CHAPTER
14
Metabolism: Basic
Concepts and Design
14.1 Metabolism Is Composed
of Many Interconnecting
Reactions
14.2 ATP Is the Universal Currency
of Free Energy
14.3 The Oxidation of Carbon Fuels
Is an Important Source
of Cellular Energy
14.4 Metabolic Pathways Contain
Many Recurring Motifs
14.5 Metabolic Processes
Are Regulated in Three
Principal Ways
Complex patterns can be constructed from simple geometrical shapes that are repeated on
different scales, as in fractals. Likewise, the complex biochemistry of a cell—intermediary
metabolism—is constructed from a limited number of recurring motifs, reactions, and
molecules. [© Joan Kerrigan/Dreamstime.com.]
L
iving organisms require a continual input of free energy for three major
purposes: (1) the performance of mechanical work in muscle contraction and
cellular movements, (2) the active transport of molecules and ions, and (3) the
synthesis of macromolecules and other biomolecules from simple precursors.
The free energy used in these processes is derived from the environment. Photosynthetic organisms, or phototrophs, obtain this energy by trapping sunlight,
whereas chemotrophs, which include animals, obtain energy through the oxidation of carbon fuels. Recall that these carbon fuels are ingested as meals and prepared for use by the cells in the process of digestion. In this chapter, we will
examine some of the basic principles that underlie energy flow in all living
systems. These principles are:
1. Fuels are degraded and large molecules are constructed step by step in a series
of linked reactions called metabolic pathways.
203
2. An energy currency common to all life forms, adenosine triphosphate (ATP),
links energy-releasing pathways with energy-requiring pathways.
CH2OH
O
OH
3. The oxidation of carbon fuels powers the formation of ATP.
HO
OH
4. Although there are many metabolic pathways, a limited number of types of
reactions and particular intermediates are common to many pathways.
OH
Glucose
5. Metabolic pathways are highly regulated.
10 steps
14.1 Metabolism Is Composed of Many
Interconnecting Reactions
O
C
H3C
C
O
–
O
Pyruvate
Anaerobic
Aerobic
C
H3C
O
OH
H
C
O
O
–
C
H3C
CoA
S
Acetyl CoA
Metabolism is essentially a linked series of chemical reactions that begins with a
particular biochemical and converts it into some other required biochemical in
a carefully defined fashion (Figure 14.1). These metabolic pathways process a
biochemical from a starting point (glucose, for instance) to an end point (carbon dioxide, water, and biochemically useful energy, in regard to glucose) without the generation of wasteful or harmful side products. There are many such
defined pathways in the cell (Figure 14.2), together called intermediary metabolism, and we will examine many of them in some detail later. These pathways
are interdependent—a biochemical ecosystem—and their activities are coordinated by exquisitely sensitive means of communication in which allosteric
enzymes are predominant. We considered the principles of this communication
in Chapter 12.
Lactate
Figure 14.1 Glucose metabolism. Glucose
is metabolized to pyruvate in 10 linked
reactions. Under anaerobic conditions,
pyruvate is metabolized to lactate and,
under aerobic conditions, to acetyl CoA.
The glucose-derived carbon atoms of acetyl
CoA are subsequently oxidized to CO2.
Metabolism of
Cofactors and Vitamins
Metabolism of
Complex Carbohydrates
Nucleotide
Metabolism
Metabolism of
Complex Lipids
Carbohydrate
Metabolism
Metabolism of
Other Amino Acids
Lipid
Metabolism
Amino Acid
Metabolism
Energy
Metabolism
Metabolism of
Other Substances
Figure 14.2 Metabolic pathways. [From the Kyoto Encyclopedia of Genes and Genomes
(www.genome.ad.jp/kegg).]
204
Metabolism Consists of Energy-Yielding Reactions
and Energy-Requiring Reactions
We can divide metabolic pathways into two broad classes: (1) those that convert
energy from fuels into biologically useful forms and (2) those that require
inputs of energy to proceed. Although this division is often imprecise, it is
nonetheless a useful distinction in an examination of metabolism. Those reactions that transform fuels into cellular energy are called catabolic reactions or,
more generally, catabolism.
Catabolism
Fuel (carbohydrates, fats) 9999: CO2 + H2O + useful energy
Those reactions that require energy—such as the synthesis of glucose, fats, or
DNA—are anabolic reactions or anabolism. The useful forms of energy that are
produced in catabolism are employed in anabolism to generate complex structures from simple ones, or energy-rich states from energy-poor ones.
Anabolism
Useful energy + simple precursors 9999: complex molecules
Some pathways can be either anabolic or catabolic, depending on the energy
conditions in the cell. They are referred to as amphibolic pathways.
An important general principle of metabolism is that biosynthetic and
degradative pathways are almost always distinct from each other. This separation is
necessary for energetic reasons, as will be evident in subsequent chapters. It also
facilitates the control of metabolism.
A Thermodynamically Unfavorable Reaction Can Be
Driven by a Favorable Reaction
How are specific pathways constructed from individual reactions? A pathway must
satisfy minimally two criteria: (1) the individual reactions must be specific and (2)
the entire set of reactions that constitute the pathway must be thermodynamically
favored. A reaction that is specific will yield only one particular product or set of
products from its reactants. For example, glucose can undergo step-by-step conversion to yield carbon dioxide and water as well as useful energy. This conversion
is extremely energy efficient because each step is facilitated by enzymes—highly
specific catalysts. The thermodynamics of metabolism is most readily approached
in relation to free energy, which was discussed in Chapter 5. A reaction can take
place spontaneously only if ⌬G, the change in free energy, is negative. Recall that
⌬G for the formation of products C and D from substrates A and B is given by
¢G = ¢G°¿ + RT ln
[C][D]
[A][B]
Thus, the ⌬G of a reaction depends on the nature of the reactants and products
(expressed by the ⌬G°⬘ term, the standard free-energy change) and on their
concentrations (expressed by the second term).
