Glycolysis and Gluconeogenesis Alice Skoumalová. Metabolism of glucose - overview

  • View
    214

  • Download
    2

Embed Size (px)

Text of Glycolysis and Gluconeogenesis Alice Skoumalová. Metabolism of glucose - overview

  • Slide 1
  • Glycolysis and Gluconeogenesis Alice Skoumalov
  • Slide 2
  • Metabolism of glucose - overview
  • Slide 3
  • Slide 4
  • 1. Glycolysis
  • Slide 5
  • Glucose: the universal fuel for human cells Sources: diet (the major sugar in our diet) internal glycogen stores blood (glucose homeostasis) Glucose oxidation: after a meal: almost all tissues during fasting: brain, erythrocytes
  • Slide 6
  • Glycolysis: oxidation and cleavage of glucose ATP generation (with and without oxygen) all cells in the cytosol (the reducing equivalents are transferred to the electron-transport chain by the shuttle) ATP is generated: 1. via substrate-level phosphorylation 2. from NADH 3. from oxidation of pyruvate Regulation of glycolysis: 1. Hexokinase 2. Phosphofructokinase 3. Pyruvate Kinase Generation of precursors for biosynthesis: fatty acids amino acids ribosis-5-P
  • Slide 7
  • Anaerobic glycolysis a limited supply of O 2 no mitochondria increased demands for ATP Lactic acidemia in hypoxia
  • Slide 8
  • Phosphorylation of glucose: irreversible Glucose 6-P: cannot be transported back across the plasma membrane a precursor for many pathways that uses glucose Hexokinases Glucokinase (liver, -cell of the pancreas) high K m
  • Slide 9
  • Michaelis-Menten kinetics
  • Slide 10
  • 1. Conversion of glucose 6-P to the triose phosphates 2. Oxidation and substrate-level phosphorylation
  • Slide 11
  • 1. Conversion of glucose 6-P to the triose phosphates irreversible regulation essential for the subsequent cleavage
  • Slide 12
  • Substrate-level phosphorylation 2. Oxidation and substrate-level phosphorylation
  • Slide 13
  • Summary of the glycolytic pathway: Glucosis + 2 NAD + + 2 P i + 2 ADP 2 pyruvate + 2 NADH + 4 H + + 2 ATP + 2 H 2 O G 0 = - 22 kcal (it cannot be reversed without the expenditure of energy!)
  • Slide 14
  • Clinical correlations: Hypoxemia (lack of oxygen in tissues) Acute hemorrhage (hypotension, lost of erythrocytes) - anaerobic glycolysis - lactate formation, metabolic acidosis Chronic obstructive pulmonary disease (an insuficient ventilation) - anaerobic glycolysis, lactate formation, metabolic acidosis - accumulation of CO 2, respiratory acidosis Myocardial infarction (lack of oxygen in myocardium) - anaerobic glycolysis, lactate formation - lack of ATP
  • Slide 15
  • Aerobic glycolysis: involving shuttles that transfer reducing equivalents across the mitochondrial membrane
  • Slide 16
  • Glycerol 3-phosphate shuttle:
  • Slide 17
  • Malate-aspartate shuttle:
  • Slide 18
  • Anaerobic glycolysis: Energy yield 2 mol of ATP dissociation and formation of H +
  • Slide 19
  • Daily lactate production115 (g/d) Erythrocytes29 Skin20 Brain17 Sceletal muscle16 Renal medulla15 Intestinal mucosa8 Other tissues10 Major tissues of lactate production: (in a resting state)
  • Slide 20
  • Cori cycle: Lactate can be further metabolized by: heart, sceletal muscle Lactate dehydrogenase: a tetramer (subunits M and H)
  • Slide 21
  • Lactate dehydrogenase Pyruvate + NADH + H + lactate + NAD + LD 5 isoenzymes: Heart (lactate) Muscle (pyruvate)
  • Slide 22
  • Biosynthetic functions of glycolysis:
  • Slide 23
  • Clinical correlations: Long-intensity exercise (for example a sprint) - the need for ATP exceeds the capacity of the mitochondria for oxidative phosphorylation, anaerobic glycolysis lactate formation, muscle fatigue and pain - a training the amounts of mitochondria and myoglobin increase
