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Glycolysis and Gluconeogenesis

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Title: Glycolysis and Gluconeogenesis


1
Glycolysis and Gluconeogenesis
  • Alice Skoumalová

2
(No Transcript)
3
1. Glycolysis
4
  • 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

5
  • 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

6
  • Anaerobic glycolysis
  • a limited supply of O2
  • no mitochondria
  • increased demands for ATP
  • Lactic acidemia
  • in hypoxia

7
  • 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, ß-cell of the pancreas)
  • high Km

8
Michaelis-Menten kinetics
9
1. Conversion of glucose 6-P to the triose
phosphates
2. Oxidation and substrate-level phosphorylation
10
1. Conversion of glucose 6-P to the triose
phosphates
essential for the subsequent cleavage
  • irreversible
  • regulation

11
2. Oxidation and substrate-level phosphorylation
Substrate-level phophorylation
Substrate-level phophorylation
12
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!)
13
  • 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 CO2, respiratory acidosis
  • Myocardial infarction (lack of oxygen in
    myocardium)
  • - anaerobic glycolysis, lactate formation
  • - lack of ATP

14
  • Aerobic glycolysis
  • involving shuttles that transfer reducing
    equivalents across the mitochondrial membrane

15
Glycerol 3-phosphate shuttle
16
Malate-aspartate shuttle
17
Anaerobic glycolysis
dissociation and formation of H
Energy yield 2 mol of ATP
18
Major tissues of lactate production (in a
resting state)
Daily lactate production 115 (g/d)
Erythrocytes 29
Skin 20
Brain 17
Sceletal muscle 16
Renal medulla 15
Intestinal mucosa 8
Other tissues 10
19
Cori cycle
  • Lactate can be further metabolized by
  • heart, sceletal muscle
  • Lactate dehydrogenase a tetramer (subunits M and
    H)

20
Lactate dehydrogenase
LD
Pyruvate NADH H lactate NAD
5 isoenzymes
Heart (lactate)
Muscle (pyruvate)
21
Biosynthetic functions of glycolysis
22
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
23
Regulation
24
  • tissue-specific isoenzymes (low Km, a high
    afinity)
  • glucokinase (high Km)
  • the rate-limiting, allosteric enzyme
  • tissue-specific isoenzymes
  • 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)

25
the liver isoenzyme - inhibition by
cAMP-dependent protein kinase (inhibition of
glycolysis during fasting)
Lactic acidemia increased NADH/NAD
ratio inhibition of pyruvate dehydrogenase
26
2. Gluconeogenesis
27
  • 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
  • Pyruvate ? Phosphoenolpyruvate
  • Fructose-1,6-P ? Fructose-6-P
  • Glucose-6-P ? Glucose

28
  • Precursors for gluconeogenesis
  • lactate (anaerobic glycolysis)
  • amino acids (muscle proteins)
  • glycerol (adipose tissue)

29
Conversion of pyruvate to phosphoenolpyruvate
  • 1. Pyruvate ? Oxaloacetate
  • Pyruvate carboxylase
  • 2. Oxaloacetate ? PEP
  • Phosphoenolpyruvate-carboxykinase

30
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)

31
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
32
  • 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

33
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34
  • 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

35
Pictures used in the presentation Marks Basic
Medical Biochemistry, A Clinical Approach, third
edition, 2009 (M. Lieberman, A.D. Marks)
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