Glycolysis and Gluconeogenesis - and... · Anaerobic glycolysis a limited supply of O 2 no mitochondria

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  • Glycolysis and

    Gluconeogenesis

    Alice Skoumalová

  • 1. Glycolysis

  • 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

  • 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

  • Anaerobic glycolysis

    a limited supply of O2

    no mitochondria

    increased demands for ATP

    Lactic acidemia

    in hypoxia

  • 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, β-cell of the pancreas)

     high Km

  • Michaelis-Menten kinetics

  • 1. Conversion of glucose 6-P to the triose

    phosphates

    2. Oxidation and substrate-level

    phosphorylation

  • 1. Conversion of glucose 6-P to the triose phosphates

    • irreversible

    • regulation

    essential for

    the subsequent

    cleavage

  • Substrate-level

    phophorylation

    Substrate-level

    phophorylation

    2. Oxidation and substrate-level phosphorylation

  • Summary of the glycolytic pathway:

    Glucosis + 2 NAD+ + 2 Pi + 2 ADP

    2 pyruvate + 2 NADH + 4 H+ + 2 ATP + 2 H2O

    ∆G0´ = - 22 kcal (it cannot be reversed without the expenditure of energy!)

  • Aerobic glycolysis:

     involving shuttles that transfer reducing equivalents across the mitochondrial membrane

  • Glycerol 3-phosphate shuttle:

  • Malate-aspartate shuttle:

  • Anaerobic glycolysis:

    Energy yield 2 mol of ATP

    dissociation and

    formation of H+

  • Daily lactate production 115 (g/d)

    Erythrocytes 29

    Skin 20

    Brain 17

    Sceletal muscle 16

    Renal medulla 15

    Intestinal mucosa 8

    Other tissues 10

    Major tissues of lactate production:

    (in a resting state)

  • Cori cycle:

    Lactate can be further metabolized by:

     heart, sceletal muscle

    Lactate dehydrogenase: a tetramer (subunits M and H)

  • Lactate dehydrogenase

    Pyruvate + NADH + H+ lactate + NAD+ LD

    5 isoenzymes:

    Heart (lactate)

    Muscle (pyruvate)

  • Biosynthetic functions of glycolysis:

  • Regulation

  • 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 Km, a high afinity)

    • glucokinase (high Km)

    • the rate-limiting, allosteric enzyme

    • tissue-specific isoenzymes

  • the liver isoenzyme - inhibition by

    cAMP-dependent protein kinase

    (inhibition of glycolysis during

    fasting)

    Lactic acidemia:

    increased NADH/NAD+ ratio inhibition of pyruvate dehydrogenase

  • 2. Gluconeogenesis

  • 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

  • Precursors for gluconeogenesis

    1. lactate (anaerobic glycolysis)

    2. amino acids (muscle proteins)

    3. glycerol (adipose tissue)

  • Conversion of pyruvate to phosphoenolpyruvate

    1. Pyruvate → Oxaloacetate  Pyruvate carboxylase

    2. Oxaloacetate → PEP

     Phosphoenolpyruvate-

    carboxykinase

  • 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)

  • 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

  • Summary

    Glycolysis

    • Generation of ATP (with or without oxygen)

    • The role of glycolysis in different tissues

    • Lactate production

    • Regulation

    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

  • Pictures used in the presentation:

    Marks´ Basic Medical Biochemistry, A Clinical Approach, third edition, 2009 (M.

    Lieberman, A.D. Marks)