An important thermodynamic fact is that the overall free-energy change for
a chemically coupled series of reactions is equal to the sum of the free-energy
changes of the individual steps. Consider the following reactions:
A Δ B + C
¢G°¿ = + 21 kJ mol - 1 ( + 5 kcal mol - 1)
B Δ D
¢G°¿ = - 34 kJ mol - 1 ( - 8 kcal mol - 1)
A Δ C + D
¢G°¿ = - 13 kJ mol - 1 ( - 3 kcal mol - 1)
Under standard conditions, A cannot be spontaneously converted into B and C,
because ⌬G°⬘ is positive. However, the conversion of B into D under standard conditions is thermodynamically feasible. Because free-energy changes are additive,
the conversion of A into C and D has a ⌬G°⬘ of ⫺13 kJ mol⫺1 (⫺3 kcal mol⫺1),
205
14.1 Coupled Reactions
which means that it can take place spontaneously under standard conditions.
Thus, a thermodynamically unfavorable reaction can be driven by a thermodynamically favorable reaction to which it is coupled. In this example, the reactions are
coupled by the shared chemical intermediate B. Metabolic pathways are formed
by the coupling of enzyme-catalyzed reactions such that the overall free energy of
the pathway is negative.
206
14 Metabolism: Basic Concepts and Design
14.2 ATP Is the Universal Currency of Free Energy
Just as commerce is facilitated by the use of a common monetary currency, the
commerce of the cell—metabolism—is facilitated by the use of a common energy
currency, adenosine triphosphate (ATP). Part of the free energy derived from the
oxidation of carbon fuels and from light is transformed into this readily available
molecule, which acts as the free-energy donor in most energy-requiring processes
such as motion, active transport, or biosynthesis. Indeed, most of catabolism consists of reactions that extract energy from fuels such as carbohydrates and fats and
convert it into ATP.
ATP Hydrolysis Is Exergonic
ATP is a nucleotide consisting of adenine, a ribose, and a triphosphate unit
(Figure 14.3). In considering the role of ATP as an energy carrier, we can focus on
its triphosphate moiety. ATP is an energy-rich molecule because its triphosphate unit
contains two phosphoanhydride bonds. Phosphoanhydride bonds are formed
between two phosphoryl groups accompanied by the loss of a molecule of water.
A large amount of free energy is liberated when ATP is hydrolyzed to adenosine
diphosphate (ADP) and orthophosphate (Pi) or when ATP is hydrolyzed to
adenosine monophosphate (AMP) and pyrophosphate (PPi).
¢G°¿ = - 30.5 kJ mol - 1 ( - 7.3 kcal mol - 1)
ATP + H2O Δ ADP + Pi
ATP + H2O Δ AMP + PPi ¢G°¿ = - 45.6 kJ mol - 1 ( - 10.9 kcal mol - 1)
The precise ⌬G°⬘ for these reactions depends on the ionic strength of the medium
and on the concentrations of Mg2⫹ and other metal ions in the medium. Under
NH2
2–
– O
O
P
O
␥
P
O
O
– O
␤
P
O
O
N
␣
O
N
N
O
HO
O
P
O
N
O
N
–
2– O
P
O
O
O
OH
HO
NH2
O
P
O
OH
Adenosine diphosphate (ADP)
N
2–
N
O
Adenosine triphosphate (ATP)
Figure 14.3 Structures of ATP, ADP, and
AMP. These adenylates consist of adenine
(blue), a ribose (black), and a tri-, di-, or
monophosphate unit (red). The
innermost phosphorus atom of ATP is
designated P␣, the middle one P␤, and
the outermost one P␥.
N
O
O
O
N
O
HO
N
N
OH
Adenosine monophosphate (AMP)
typical cellular concentrations, the actual ⌬G for these hydrolyses is approximately
⫺50 kJ mol⫺1 (⫺12 kcal mol⫺1).
The free energy liberated in the hydrolysis of ATP is harnessed to drive reactions that require an input of free energy, such as muscle contraction. In turn, ATP
is formed from ADP and Pi when fuel molecules are oxidized in chemotrophs or
when light is trapped by phototrophs. This ATP–ADP cycle is the fundamental
mode of energy exchange in biological systems.
ATP Hydrolysis Drives Metabolism by Shifting
the Equilibrium of Coupled Reactions
An otherwise unfavorable reaction can be made possible by coupling to ATP
hydrolysis. Consider a chemical reaction that is thermodynamically unfavorable
without an input of free energy, a situation common to many biosynthetic
reactions. Suppose that the standard free energy of the conversion of compound
A into compound B is ⫹16.7 kJ mol⫺1 (⫹4.0 kcal mol⫺1):
A Δ B
¢G°¿ = + 16.7 kJ mol - 1 ( + 4.0 kcal mol - 1)
⬘ of this reaction at 25°C is related to ⌬G°⬘ (in units
The equilibrium constant K eq
of kilojoules per mole) by
œ
K eq
= [B]eq/[A]eq = 10 - ¢G°¿/5.69 = 1.15 * 10 - 3
Thus, the net conversion of A into B cannot take place when the molar ratio of B
to A is equal to or greater than 1.15 ⫻ 10⫺3. However, A can be converted into B
under these conditions if the reaction is coupled to the hydrolysis of ATP. Under
standard conditions, the ⌬G°⬘ of hydrolysis is approximately ⫺30.5 kJ mol⫺1
(⫺7.3 kcal mol⫺1). The new overall reaction is
A + ATP + H2O Δ B + ADP + Pi
¢G°¿ = -13.8 kJ mol - 1 ( - 3.3 kcal mol - 1)
Its free-energy change of ⫺13.8 kJ mol⫺1 (⫺3.3 kcal mol⫺1) is the sum of the
value of ⌬G°⬘ for the conversion of A into B [⫹16.7 kJ mol⫺1 (⫹4.0 kcal mol⫺1)]
and the value of ⌬G°⬘ for the hydrolysis of ATP [⫺30.5 kJ mol⫺1 (⫺7.3 kcal
mol⫺1)]. At pH 7, the equilibrium constant of this coupled reaction is
œ
K eq
=
[B]eq
[A]eq
*
[ADP]eq[Pi]eq
[ATP]eq
= 1013.8/5.69 = 2.67 * 102
At equilibrium, the ratio of [B] to [A] is given by
[B]eq
[A]eq
œ
= K eq
[ATP]eq
[ADP]eq[Pi]eq
which means that the hydrolysis of ATP enables A to be converted into B until the
[B]/[A] ratio reaches a value of 2.67 ⫻ 102. This equilibrium ratio is strikingly different from the value of 1.15 ⫻ 10⫺3 for the reaction A : B in the absence of ATP
hydrolysis. In other words, coupling the hydrolysis of ATP with the conversion of
A into B under standard conditions has changed the equilibrium ratio of B to A
by a factor of about 105. If we were to use the ⌬G of hydrolysis of ATP under cellular conditions [⫺50.2 kJ mol⫺1 (⫺12 kcal mol⫺1)] in our calculations instead
of ⌬G°⬘, the change in the equilibrium ratio would be even more dramatic, of the
order of 108.
