clase I integración metabólica 17 abril 2012

7/30/2019 clase I integracin metablica 17 abril 2012

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Biochemistry

Sixth Edition

Chapter 27

The Integration of Metabolism

Copyright 2007 by W. H. Freeman and Company

Berg Tymoczko Stryer


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Metabolism consists of highly interconnected pathways

1. ATP is the universal currency of energy.

2. ATP is generated by the oxidation of fuel molecules

such as glucose, fatty acids, and amino acids.

3. NADPH is the major electron donor in reductive biosyntheses.

4. Biomolecules are constructed from a small set of building blocks.

5. Biosynthetic and degradative pathways are almost always distinct.


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Recurring motifs are common in metabolic regulation

1. Allosteric interactions. Phosphofructokinase is the classicexample of allosteric regulation.


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1. Allosteric interactions.ATP/AMP ratio regulates

allosterically phosphofructokinase activity.

Fructose 1,6-bisphosphate


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1. Allosteric interactions.Allosteric regulation of phosphofructokinase.

A high level of ATP inhibits the enzyme by decreasing its affinity for fructose6-phosphate. AMP diminishes and citrate enhances the inhibitory effect of ATP.


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1. Allosteric interactions. Regulation of phosphofructokinase by fructose

2,6-bisphosphate (F-2,6-BP). In high concentrations, fructose 6-phosphate

(F-6P) activates the enzyme phosphofructokinase (PFK) through an

intermediary, fructose 2,6-bisphosphate (F-2,6-BP).


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1. Allosteric interactions.Activation of phosphofructokinase by fructose

2,6-bisphosphate (F-2,6-BP). (A) The sigmoidal dependence of velocity on substrate

concentration becomes hyperbolic in the presence of 1 mM fructose 2,6-bisphosphate.

(B) ATP, acting as a substrate, initially stimulates the reaction. As the concentration of

ATP increases, it acts as an allosteric inhibitor. The inhibitory effect of ATP isreversed by fructose 2,6-bisphosphate.


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2. Covalent modifications.The classic example of reversible

covalent modification of proteins is the phosphorylation.


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2. Covalent modifications.Other examples of reversible

covalent modifications of proteins.


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3. Adjustment of enzyme levels. New protein synthesis requiresactivation of the machinery of transcription and translation.


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3. Adjustment of enzyme levels. In the protein degradation pathway mediated

by ubiquitin-proteasome, energy from ATP is used to tag an unwanted protein

with a chain of ubiquitins marking it for destruction. The protein is then

hydrolyzed into small peptides by the proteasome.



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3. Adjustment of enzyme levels.An enzyme changes its Vmax in

response to changes in total enzyme.



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4. Compartmentation.


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5. Metabolic specializations of organs.


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Major metabolic pathways have specific control sites

1. Glycolysis. Phosphofructokinase is the key enzyme in the regulation of glycolysis.


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1. Glycolysis.Regulation of glycolysis in muscle.At rest (left), glycolysis is not very active

(thin arrows). The high concentration of ATP inhibits phosphofructokinase (PFK), pyruvate kinase,

and hexokinase. Glucose 6-phosphate is converted into glycogen. During exercise (right), the

decrease in the ATP/AMP ratio resulting from muscle contraction activates PFK and hence glycolysis.The flux down the pathway is increased, as represented by the thick arrows.

M j b li h h ifi l i


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2. Gluconeogenesis. Fructose 1,6-bisphosphatase is the principal enzymecontrolling the rate of gluconeogenesis.


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Reciprocal regulation of gluconeogenesis and glycolysis in the liver. The

level of fructose 2,6-bisphosphate is high in the fed state and low in starvation. Anotherimportant control is the inhibition of pyruvate kinase by phosphorylation during starvation.


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Pathway integration: Cooperation between glycolysis and gluconeogenesis during a sprint.In skeletal leg muscle, glucose will be metabolized aerobically to CO2 and H20 or, more likely (thick arrows) during a

sprint, anaerobically to lactate. In cardiac muscle, the lactate can be converted into pyruvate and used as a fuel,

along with glucose, to power the sprint. Gluconeogenesis, a primary function of the liver, will be taking place rapidly

(thick arrows) to ensure that enough glucose in present in the blood for skeletal and cardiac muscle, as well as for

other tissues. Glycogen, glycerol, and amino acids are other sources of energy.


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Cellular respiration.The citricacid cycle constitutes the first stage in cellular respiration, theremoval of high-energy electrons from carbon fuels (left). These electrons reduce O2 to generate a

proton gradient (pink pathway), which is used to synthesize ATP (green pathway). The reduction of

O2 and the synthesis of ATP constitute oxidative phosphorylation.


