6-Phosphatase • Together with Pyruvate Carboxylase, these are key enzymes in the reaction GLUCONEOGENESIS
- 6. 1. Lactate: From anaerobic glycolysis (Cori Cycle/Lactic Acid Cycle) 2. Glycerol: From triglyceride breakdown (Lipolysis) 3. Amino Acids: Mainly Alanine and Glutamine (Protein Catabolism) 4. Propionyl CoA: Odd Chain Fatty Acid Oxidation PRECURSORS
- 7. • After strenuous exercise, glucose is anaerobically converted to lactate in the skeletal muscles. • Accumulation of lactic acid is assumed to be the cause of fatigue. • Usually, Lactate is taken to the liver where it is converted to pyruvate first, then reversed to Glucose for reuse via Cori Cycle or Lactic Acid Cycle. • In the case of Gluconeogenesis, it is converted to pyruvate which then enters the Mitochondria to yield Oxaloacetate. • PEP formed will reverse the glycolytic pathway to form glucose LACTATE
- 8. GLYCEROL Lipolysis (breakdown of Triacylglycerides) gives two major components – a Glycerol backbone and 3 Fatty Acids The glycerol is phosphorylated by Glycerol Kinase to yield Glycerol-3-phosphate. Glycerol-3-Phosphate is further converted Dihydroxyacetone Phosphate (DHAP). DHAP is a glycolytic intermediate from the Splitting Phase (Step 4). It is a keto isomer of Glyceraldehyde-3-Phosphate (G3P). Conversion of DHAP to G3P is catalyzed by Phosphotriose isomerase G3P then reverses to yield glucose glycerol
- 9. • Proteins catabolize to form Amino Acids. These Amino acids (Alanine) react with a Keto acid (usually alpha-ketoglutarate) • The product is a modified Keto acid and a new Amino acid (Glutamate) • The modified keto acid can form Pyruvate (Pyruvate – Ocaloacetate – Malate – Oxaloacetate – PEP) • The Keto acid can also be converted to Acetyl CoA or TCA Intermediates (alpha- ketoglutarate or Succinyl CoA) which can yield all Malate. • The Malate exits to be Oxaloacetate and finally PEP Amino acids
- 10. • Odd Chain Fatty Acid Oxidation involves removal of two Carbons consecutively to yield a 3-Carbon Propionyl CoA. • P-CoA is carboxylated to D-Methylmalonyl CoA in the presence of Biotin (Vitamin B7) and ATP. • A racemase enzyme converts the D- Methylmalonyl CoA to L-Methylmalonyl CoA • A mutase rearranges L-Methylmalonyl CoA to Succinyl CoA (TCA intermediate) • Succinyl CoA continues in the TCA cycle to yield Malate. • Malate – Oxaloacetate – PEP – Glucose PROPIONyl Coa
- 13. 1. ENZYMATIC • Pyruvate carboxylase • PEP carboxykinase (PEPCK) • Fructose-1,6-bisphosphatase 2. HORMONAL • Positive Regulators: Glucagon, Cortisol, Acetyl-CoA • Negative Regulators: Insulin, AMP regulation
- 14. Overactivation: Seen in diabetes, leading to hyperglycemia. Deficiencies: Rare enzyme defects causing hypoglycemia. Clinical correlation
- 15. • Gluconeogenesis is like a recycling plant, turning waste (lactate, amino acids) into treasure (glucose). Fun fact/analogy
- 16. QUESTIONS