We see here the thermodynamic essence of ATP’s action as an energycoupling agent. In the cell, the hydrolysis of an ATP molecule in a coupled reaction
changes the equilibrium ratio of products to reactants by a very large factor, of the
207
14.2 ATP: Currency of Free Energy
order of 108. Thus, a thermodynamically unfavorable reaction sequence can be converted
into a favorable one by coupling it to the hydrolysis of ATP molecules in a new reaction.
We should also emphasize that A and B in the preceding coupled reaction may be
interpreted very generally, not only as different chemical species. For example, A and
B may represent activated and unactivated conformations of a protein that is activated
by phosphorylation with ATP. Through such changes in protein conformation, muscle proteins convert the chemical energy of ATP into the mechanical energy of muscle contraction. Alternatively, A and B may refer to the concentrations of an ion or
molecule on the outside and inside of a cell, as in the active transport of a nutrient.
208
14 Metabolism: Basic Concepts and Design
The High Phosphoryl Potential of ATP Results from
Structural Differences Between ATP and Its Hydrolysis Products
What makes ATP a particularly efficient energy currency? Let us compare the standard free energy of hydrolysis of ATP with that of a phosphate ester, such as
glycerol 3-phosphate:
¢G°¿ = - 30.5 kJ mol - 1 ( - 7.3 kcal mol - 1)
ATP + H2O Δ ADP + Pi
Glycerol 3-phosphate + H2O Δ glycerol + Pi
¢G°¿ = - 9.2 kJ mol - 1 ( - 2.2 kcal mol - 1)
O–
O
P
HO
P
O–
O–
HO
O–
O
O–
1. Electrostatic Repulsion. At pH 7, the triphosphate unit of ATP carries about four
negative charges (see Figure 14.3). These charges repel one another because they
are in close proximity. The repulsion between them is reduced when ATP is
hydrolyzed.
O–
P
HO
The magnitude of ⌬G°⬘ for the hydrolysis of glycerol 3-phosphate is much smaller
than that of ATP, which means that ATP has a stronger tendency to transfer its terminal phosphoryl group to water than does glycerol 3-phosphate. In other words,
ATP has a higher phosphoryl-transfer potential (phosphoryl-group-transfer potential) than does glycerol 3-phosphate.
The high phosphoryl-transfer potential of ATP can be explained by features
of the ATP structure. Because ⌬G°⬘ depends on the difference in free energies of
the products and reactants, we need to examine the structures of both ATP and
its hydrolysis products, ADP and Pi, to understand the basis of high phosphoryltransfer potential. Three factors are important: electrostatic repulsion, resonance
stabilization, and stabilization due to hydration.
+HO
O
O–
P
O–
O–
2. Resonance Stabilization. ADP and, particularly, Pi have greater resonance stabilization than does ATP. Orthophosphate has a number of resonance forms of
similar energy (Figure 14.4), whereas the ␥ phosphoryl group of ATP has a
smaller number (Figure 14.5). Forms like that shown on the right in Figure 14.5
are unfavorable because a positively charged oxygen atom is adjacent to a positively charged phosphorus atom, an electrostatically unfavorable juxtaposition.
Figure 14.4 Resonance structures of
orthophosphate.
3. Stabilization Due to Hydration. More water can bind more effectively to ADP
and Pi than can bind to the phosphoanhydride part of ATP, stabilizing the ADP
and Pi by hydration.
QUICK QUIZ 1 What properties of
ATP make it an especially effective
phophoryl-transfer-potential compound?
O
O
P
AMP
O
–
O
P
O
O–
O–
O
O–
P
AMP
O
O–
P
O
O
O–
O
O–
P
AMP
O
O–
P+
P
O
O
O–
O–
O
AMP
O
O–
+
O
P
O–
O–
Figure 14.5 Improbable resonance structure. There are fewer resonance structures available
to the ␥-phosphate of ATP than to free orthophosphate.
Phosphoryl-Transfer Potential Is an Important Form
of Cellular Energy Transformation
209
14.2 ATP: Currency of Free Energy
The standard free energies of hydrolysis provide a convenient means of comparing the
phosphoryl-transfer potential of phosphorylated compounds. Such comparisons
reveal that ATP is not the only compound with a high phosphoryl-transfer potential.
In fact, some compounds in biological systems have a higher phosphoryl-transfer
potential than that of ATP. These compounds include phosphoenolpyruvate (PEP),
1,3-bisphosphoglycerate (1,3-BPG), and creatine phosphate (Figure 14.6).
H
O
–
C
C
H
2–
O
O
P
C
O
NH
O
O
–
C
O
O
Phosphoenolpyruvate (PEP)
H2
C
2–
O
P
C
N
N
H
O
O
CH3
2– O
H2
C
P
O
O
O
C
C
HO
Creatine phosphate
Thus, PEP can transfer its phosphoryl group to ADP to form ATP. Indeed, this transfer
is one of the ways in which ATP is generated in the breakdown of sugars (pp. 231 and
233). Of significance is that ATP has a phosphoryl-transfer potential that is intermediate among the biologically important phosphorylated molecules (Table 14.1). This
intermediate position enables ATP to function efficiently as a carrier of phosphoryl groups.