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Response of the pyruvate dehydrogenase complex to the

energy charge.The pyruvate dehydrogenase complex is regulated torespond to the energy charge of the cell. (A) The complex is inhibited

by its immediate products, NADH and acetyl CoA, as well as by the

ultimate product of cellular respiration, ATP. (B) The complex is

activated by pyruvate and ADP, which inhibit the kinase thatphosphorylates PDH.

From glucose to acetyl

CoA. The synthesis of acetylCoA by the pyruvate

dehydrogenase complex is a

key irreversible step in the

metabolism of glucose.


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Control of the citric acid cycle. The citric acid cycle is regulated primarily by theconcentration of ATP and NADH. The key control points are the enzymes isocitrate

dehydrogenase and a-ketoglutarate dehydrogenase.


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Biosynthetic roles of the citric acid cycle. Intermediates are drawn off for thebiosyntheses (shown by pink arrows) when the energy needs of the cell are met.

Intermediates are replenished by the formation of oxaloacetate from pyruvate.



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Pathway integration: Pathways active during exercise after a nights rest.The rate of the citric acid cycle increases during exercise, requiring the replenishment of

oxaloacetate and acetyl CoA. Oxaloacetate is replenished by its formation from pyruvate.

Acetyl CoA may be produced from the metabolism of both pyruvate and fatty acids.


Regulation of the pentose phosphate pathway


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Regulation of the pentose phosphate pathway

The dehydrogenation of glucose 6-phosphate is the committed step

in the pentose phosphate pathway

Regulation of glycogen metabolism


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Regulation of glycogen metabolism

Pathway integration: Hormonal control of glycogen breakdown.Glucagon

stimulates liver glycogen breakdown when blood glucose is low. Epinephrine enhancesglycogen breakdown in muscle and the liver to provide fuel for muscle contraction.

Regulation of fatty acid synthesis


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Regulation of fatty acid synthesis

Acetyl CoA carboxylase is the key control site in fatty acid synthesis

Control of fatty acid degradation


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Control of fatty acid degradation

Malonyl CoA inhibits fatty acid degradation by inhibiting the formation

of acyl carnitine

Glucose 6-phosphate pyruvate and acetyl CoA are



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Glucose 6-phosphate, pyruvate, and acetyl CoA are

key junctions in metabolism

Metabolic fates of glucose 6-phosphate


key junctions in metabolism


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Each organ has a unique metabolic profile: the brain


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key junctions in metabolismEach organ has a unique metabolic profile: the brain

a) lacks fuel stores and hence requires a continuous supply of glucose.

b) Consumes about 120 g of glucose daily, accounting for some 60%

of the utilization of glucose by the whole body in the resting state.

c) Uses much of the energy (60-70%) to power transport mechanisms

that maintain the Na+-K+ membrane potential required for the transmission

of the nerve impulses.

Glucose is virtually the sole fuel for the human brain, except

during prolonged starvation.

Brain:


Each organ has a unique metabolic profile: the brain


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key junctions in metabolismEach organ has a unique metabolic profile: the brain

d) Uptakes glucose by the glucose transporter GLUT3, which has a low

value of KM

for glucose (1.6 mM). GLUT3 is nearly saturated under most

conditions, given during fasting the concentration of glucose in the blood

and in the brain are 4.7 mM (84.7 mg/dL) and 1 mM, respectively.

e) Slows its glycolysis rate when the glucose level approaches the KM

value of hexokinase (~ 50 mM), the enzyme that traps glucose in the cell.This danger point is reached when the plasma-glucose level drops below

about 2.2 mM (39.6 mg/dL) and thus approaches the KM value of GLUT3.

f) Does not uses fatty acids as fuel. In starvation, ketone bodies

generated by the liver partly replace glucose as fuel for the brain.

Glucose is virtually the sole fuel for the human brain, except

during prolonged starvation.

Brain:

Each organ has a unique metabolic profile: the muscle


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The major fuels for skeletal muscle are fatty acids,

glucose, and ketone bodies.


In resting skeletal muscle, fatty acids are the major fuel,

meeting 85% of the energy needs.

Muscle differs from the brain in having a large store of glycogen,

equivalent to 5,000 kJ of energy (about total glycogen

is stored in muscle).

Muscle, like the brain, lacks glucose 6-phosphatase, and so it does

not export glucose. Rather, muscle retains glucose, its preferred

fuel for bursts of activity.



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Metabolic interchanges between muscle and the liver


Pathway integration: the glucose-alanine cycle


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Pathway integration: the glucose-alanine cycle

During prolonged exercise and fasting, muscle uses branched-chain amino acid as fuel. The nitrogen

removed is transferred (through glutamate) to alanine, which is released into the bloodstream. Inthe liver, alanine is taken up and converted into pyruvate for the subsequent synthesis of glucose.

