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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
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
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)
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
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