Table 14.1 Standard free energies of hydrolysis of some phosphorylated compounds
kJ mol⫺1
Phosphoenolpyruvate
1,3-Bisphosphoglycerate
Creatine phosphate
ATP (to ADP)
Glucose 1-phosphate
Pyrophosphate
Glucose 6-phosphate
Glycerol 3-phosphate
⫺61.9
⫺49.4
⫺43.1
⫺30.5
⫺20.9
⫺19.3
⫺13.8
⫺9.2
O
O
1,3-Bisphosphoglycerate (1,3-BPG)
Figure 14.6 Compounds with high phosphoryl-transfer potential. These compounds have a
higher phosphoryl-transfer potential than that of ATP and can be used to phosphorylate
ADP to form ATP.
Compound
P
O
H
2–
O
O
kcal mol⫺1
⫺14.8
⫺11.8
⫺10.3
⫺7.3
⫺5.0
⫺4.6
⫺3.3
⫺2.2
Clinical Insight
Exercise Depends on Various Means of Generating ATP
At rest, muscle contains only enough ATP to sustain contractile activity for less than
a second. Creatine phosphate, a high-phosphoryl-transfer-potential molecule in
vertebrate muscle, serves as a reservoir of high-potential phosphoryl groups that can
be readily transferred to ATP. This reaction is catalyzed by creatine kinase.
Creatine
kinase
Creatine phosphate + ADP ERRF ATP + creatine
In resting muscle, typical concentrations of these metabolites are [ATP] ⫽ 4 mM,
[ADP] ⫽ 0.013 mM, [creatine phosphate] ⫽ 25 mM, and [creatine] ⫽13 mM.
Because of its abundance and high phosphoryl-transfer potential relative to that
of ATP (see Table 14.1), creatine phosphate is a highly effective phosphoryl buffer.
Indeed, creatine phosphate is the major source of phosphoryl groups for ATP
regeneration for activities that require quick bursts of energy or short, intense
sprints (Figure 14.7). The fact that creatine phosphate can replenish ATP pools is
210
14 Metabolism: Basic Concepts and Design
Figure 14.7 Sprint to the finish. Creatine
phosphate is an energy source for intense
sprints. Here, Alessandro Petacchi sprints
to a victory in a stage of the 2007 Vuelta
a España. [Jose Luis Roca/AFP/Getty Images.]
the basis of creatine’s use as a dietary supplement by athletes in sports requiring
short bursts of intense activity. After the creatine phosphate pool is depleted, ATP
must be generated through metabolism (Figure 14.8). ■
ATP
Aerobic metabolism
(Sections 8 and 9)
Creatine phosphate
Seconds
Minutes
Hours
14.3 The Oxidation of Carbon Fuels Is an Important Source
of Cellular Energy
Motion
Active transport
Biosyntheses
Signal amplification
ATP
Energy
Figure 14.8 Sources of ATP during
exercise. Exercise is initially powered by
existing high-phosphoryl-transfer
compounds (ATP and creatine phosphate).
Subsequently, the ATP must be
regenerated by metabolic pathways.
Anaerobic
metabolism
(Section 7)
ADP
Oxidation of fuel
molecules
or
Photosynthesis
Figure 14.9 The ATP–ADP cycle. This cycle
is the fundamental mode of energy
exchange in biological systems.
ATP serves as the principal immediate donor of free energy in biological systems
rather than as a long-term storage form of free energy. In a typical cell, an ATP
molecule is consumed within a minute of its formation. Although the total quantity of ATP in the body is limited to approximately 100 g, the turnover of this small
quantity of ATP is very high. For example, a resting human being consumes about
40 kg (88 pounds) of ATP in 24 hours. During strenuous exertion, the rate of utilization of ATP may be as high as 0.5 kg (1.1 pounds) per minute. For a 2-hour
run, 60 kg (132 pounds) of ATP is utilized. Clearly, having mechanisms for regenerating ATP is vital. Motion, active transport, signal amplification, and biosynthesis can take place only if ATP is continually regenerated from ADP (Figure 14.9).
The generation of ATP is one of the primary roles of catabolism. The carbon in
fuel molecules—such as glucose and fats—is oxidized to CO2, and the energy
released is used to regenerate ATP from ADP and Pi.
Carbon Oxidation Is Paired with a Reduction
211
14.3 Oxidation of Carbon Fuels
All oxidation reactions include the loss of electrons from the molecule being
oxidized—carbon fuels in this case—and the gaining of those electrons by some
other molecule, a process termed reduction. Such coupled reactions are called
oxidation–reduction or redox reactions. In aerobic organisms, the ultimate electron
acceptor in the oxidation of carbon is O2 and the oxidation product is CO2. Consequently, the more reduced a carbon is to begin with, the more free energy is
released by its oxidation. Figure 14.10 shows the ⌬G°⬘ of oxidation for onecarbon compounds.
Most energy
Least energy
H
C
H
O
OH
H
H
C
H
H
H
H
O
O
C
C
C
H
H
OH
O
Methane
Methanol
Formaldehyde
Formic acid
Carbon dioxide
ΔG°ⴕoxidation
(kJ mol–1)
–820
–703
–523
–285
0
ΔG°ⴕoxidation
(kcal mol–1)
–196
–168
–125
–68
0
Figure 14.10 Free energy of oxidation of single-carbon compounds.
Although fuel molecules are more complex (Figure 14.11) than the singlecarbon compounds depicted in Figure 14.10, when a fuel is oxidized, the oxidation takes place one carbon at a time. The carbon-oxidation energy is used in
some cases to create a compound with high phosphoryl-transfer potential and in
other cases to create an ion gradient (Section 9). In either case, the end point is
the formation of ATP.