  • Slide 24
  • Regulation
  • Slide 25
  • Fructose 2,6-bis-phosphate: is not an intermediate of glycolysis! Phosphofructokinase-2:inhibited through phosphorylation - cAMP-dependent protein kinase (inhibition of glycolysis during fasting-glucagon) tissue-specific isoenzymes (low K m, a high afinity) glucokinase (high K m ) the rate-limiting, allosteric enzyme tissue-specific isoenzymes
  • Slide 26
  • the liver isoenzyme - inhibition by cAMP-dependent protein kinase (inhibition of glycolysis during fasting) Lactic acidemia: increased NADH/NAD + ratioinhibition of pyruvate dehydrogenase
  • Slide 27
  • 2. Gluconeogenesis
  • Slide 28
  • Gluconeogenesis: synthesis of glucose from noncarbohydrate precursors to maintain blood glucose levels during fasting liver, kidney fasting, prolonged exercise, a high- protein diet, stress Specific pathways: 1.Pyruvate Phosphoenolpyruvate 2.Fructose-1,6-P Fructose-6-P 3.Glucose-6-P Glucose
  • Slide 29
  • Precursors for gluconeogenesis 1.lactate (anaerobic glycolysis) 2.amino acids (muscle proteins) 3.glycerol (adipose tissue)
  • Slide 30
  • Conversion of pyruvate to phosphoenolpyruvate 1. Pyruvate Oxaloacetate Pyruvate carboxylase 2. Oxaloacetate PEP Phosphoenolpyruvate- carboxykinase
  • Slide 31
  • Conversion of phosphoenolpyruvate to glucose 3. Fructose-1,6-P Fructose-6-P Fructose 1,6-bisphosphatase (cytosol) 4. Glucose-6-P Glucose Glucose 6-phosphatase (ER)
  • Slide 32
  • Clinical correlations: Alcoholism - excessive ethanol consumption increase NADH/NAD + ratio that drive the lactate dehydrogenase reaction toward lactate - lack of precursors for gluconeogenesis its inhibition - insuficient diet - reduced glucose in the blood, consumption of glycogen in the liver hypoglycemia
  • Slide 33
  • 3. Regulations
  • Slide 34
  • TypeMechanismExample Substrate concentrationSaturation kinetics (according Michaelis- Menten) Glucokinase (activation after meal- high K m ) AllostericConformational changes induced by the binding of the allosteric efector Enzymes of glycolysis and glukoneogenesis (allosteric effectors ATP, AMP, citrate) Covalent modificationConformational changes induced by phosphorylation by proteinkinases Phosphorylation og glycogensynthase and glycogenphosphorylase (glucagon) Protein-protein interaction Conformational changes as a result of different protein binding Muscle glycogenphosphorylase (activated by Ca 2+ -calmodulin) Proteolytic cleavageActivation by proteolytic cleavage of precursor molecule Proteins of coagulation cascade (zymogens) Enzyme synthesisInduction or repression of the enzyme synthesis Enzymes of gluconeogenesis (induced during fasting) Enzyme regulation:
  • Slide 35
  • Second messenger - cAMP: Glucagon Adenylate- cyclase
  • Slide 36
  • Regulation of gluconeogenesis: concomitant inactivation of the glycolytic enzymes and activation of the enzymes of gluconeogenesis 1. Pyruvate PEP Phosphoenolpyruvate carboxykinase - induced by glucagon, epinephrine, and cortisol 2. Fructose 1,6-P Fructose 6-P Fructose 1,6-bisphosphatase - inhibited by fructose 2,6-P 3. Glucose 6-P Glucose Glucose 6-phosphatase - induced during fasting
  • Slide 37
  • Summary Glycolysis Generation of ATP (with or without oxygen) The role of glycolysis in different tissues Lactate production Regulation (3 key enzymes) Gluconeogenesis Activation during fasting, prolonged exercise, after a high- protein diet Precursors: lactate, glycerol, amino acids 3 key reactions:Pyruvate PEP Fructose-1,6-P Fructose-6-P Glucose-6-P Glucose Regulation
  • Slide 38
  • Slide 39
  • Pictures used in the presentation: Marks Basic Medical Biochemistry, A Clinical Approach, third edition, 2009 (M. Lieberman, A.D. Marks)