integration of metabolism
• Metabolism is essentially a linked series of chemical reactions that begins with a particular molecule and converts into some other
molecule(s) in a carefully defined fashion
• Interplay of metabolic pathways for energy productin
• E.g. glucose metabolism (for the production of ATP)
• Oxidation of glucose => interplay among glycolysis, the citric acid cycle, and oxidative phosphorylation
Major metabolic pathways and control sites:
1. Glycolysis:
-> F-2,6-BP formation catalysed by PFK-2: bifunctional enzyme
-> When blood-glucose level is low => Activation of phosphatase FBPase2 => low level of F-2,6-BP => reduction of
phosphofructiokinase activity => glycolysis is slowed
-> Any spared glucose is release into the blood`
2. Gluconeogenesis:
-> Glucose can be synthesized by the liver and kidneys from non-carbohydrate precursors such as lactate, glycerol, and amino acids
-> 1st bypass: Pyruvate => oxaloacetate => Phosphoenolpyruvate ==> Glucose
=> Also, two hydrolytic steps that bypass the irreversible reaction of glycolysis => 2nd and 3rd bypass
• Gluconeogenesis and glycolysis are usually reciprocally regulated so that one pathway is minimally active while the other is highly active
• AMP inhibits fructose 1,6-biphosphatase whereas citrate activates this enzyme
-> A high level of AMP indicates that the energy charge is low and signals the need for ATP generation -> glycolysis is activated
whereas gluconeogenesis is deactivated
-> Conversely, high levels of ATP and citrate indicate that the energy charge is high and that biosynthetic intermediates are
abundant -> glycolysis is deactivated whereas gluconeogenesis is activated
-> Fuctose-2,6-biphosphate inhibits fructose 1,6-biphosphatase. Therefore, when glucose is abundant, the high level of F-2,6-BP
inhibits gluconeogenesis and activates glycolysis
3. Glycogen synthesis and degradation:
-> Glycogen degradation = glycogen phosphorylase cleaves glycogen => glucose 1-
phosphate is rapidly converted into glucose 6-phosphate (phosphoglucomutase) ==>
further metabolism.
-> Glycogen synthesis => Glucose 1-phosphate +UTP => activated intermediate
UDP-glucose => glucose from UDP-glucose is transferred to the growing strand of
glycogen by glycogen synthase
-> Glycogen degradation and synthesis are coordinately controlled by the
epinephrine-triggered amplifying cascade so that the phosphorylase is active when
synthase is inactive and vice versa
, 4. Citric acid cycle and oxidative phosphorylation:
-> Oxidation of carbohydrates, amino acids, and fatty acids (in the form of acetyl CoA). There is a tight coupling=> respiratory
control = ensures that the rate of the citric acid cycle matches the need for ATP.
ATP diminishes the activities of two enzymes in the cycle: isocitrate dehydrogenase and α-ketoglutarate dehydrogenase
Key Junctions:
1. Glucose 6-phosphate:
Fate: Stored as glycogen, degraded to pyruvate, or converted into ribose 5-phosphate (through the pentose phosphate pathway)
Glycogen formation only when ATP is abundant
Glycolytic pathway when ATP or carbon skeletons for biosynthesis are needed (*can be anabolic as well as catabolic)
Pentose phosphate pathway, provides NADPH for reductive biosynthesis and ribose 5-phosphate for the synthesis of nucleotides
Glucose 6-phosphate can be formed by the mobilisation of glycogen or it can be synthesized from pyruvate by the gluconeogenic
pathway
2. Pyruvate:
-> Mainly derived from: glucose 6-phosphate, alanine and lactate
There are 4 fates (1-4):
1. Anaerobic conditions: pyruvate is reduced to lactate by lactate (1)dehydrogenase => which regenerates NAD+
2. Transamination of pyruvate =>conversion of an α-ketoacid to the corresponding amino acid => alanine (2) by aminotransferase
*Transamination is a major link between amino acid and carbohydrate metabolism
3. Carboxylation of pyruvate to oxaloacetate (3) => first step of gluconeogenesis. This carboxylation is also important for
replenishing intermediates of the citric acid cycle.
4. Oxidative decarboxylation to acetyl CoA (4). An irreversible reaction inside mitochondria => It commits the carbon atoms to
oxidation by the citric acid cycle or the synthesis of lipids. Pyruvate dehydrogenase complex (one of the enzymes is pyruvate
decarboxylase)
3. Acetyl CoA:
• Main sources: Pyruvate following oxidative decarboxylation AND β-oxidation of fatty acids.