CH2OH
O H
H
OH H
OH
HO
H OH
H
–
O
O
H2
C
C
C
H2
H2
C
C
H2
H2
C
C
H2
Glucose
H2
C
C
H2
H2
C
C
H2
H2
C
C
H2
H2
C
C
H2
CH3
Fatty acid
Figure 14.11 Prominent fuels. Fats are a more efficient fuel source than carbohydrates such
as glucose because the carbon in fats is more reduced.
Compounds with High Phosphoryl-Transfer Potential
Can Couple Carbon Oxidation to ATP Synthesis
O
How is the energy released in the oxidation of a carbon compound converted into
ATP? As an example, consider glyceraldehyde 3-phosphate (shown in the margin),
which is a metabolite of glucose formed in the oxidation of that sugar. The C-1
carbon atom (shown in red) is at the aldehyde-oxidation level and is not in its
most oxidized state. Oxidation of the aldehyde to an acid will release energy.
O
C
H
C
O
H
OH
C
OH
CH2OPO32–
Glyceraldehyde 3-phosphate
Oxidation
H
C
OH
CH2OPO32–
3-Phosphoglyceric acid
H
C
C
H
OH
CH2OPO32–
Glyceraldehyde 3-phosphate
(GAP)
212
14 Metabolism: Basic Concepts and Design
However, the oxidation does not take place directly. Instead, the carbon
oxidation generates an acyl phosphate, 1,3-bisphosphoglycerate. The electrons
released are captured by NAD⫹, which we will consider shortly.
O
C
H
C
O
H
+ NAD+ + HPO42–
OH
H
CH2OPO32–
C
C
OPO32–
+ NADH + H+
OH
CH2OPO32–
Glyceraldehyde 3-phosphate
(GAP)
1,3-Bisphosphoglycerate
(1,3-BPG)
For reasons similar to those discussed for ATP, 1,3-bisphosphoglycerate has a
high phosphoryl-transfer potential. Thus, the cleavage of 1, 3-BPG can be coupled to the synthesis of ATP.
O
H
C
C
OPO32–
OH
CH2OPO32–
1,3-Bisphosphoglycerate
O
OH
C
+ ADP
H
C
OH
+ ATP
CH2OPO32–
3-Phosphoglyceric acid
The energy of oxidation is initially trapped as a high-phosphoryl-transfer-potential
compound and then used to form ATP. The oxidation energy of a carbon atom is
transformed into phosphoryl-transfer potential—first, as 1,3-bisphosphoglycerate and, ultimately, as ATP. We will consider these reactions in mechanistic detail
on page 230.
14.4 Metabolic Pathways Contain Many Recurring Motifs
At first glance, metabolism appears intimidating because of the sheer number of
reactants and reactions. Nevertheless, there are unifying themes that make the
comprehension of this complexity more manageable. These unifying themes
include common metabolites and regulatory schemes that stem from a common
evolutionary heritage.
Activated Carriers Exemplify the Modular Design
and Economy of Metabolism
We have seen that phosphoryl transfer can be used to drive otherwise thermodynamically unfavorable reactions, alter the energy or conformation of a protein, or
serve as a signal to alter the activity of a protein. The phosphoryl-group donor in
all of these reactions is ATP. In other words, ATP is an activated carrier of phosphoryl groups because phosphoryl transfer from ATP is an energetically favorable, or
exergonic, process. The use of activated carriers is a recurring motif in biochemistry, and we will consider several such carriers here. Many such activated carriers
function as coenzymes—small organic molecules that serve as cofactors for
enzymes (p. 65):
1. Activated Carriers of Electrons for Fuel Oxidation. In aerobic organisms, the
ultimate electron acceptor in the oxidation of fuel molecules is O2. However,
electrons are not transferred directly to O2. Instead, fuel molecules transfer electrons to special carriers, which are either pyridine nucleotides or flavins. The
reduced forms of these carriers then transfer their high-potential electrons to O2.
In other words, these carriers have a higher affinity for electrons than do carbon
fuels but a lower affinity for electrons than does O2; consequently, the electrons
flow from an unstable configuration (low affinity) to a stable one (high affinity).
(A)
Reactive site
H
H
O
H
O
O P
–
O
O
(B)
N+
O
H
C
NH2
O P
–
O
O
O
HO
N
N
NH2 + H+
N
R
H
O
C
NH2 + 2 H+ + 2 e+
N
N
H
H
+
N
OH H
HO
O
H
NH2
R
NAD
NADH
Figure 14.12 A nicotinamide-derived electron carrier. (A) Nicotinamide adenine
dinucleotide (NAD⫹) is a prominent carrier of high-energy electrons derived from
the vitamin niacin (nicotinamide) shown in red. (B) NAD⫹ is reduced to NADH.
OH
Indeed, the tendency of these electrons to flow toward a more stable arrangement
accounts for describing them as being activated. The energy that is released is
converted into ATP by mechanisms to be discussed in Chapter 20.
Nicotinamide adenine dinucleotide (NAD⫹), a pyridine nucleotide, is a major
electron carrier in the oxidation of fuel molecules (Figure 14.12). The reactive
part of NAD⫹ is its nicotinamide ring, a pyridine derivative synthesized from the
vitamin niacin. In the oxidation of a substrate, the nicotinamide ring of NAD⫹
accepts a hydrogen ion and two electrons, which are equivalent to a hydride ion (H≠-).
The reduced form of this carrier is called NADH. In the oxidized form, the nitrogen atom carries a positive charge, as indicated by NAD⫹. Nicotinamide adenine
dinucleotide, or NAD⫹, is the electron acceptor in many reactions of the following type:
OH
O
+ NAD+
C
R
H
+ NADH + H+
C
R⬘
R
R⬘
This redox reaction is often referred to as a dehydrogenation because protons
accompany the electrons. One proton and two electrons of the substrate are directly
transferred to NAD⫹, whereas the other proton appears in the solvent as a proton.