Each organ has a unique metabolic profile: the muscle.


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Each organ has a unique metabolic profile: the muscle.

Unlikely skeletal muscle, heart muscle functions almost

exclusively aerobically.

The heart has virtually no glycogen reserves.

Fatty acids are the hearts main source of fuel, although

ketone bodies as well as lactate can serve as fuel.

Each organ has a unique metabolic profile:


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Each organ has a unique metabolic profile:

the adipose tissue

The triacylglycerols stored in adipose tissue are

an enormous reservoir of metabolic fuel.

In a typical 70-kg man, the 15 kg of tryacylglycerols have an

energy content of 565,000 kJ.

Adipose tissue is specialized for the esterification of fatty acids

to form triacylglycerols and for ther release from triacylglycerols.

Each organ has a unique metabolic profile: the adipose tissue


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Each organ has a unique metabolic profile: the adipose tissue

Synthesis and degradation of triacylglycerols by adipose tissue. Fatty acids from

the liver are delivered to adipose cells in the form of triacylglycerols contained in very lowdensity lipoproteins (VLDLs). Fatty acids from the diet are transported in chylomicrons.

Each organ has a unique metabolic profile: the kidney


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Each organ has a unique metabolic profile: the kidney

The major purpose of the kidneys is to produce urine.

Urine serves as a vehicle for excreting metabolic waste products

and for maintaining the osmolarity of the body fluids.

The kidneys requiere large amounts of energy to accomplishrenal reabsorption. Although constituting only 0.5% of body mass,

the kidneys consume 10% of the oxygen used in cellular respiration.

Much of the glucose that is reabsorbed is carried into the kidney

cells by the sodium-glucose cotransporter.

During starvation, the kidney becomes an important site of

gluconeogenesis and may contribute as much as half of the

blood glucose.

Each organ has a unique metabolic profile: the liver


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The metabolic activities of the liver are essential for

providing fuel to the brain, muscle, and other

peripheral organs.

The liver, which can be from 2-4% of body weight,

is an organisms metabolic hub.



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How the liver metabolizes carbohydrates? The liver:

a) removes 2/3 of the glucose from the blood andall the remaining monosaccharides after meals.

b) left some glucose in blood for use by other tissues.

c) converts absorbed glucose into glucose 6-phosphate, mainlyfor glycogen synthesis. Excess of glucose 6-phosphate is

metabolized to acetyl CoA, which is used to form fatty acids,

cholesterol, and bile salts.

d) supplies NADPH for reductive biosynthesis through proccesing

glucose 6-phosphate by the pentose phosphate pathway.

e) produces glucose for release into the blood by breaking down

its store of glycogen and by carrying out gluconeogenesis from

lactate and alanine from muscle, glycerol from adipose tissue,

and glucogenic amino acid from the diet.



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How the liver metabolizes lipids? The liver:

a) Sterifies and secretes as VLDLs the fatty acids from the diet

or synthesized by the liver when fuels are abundant.

b) Converts fatty acids into ketone bodies in the fasting state.



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ac o ga as a u que etabo c p o e t e e

Lipolysis generates fatty acids and glycerol.The fatty acids are used as fuel bymany tissues. The liver processes glycerol by either the glycolytic or the gluconeogenic

pathway, depending on its metabolic circumstances.



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g q p

Diabetic ketosis results when insulin is absent.In the absence of insulin, fats are releasedfrom adipose tissue, and glucose cannot be absorbed by the liver or adipose tissue. The liver

degrades the fatty acids by b-oxidation but cannot process the acetyl CoA, because of a lack of

glucose-derived oxaloacetate (OAA). Excess ketone bodies are formed and released into the blood.


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Food intake and starvation induce metabolic changes


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g

Fuel choice during starvation.The plasma levels of fatty acids and ketone

bodies increase in starvation, whereas that of glucose decreases.

Metabolic adaptations in prolonged starvation


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p p g

mimimize protein degradation

After several weeks of starvation, ketone


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,

bodies become the major fuel of the brain

Synthesis of ketone bodiesby the liver

Entry of ketone bodies intothe citric acid cycle

Fuel choice during exercise is determined


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g

by the intensity and duration of activity


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Fuel choice during exercise is determined


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Dependence of the velocity of running on the duration of the race.The values shown are world track records.

by the intensity and duration of activity

Shuttle for transfer of acetyl groups from mitochondria to the cytosol


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Shuttle for transfer of acetyl groups from mitochondria to the cytosol

Role of PPAR-gamma Coactivators in Obesity and Thermogenesis


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clase I integración metabólica 17 abril 2012

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