Berg Tymoczko Stryer

Biochemistry
Sixth Edition

Chapter 27 The Integration of Metabolism

Copyright 2007 by W. H. Freeman and Company

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.

Recurring motifs are common in metabolic regulation

1. Allosteric interactions. Phosphofructokinase is the classic

example of allosteric regulation.

Recurring motifs are common in metabolic regulation

Fructose 1,6-bisphosphate

1. Allosteric interactions. ATP/AMP ratio regulates

allosterically phosphofructokinase activity.

Recurring motifs are common in metabolic regulation

1. Allosteric interactions. Allosteric regulation of phosphofructokinase.

A high level of ATP inhibits the enzyme by decreasing its affinity for fructose 6-phosphate. AMP diminishes and citrate enhances the inhibitory effect of ATP.

Recurring motifs are common in metabolic regulation

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).

Recurring motifs are common in metabolic regulation

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 is reversed by fructose 2,6-bisphosphate.

Recurring motifs are common in metabolic regulation

2. Covalent modifications. The classic example of reversible covalent modification of proteins is the phosphorylation.

Recurring motifs are common in metabolic regulation

2. Covalent modifications. Other examples of reversible

covalent modifications of proteins.

Recurring motifs are common in metabolic regulation

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

Recurring motifs are common in metabolic regulation

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.

Recurring motifs are common in metabolic regulation

3. Adjustment of enzyme levels. An enzyme changes its Vmax in response to changes in total enzyme.

Recurring motifs are common in metabolic regulation

4. Compartmentation.

Recurring motifs are common in metabolic regulation

5. Metabolic specializations of organs.

Major metabolic pathways have specific control sites

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

Major metabolic pathways have specific control sites

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.

Major metabolic pathways have specific control sites

2. Gluconeogenesis. Fructose 1,6-bisphosphatase is the principal enzyme

controlling the rate of gluconeogenesis.

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. Another important control is the inhibition of pyruvate kinase by phosphorylation during starvation.

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.

Cellular respiration. The citric acid cycle constitutes the first stage in cellular respiration, the
removal 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.

From glucose to acetyl

Response of the pyruvate dehydrogenase complex to the energy charge. The pyruvate dehydrogenase complex is regulated to
respond 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 that phosphorylates PDH.

CoA. The synthesis of acetyl

CoA by the pyruvate dehydrogenase complex is a key irreversible step in the metabolism of glucose.

Control of the citric acid cycle. The citric acid cycle is regulated primarily by the
concentration of ATP and NADH. The key control points are the enzymes isocitrate dehydrogenase and a-ketoglutarate dehydrogenase.

Biosynthetic roles of the citric acid cycle. Intermediates are drawn off for the
biosyntheses (shown by pink arrows) when the energy needs of the cell are met. Intermediates are replenished by the formation of oxaloacetate from pyruvate.

Major metabolic pathways have specific control sites

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

The dehydrogenation of glucose 6-phosphate is the committed step in the pentose phosphate pathway

Regulation of glycogen metabolism

Pathway integration: Hormonal control of glycogen breakdown. Glucagon

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

Regulation of fatty acid synthesis

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

Control of fatty acid degradation

Malonyl CoA inhibits fatty acid degradation by inhibiting the formation of acyl carnitine

Glucose6-phosphate, 6-phosphate, pyruvate, pyruvate, and andacetyl acetyl CoA CoAare are Glucose keyjunctions junctionsin inmetabolism metabolism key

Metabolic fates of glucose 6-phosphate

Glucose 6-phosphate, pyruvate, and acetyl CoA are key junctions in metabolism

Major metabolic fates of pyruvate and acetyl CoA in mammals

Glucose 6-phosphate, pyruvate, and acetyl the CoA are Each organ has a unique metabolic profile: brain key junctions in metabolism
Glucose is virtually the sole fuel for the human brain, except during prolonged starvation. 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 6-phosphate, pyruvate, and acetyl the CoA are Each organ has a unique metabolic profile: brain key junctions in metabolism
Glucose is virtually the sole fuel for the human brain, except during prolonged starvation. 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.

Each organ has a unique metabolic profile: the muscle

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.

Each organ has a unique metabolic profile: the muscle

Metabolic interchanges between muscle and the liver

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. In the liver, alanine is taken up and converted into pyruvate for the subsequent synthesis of glucose.

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: 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

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 low density lipoproteins (VLDLs). Fatty acids from the diet are transported in chylomicrons.

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 accomplish renal 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

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.

Each organ has a unique metabolic profile: the liver

How the liver metabolizes carbohydrates? The liver:
a) removes 2/3 of the glucose from the blood and all the remaining monosaccharides after meals. b) left some glucose in blood for use by other tissues. c) converts absorbed glucose into glucose 6-phosphate, mainly for 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.

Each organ has a unique metabolic profile: the liver

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.

Each organ has a unique metabolic profile: the liver

Lipolysis generates fatty acids and glycerol. The fatty acids are used as fuel by
many tissues. The liver processes glycerol by either the glycolytic or the gluconeogenic pathway, depending on its metabolic circumstances.

Each organ has a unique metabolic profile: the liver

Diabetic ketosis results when insulin is absent. In the absence of insulin, fats are released
from 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.

Each organ has a unique metabolic profile: the liver

Pathway integration: Liver supplies ketone bodies to the peripheral tissues. During fasting or in
untreated diabetics, the liver converts fatty acids into ketone bodies, which are a fuel source for a number of tissues. Ketone-body production is especially important during starvation, when they are the predominant fuel.

Food intake and starvation induce metabolic changes

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 mimimize protein degradation

After several weeks of starvation, ketone bodies become the major fuel of the brain

Synthesis of ketone bodies by the liver

Entry of ketone bodies into the citric acid cycle

Fuel choice during exercise is determined by the intensity and duration of activity

Fuel choice during exercise is determined by the intensity and duration of activity

Dependence of the velocity of running on the duration of the race.

The values shown are world track records.

Shuttle for transfer of acetyl groups from mitochondria to the cytosol

Role of PPAR-gamma Coactivators in Obesity and Thermogenesis