The other major electron carrier in the oxidation of fuel molecules is the
coenzyme flavin adenine dinucleotide (Figure 14.13). The abbreviations for the
O
H
Reactive sites
N
H3C
NH
N
N
H3C
H
H
C
H
H
C
OH
H
C
OH
H
C
OH O
H2C
P
O
O
O
–
O
P
O
–
O
O
N
N
N
O
HO
NH2
N
H
OH
H
Figure 14.13 The structure of the oxidized
form of flavin adenine dinucleotide (FAD).
This electron carrier consists of vitamin
riboflavin (shown in blue) and an ADP unit
(shown in black).
213
214
14 Metabolism: Basic Concepts and Design
oxidized and reduced forms of this carrier are FAD and FADH2, respectively. FAD
is the electron acceptor in reactions of the following type:
H
H
C
R
R⬘
R
C
H
R⬘
C
+ FAD
+ FADH2
C
H
H
H
The reactive part of FAD is its isoalloxazine ring, a derivative of the vitamin
riboflavin (Figure 14.14). FAD, like NAD⫹, can accept two electrons. In doing
so, FAD, unlike NAD⫹, takes up two protons. These carriers of high-potential
electrons as well as flavin mononucleotide (FMN), an electron carrier related to
FAD, will be considered further in Chapters 19 and 20.
O
H
H3C
N
H3C
NH
H3C
N
H
H
H
N
O
N
NH
+ 2 H+ + 2 e–
O
H3C
N
H
R
Oxidized form
(FAD)
R
N
O
H
Reduced form
(FADH2)
Figure 14.14 Structures of the reactive parts of FAD and FADH2. The electrons and protons
are carried by the isoalloxazine ring component of FAD and FADH2.
2. Activated Carriers of Electrons for the Synthesis of Biomolecules. High-potential electrons are required in most biosyntheses because the precursors are more oxidized
than the products. Hence, reducing power is needed in addition to ATP. This process
is called reductive biosynthesis. For example, in the biosynthesis of fatty acids, the keto
group of a two-carbon unit is reduced to a methylene group in several steps. This
sequence of reactions requires an input of four electrons.
H2
C
R
R⬘
C
+ 4
H+
+ 4
H2
C
e–
R
R⬘
C
H2
+ H2O
O
The electron donor in most reductive biosyntheses is NADPH, the reduced form
of nicotinamide adenine dinucleotide phosphate (NADP⫹). NADPH differs from
NADH in that the 2⬘-hydroxyl group of its adenosine moiety is esterified with
phosphate (Figure 14.15). NADPH carries electrons in the same way as NADH.
However, NADPH is used almost exclusively for reductive biosyntheses, whereas
NADH is used primarily for the generation of ATP. The extra phosphoryl group on
Reactive site
H
H
O
H
O
O P
–
O
O
Figure 14.15 The structure of
nicotinamide adenine dinucleotide
phosphate (NADP⫹). NADP⫹ provides
electrons for biosynthetic purposes. Notice
that the reactive site is the same in
NADP⫹ and NAD⫹.
N+
O
H
NH2
NH2
N
OH H
HO
O P
–
O
O
O
HO
N
N
N
OPO32–
H
Reactive group
HS
H
N
H
N
H
–O
OH
O
O H3C
O
–
CH3
P
O
O
O
N
N
N
O
2–O
OH
3PO
β-Mercaptoethylamine unit
14.4 Recurring Motifs
O
P
O
215
NH2
N
Figure 14.16 The structure of coenzyme
A (CoA-SH).
Pantothenate unit
NADPH is a tag that enables enzymes to distinguish between high-potential electrons to be used in anabolism and those to be used in catabolism.
3. An Activated Carrier of Two-Carbon Fragments. Coenzyme A (also called
CoA-SH), another central molecule in metabolism, is a carrier of acyl groups
(Figure 14.16). A key constituent of coenzyme A is the vitamin pantothenate.
Acyl groups are important constituents both in catabolism, as in the oxidation
of fatty acids, and in anabolism, as in the synthesis of membrane lipids. The terminal sulfhydryl group in CoA is the reactive site. Acyl groups are linked to the
sulfhydryl group of CoA by thioester bonds. The resulting derivative is called an
acyl CoA. An acyl group often linked to CoA is the acetyl unit; this derivative is
called acetyl CoA. The ⌬G°⬘ for the hydrolysis of acetyl CoA has a large negative
value:
O
O
CoA
C
R
S
Acyl CoA
S
Acetyl CoA
O–
O
R⬘
C
+
R
Acetyl CoA + H2O Δ acetate + CoA + H
¢G°¿ = - 31.4 kJ mol - 1( - 7.5 kcal mol - 1)
C
R
O
+
R⬘
+
R⬘
O
O–
O
C
R⬘
C
The hydrolysis of a thioester is thermodynamically more favorable than that of an
oxygen ester, such as those in fatty acids, because the electrons of the C “ O bond
form less-stable resonance structures with the C ¬ S bond than with the C ¬ O
bond. Consequently, acetyl CoA has a high acetyl-group-transfer potential because
transfer of the acetyl group is exergonic. Acetyl CoA carries an activated acetyl
group, just as ATP carries an activated phosphoryl group.
CoA
C
H3C
R
R
S
S
Oxygen esters are stabilized by resonance
structures not available to thioesters.
Clinical Insight
Coenzyme A and Nazi Medical Practice
Hallervorden–Spatz syndrome is a pathological condition characterized by neurodegeneration and iron accumulation in the brain. Specifically, a patient having
this syndrome displays abnormal postures and disrupted movement (dystonia), an
inability to articulate words (dysarthria), involuntary writhing movements (choreathetosis), and muscle rigidity and resting tremors (parkinsonism). All patients with
classic Hallervorden–Spatz syndrome lack the enzyme pantothenate kinase.
An important regulatory enzyme in the biosynthetic pathway for coenzyme
A, pantothenate kinase activates the vitamin pantothenate by phosphorylating it
at the expense of ATP.
[FoodCollection/AgeFotostock.]
