Title: Glycolysis and Gluconeogenesis
1Glycolysis and Gluconeogenesis
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31. 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
8Michaelis-Menten kinetics
91. Conversion of glucose 6-P to the triose
phosphates
2. Oxidation and substrate-level phosphorylation
101. Conversion of glucose 6-P to the triose
phosphates
essential for the subsequent cleavage
112. Oxidation and substrate-level phosphorylation
Substrate-level phophorylation
Substrate-level phophorylation
12Summary 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
15Glycerol 3-phosphate shuttle
16Malate-aspartate shuttle
17Anaerobic glycolysis
dissociation and formation of H
Energy yield 2 mol of ATP
18Major 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
19Cori cycle
- Lactate can be further metabolized by
- heart, sceletal muscle
- Lactate dehydrogenase a tetramer (subunits M and
H)
20Lactate dehydrogenase
LD
Pyruvate NADH H lactate NAD
5 isoenzymes
Heart (lactate)
Muscle (pyruvate)
21Biosynthetic functions of glycolysis
22Clinical 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
23Regulation
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)
25the liver isoenzyme - inhibition by
cAMP-dependent protein kinase (inhibition of
glycolysis during fasting)
Lactic acidemia increased NADH/NAD
ratio inhibition of pyruvate dehydrogenase
262. 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)
29Conversion of pyruvate to phosphoenolpyruvate
- 1. Pyruvate ? Oxaloacetate
- Pyruvate carboxylase
- 2. Oxaloacetate ? PEP
- Phosphoenolpyruvate-carboxykinase
30Conversion 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)
31Clinical 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
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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
35Pictures used in the presentation Marks Basic
Medical Biochemistry, A Clinical Approach, third
edition, 2009 (M. Lieberman, A.D. Marks)