=> Acetyl CoA has three fates (1-3):
1. It can be oxidized to CO2 by the citric acid cycle (1)
2. Alternatively, three molecules of acetyl CoA can be converted o 3-hydroxy-3-methylglutaryl CoA(2) => precursor of cholesterol
and of ketone bodies (in mitochondria)
3. Acetyl coA can be exported to the cytosol in the form of citrate for the synthesis of fatty acids (3)
Brain:
• Sole fuel: glucose (except during prolonged starvation)
• No glucose storage
• Consumes about 120g glucose (420kcal)/day => ~60% glucose
requirement by the whole body (qat resting state)
• >50% of the energy required to maintain Na+ - K+ membrane
potential for transmitting the nerve impulse, to synthesize
neurotransmitter and their receptors
• Glucose transported to the brain by the glucose transporter GLUT3
• Concentration of glucose in the brain is about 1mM when the plasma
level is 4.7mM (84.7 mg/dl)
• Fatty acids do not serve as fuel for the brain because in the plasma
they are bound to albumin and cannot pass the blood-brain barrier
• In starvation, ketone bodies generated by the liver partly replace
glucose as fuel for the brain
• Metabolism is essentially a linked series of chemical reactions that begins with a particular molecule and converts into some other
molecule(s) in a carefully defined fashion
• Interplay of metabolic pathways for energy productin
• E.g. glucose metabolism (for the production of ATP)
• Oxidation of glucose => interplay among glycolysis, the citric acid cycle, and oxidative phosphorylation
Major metabolic pathways and control sites:
1. Glycolysis:
-> F-2,6-BP formation catalysed by PFK-2: bifunctional enzyme
-> When blood-glucose level is low => Activation of phosphatase FBPase2 => low level of F-2,6-BP => reduction of
phosphofructiokinase activity => glycolysis is slowed
-> Any spared glucose is release into the blood`
2. Gluconeogenesis:
-> Glucose can be synthesized by the liver and kidneys from non-carbohydrate precursors such as lactate, glycerol, and amino acids
-> 1st bypass: Pyruvate => oxaloacetate => Phosphoenolpyruvate ==> Glucose
=> Also, two hydrolytic steps that bypass the irreversible reaction of glycolysis => 2nd and 3rd bypass
• Gluconeogenesis and glycolysis are usually reciprocally regulated so that one pathway is minimally active while the other is highly active
• AMP inhibits fructose 1,6-biphosphatase whereas citrate activates this enzyme
-> A high level of AMP indicates that the energy charge is low and signals the need for ATP generation -> glycolysis is activated
whereas gluconeogenesis is deactivated
-> Conversely, high levels of ATP and citrate indicate that the energy charge is high and that biosynthetic intermediates are
abundant -> glycolysis is deactivated whereas gluconeogenesis is activated
-> Fuctose-2,6-biphosphate inhibits fructose 1,6-biphosphatase. Therefore, when glucose is abundant, the high level of F-2,6-BP
inhibits gluconeogenesis and activates glycolysis
3. Glycogen synthesis and degradation:
-> Glycogen degradation = glycogen phosphorylase cleaves glycogen => glucose 1-
phosphate is rapidly converted into glucose 6-phosphate (phosphoglucomutase) ==>
further metabolism.
-> Glycogen synthesis => Glucose 1-phosphate +UTP => activated intermediate
UDP-glucose => glucose from UDP-glucose is transferred to the growing strand of
glycogen by glycogen synthase
-> Glycogen degradation and synthesis are coordinately controlled by the
epinephrine-triggered amplifying cascade so that the phosphorylase is active when
synthase is inactive and vice versa
, 4. Citric acid cycle and oxidative phosphorylation:
-> Oxidation of carbohydrates, amino acids, and fatty acids (in the form of acetyl CoA). There is a tight coupling=> respiratory
control = ensures that the rate of the citric acid cycle matches the need for ATP.
ATP diminishes the activities of two enzymes in the cycle: isocitrate dehydrogenase and α-ketoglutarate dehydrogenase
Key Junctions:
1. Glucose 6-phosphate:
Fate: Stored as glycogen, degraded to pyruvate, or converted into ribose 5-phosphate (through the pentose phosphate pathway)
Glycogen formation only when ATP is abundant
Glycolytic pathway when ATP or carbon skeletons for biosynthesis are needed (*can be anabolic as well as catabolic)
Pentose phosphate pathway, provides NADPH for reductive biosynthesis and ribose 5-phosphate for the synthesis of nucleotides
Glucose 6-phosphate can be formed by the mobilisation of glycogen or it can be synthesized from pyruvate by the gluconeogenic
pathway
2. Pyruvate:
-> Mainly derived from: glucose 6-phosphate, alanine and lactate
There are 4 fates (1-4):
1. Anaerobic conditions: pyruvate is reduced to lactate by lactate (1)dehydrogenase => which regenerates NAD+
2. Transamination of pyruvate =>conversion of an α-ketoacid to the corresponding amino acid => alanine (2) by aminotransferase
*Transamination is a major link between amino acid and carbohydrate metabolism
3. Carboxylation of pyruvate to oxaloacetate (3) => first step of gluconeogenesis. This carboxylation is also important for
replenishing intermediates of the citric acid cycle.
4. Oxidative decarboxylation to acetyl CoA (4). An irreversible reaction inside mitochondria => It commits the carbon atoms to
oxidation by the citric acid cycle or the synthesis of lipids. Pyruvate dehydrogenase complex (one of the enzymes is pyruvate
decarboxylase)
3. Acetyl CoA:
• Main sources: Pyruvate following oxidative decarboxylation AND β-oxidation of fatty acids.
=> Acetyl CoA has three fates (1-3):
1. It can be oxidized to CO2 by the citric acid cycle (1)
2. Alternatively, three molecules of acetyl CoA can be converted o 3-hydroxy-3-methylglutaryl CoA(2) => precursor of cholesterol
and of ketone bodies (in mitochondria)
3. Acetyl coA can be exported to the cytosol in the form of citrate for the synthesis of fatty acids (3)
Brain:
• Sole fuel: glucose (except during prolonged starvation)
• No glucose storage
• Consumes about 120g glucose (420kcal)/day => ~60% glucose
requirement by the whole body (qat resting state)
• >50% of the energy required to maintain Na+ - K+ membrane
potential for transmitting the nerve impulse, to synthesize
neurotransmitter and their receptors
• Glucose transported to the brain by the glucose transporter GLUT3
• Concentration of glucose in the brain is about 1mM when the plasma
level is 4.7mM (84.7 mg/dl)
• Fatty acids do not serve as fuel for the brain because in the plasma
they are bound to albumin and cannot pass the blood-brain barrier
• In starvation, ketone bodies generated by the liver partly replace
glucose as fuel for the brain