Pantothenate Pantothenate is a
component of coenzyme A and a cofactor
required for fatty acid synthesis. The
vitamin is plentiful in many of foods, with
egg yolk being a rich source. A deficiency
of pantothenate alone has never been
documented
O
H
N
O
H
Pantothenate
kinase
OH + ATP
–
O
OH
O
H3C
Pantothenate
CH3
H
N
O
H
P
O
–
O
OH
O
H3C
CH3
4’-Phosphopantothenate
In subsequent steps, pantothenate phosphate is converted into coenzyme A. Presumably, the symptoms of Hallervorden–Spatz are predominately neurological
because the nervous system is absolutely dependent on aerobic metabolism, and
coenzyme A is an essential player in the aerobic metabolism of all fuels, as we will
see in Sections 8 and 9.
O
2–
O + ADP
216
14 Metabolism: Basic Concepts and Design
Recently, the name of this disorder was changed from Hallervorden–Spatz
syndrome to pantothenate kinase associated degeneration because of the malfeasance of Julius Hallervorden, who initially described the condition. Hallervorden
was an enthusiastic participant in the Nazi program that encouraged physicians
“to grant a mercy death to those judged incurably ill,” including those with perceived mental disorders. After people were gassed at death centers for the “feeble
minded,” Hallervorden removed their brains for study and even examined some
living patients prior to their being gassed. Sadly, the practice of clinical and basic
research is not always immune from corruption. ■
Additional features of activated carriers are responsible for two key aspects of
metabolism. First, NADH, NADPH, and FADH2 react slowly with O2 in the absence
of a catalyst. Likewise, ATP and acetyl CoA are hydrolyzed slowly (in times of many
hours or even days) in the absence of a catalyst. These molecules are kinetically quite
stable in the face of a large thermodynamic driving force for reaction with O2 (in
regard to the electron carriers) and H2O (for ATP and acetyl CoA). The kinetic stability of these molecules in the absence of specific catalysts is essential for their biological
function because it enables enzymes to control the flow of free energy and reducing power.
Second, most interchanges of activated groups in metabolism are accomplished
by a rather small set of carriers (Table 14.2). The existence of a recurring set of activated carriers in all organisms is one of the unifying motifs of biochemistry.
Table 14.2 Some activated carriers in metabolism
Carrier molecule in activated form
Group carried
ATP
NADH and NADPH
FADH2
FMNH2
Coenzyme A
Lipoamide
Thiamine pyrophosphate
Biotin
Tetrahydrofolate
S-Adenosylmethionine
Uridine diphosphate glucose
Cytidine diphosphate diacylglycerol
Nucleoside triphosphates
Phosphoryl
Electrons
Electrons
Electrons
Acyl
Acyl
Aldehyde
CO2
One-carbon units
Methyl
Glucose
Phosphatidate
Nucleotides
Vitamin precursor
Nicotinate (niacin)
Riboflavin (vitamin B2)
Riboflavin (vitamin B2)
Pantothenate
Thiamine (vitamin B1)
Biotin
Folate
Note: Many of the activated carriers are coenzymes that are derived from water-soluble vitamins.
Many Activated Carriers Are Derived from Vitamins
Almost all the activated carriers that act as coenzymes are derived from
vitamins—organic molecules needed in small amounts in the diets of some higher
animals. Table 14.3 lists the vitamins that act as coenzymes. The series of vitamins
known as the vitamin B group is shown in Figure 14.17. Note that, in all cases, the
vitamin must be modified before it can serve its function. We have already
touched on the roles of niacin, riboflavin, and pantothenate. These three and the
other B vitamins will appear many times in our study of biochemistry.
Vitamins serve the same important roles in nearly all forms of life, but higher
animals lost the capacity to synthesize them in the course of evolution. For
instance, whereas E. coli can thrive on glucose and organic salts, human beings
require at least 12 vitamins in their diet. The biosynthetic pathways for vitamins
Table 14.3 The B vitamins
Vitamin
Coenzyme
Typical reaction type
Consequences of deficiency
Thiamine (B1)
Thiamine pyrophosphate
Aldehyde transfer
Riboflavin (B2)
Flavin adenine
dinucleotide (FAD)
Oxidation–reduction
Pyridoxine (B6)
Pyridoxal phosphate
Nicotinic acid (niacin)
Pantothenic acid
Biotin
Nicotinamide adenine
dinucleotide (NAD⫹)
Coenzyme A
Biotin–lysine adducts (biocytin)
Group transfer to or
from amino acids
Oxidation–reduction
Folic acid
Tetrahydrofolate
B12
5⬘-Deoxyadenosyl cobalamin
Beriberi (weight loss, heart
problems, neurological
dysfunction)
Cheliosis and angular
stomatitis (lesions of the
mouth), dermatitis
Depression, confusion,
convulsions
Pellagra (dermatitis,
depression, diarrhea)
Hypertension
Rash about the eyebrows,
muscle pain, fatigue (rare)
Anemia, neural-tube defects
in development
Anemia, pernicious anemia,
methylmalonic acidosis
Acyl-group transfer
ATP-dependent carboxylation
and carboxyl-group transfer
Transfer of one-carbon
components; thymine synthesis
Transfer of methyl groups;
intramolecular rearrangements
O
H
N
O
–
H OH
C
O H3C
O
CH2OH
CH3
H3C
N
H3C
N
O
NH
N
CH2
Vitamin B5
(Pantothenate)
H
OH
H
OH
H
OH
O
–
O
CH2OH
HOH2C
+
+
N
H
Vitamin B3
(Niacin)
OH
N
H
CH3
Vitamin B6
(Pyridoxine)
CH2OH
Vitamin B2
(Riboflavin)
Figure 14.17 Structures of some of the B vitamins.
can be complex; thus, it is biologically more efficient to ingest vitamins than to
synthesize the enzymes required to construct them from simple molecules. This
efficiency comes at the cost of dependence on other organisms for chemicals
essential for life. Indeed, vitamin deficiency can generate diseases in all organisms
requiring these molecules (Table 14.4; see also Table 14.3).
Table 14.4 Noncoenzyme vitamins
Vitamin
Function
Deficiency
A
Roles in vision, growth, reproduction
Night blindness, cornea damage, damage to respiratory
and gastrointestinal tracts
C (ascorbic acid)
Antioxidant
Scurvy (swollen and bleeding gums, subdermal hemorrhaging)
D
Regulation of calcium and phosphate
metabolism
Rickets (children): skeletal deformaties, impaired growth
Osteomalacia (adults): soft, bending bones
E
Antioxidant
Inhibition of sperm production; lesions in muscles and nerves (rare)
K
Blood coagulation
Subdermal hemorrhaging
217
HO
218
O
14 Metabolism: Basic Concepts and Design
CH2OH
O
C
H
H
O–
HO
Vitamin C
(Ascorbate)
O
H3C
CH3
CH3
CH2OH
H
CH3
O
CH3
CH3
CH3
3
CH3
Vitamin K1
Vitamin A (Retinol)
CH3
CH3
H3C
HO
CH3
CH3
CH3
H3C
O
H
CH3
CH3
CH3
CH2
3
HO
Vitamin E (␣-Tocopherol)
Vitamin D2 (Ergocalciferol)
Figure 14.18 Structures of some vitamins that do not function as coenzymes.
Not all vitamins function as coenzymes. Vitamins designated by the letters
A, C, D, E, and K (Figure 14.18; see also Table 14.4) have a diverse array of functions. Vitamin A (retinol) is the precursor of retinal, the light-sensitive group in
rhodopsin and other visual pigments, and retinoic acid, an important signaling
molecule. A deficiency of this vitamin leads to night blindness. In addition,
young animals require vitamin A for growth. Vitamin C, or ascorbate, acts as an
antioxidant. A deficiency in vitamin C can lead to scurvy, a disease characterized
by skin lesions and blood-vessel fragility due to malformed collagen (p. 50).
A metabolite of vitamin D is a hormone that regulates the metabolism of calcium
and phosphorus. A deficiency in vitamin D impairs bone formation in growing
animals. Infertility in rats is a consequence of vitamin E (␣-tocopherol) deficiency.
This vitamin reacts with reactive oxygen species, such as hydroxyl radicals, and
inactivates them before they can oxidize unsaturated membrane lipids, damaging
cell structures. Vitamin K is required for normal blood clotting.
14.5 Metabolic Processes Are Regulated
in Three Principal Ways
As is evident, the complex network of metabolic reactions must be rigorously
regulated. At the same time, metabolic control must be flexible enough to adjust
metabolic activity to the constantly changing external environments of cells.
Metabolism is regulated through the control of (1) the amounts of enzymes, (2) their
catalytic activities, and (3) the accessibility of substrates.
The Amounts of Enzymes Are Controlled
The amount of a particular enzyme depends on both its rate of synthesis and its
rate of degradation. The level of many enzymes is adjusted primarily by a change
in the rate of transcription of the genes encoding them (Chapters 35 and 36). In
E. coli, for example, the presence of lactose induces within minutes a more than
50-fold increase in the rate of synthesis of ␤-galactosidase, an enzyme required
for the breakdown of this disaccharide.
219
14.5 Regulation of Metabolism
Catalytic Activity Is Regulated
The catalytic activity of enzymes is controlled in several ways. Reversible allosteric
control is especially important. For example, the first reaction in many biosynthetic pathways is allosterically inhibited by the ultimate product of the pathway,
an example of feedback inhibition. This type of control can be almost instantaneous. Another recurring mechanism is the activation and deactivation of
enzymes by reversible covalent modification. Reversible modification is often the
end point of the signal-transduction cascades discussed in Chapter 12. For example, glycogen phosphorylase, the enzyme catalyzing the breakdown of glycogen, a
storage form of glucose, is activated by the phosphorylation of a particular serine
residue when glucose is scarce.
Hormones coordinate metabolic relations between different tissues, often by
regulating the reversible modification of key enzymes. For instance, the hormone
epinephrine triggers a signal-transduction cascade in muscle, resulting in the
phosphorylation and activation of key enzymes and leading to the rapid degradation of glycogen to glucose, which is then used to supply ATP for muscle contraction. Glucagon has the same effect in liver, but the glucose is released into the
blood for other tissues to use. As described in Chapter 12, many hormones act
through intracellular messengers, such as cyclic AMP and calcium ion, that coordinate the activities of many target proteins.
Many reactions in metabolism are controlled by the energy status of the cell.
One index of the energy status is the energy charge, which is the fraction of all of
the adenine nucleotide molecules in the form of ATP plus half the fraction of adenine nucleotides in the form ADP, given that ATP contains two phosphoanhydride
linkages, whereas ADP contains one. Hence, the energy charge is defined as
Energy charge =
[ATP] + 1冫2[ADP]
[ATP] + [ADP] + [AMP]
The energy charge can have a value ranging from 0 (all AMP) to 1 (all ATP). A
high energy charge inhibits ATP-generating (catabolic) pathways, because the cell
has sufficient levels of ATP. ATP-utilizing (anabolic) pathways, on the other hand,
are stimulated by a high energy charge because ATP is available. In plots of the
reaction rates of such pathways versus the energy charge, the curves are steep near
an energy charge of 0.9, where they usually intersect (Figure 14.19). Evidently, the
control of these pathways has evolved to maintain the energy charge within rather
narrow limits. In other words, the energy charge, like the pH of a cell, is buffered.
The energy charge of most cells ranges from 0.80 to 0.95.
Relative rate
ATP-generating
pathway
ATP-utilizing
pathway
0
0.25
0.50
Energy charge
0.75
1
Figure 14.19 Energy charge regulates
metabolism. High concentrations of ATP
inhibit the relative rates of a typical
ATP-generating (catabolic) pathway and
stimulate the typical ATP-utilizing
(anabolic) pathway.
220
14 Metabolism: Basic Concepts and Design
An alternative index of the energy status is the phosphorylation potential,
which is directly related to the free-energy storage available in the form of ATP.
Phosphorylation potential is defined as
Phosphorylation potential =
[ATP]
[ADP] + [Pi]
The phosphorylation potential, in contrast with the energy charge, depends on
the concentration of Pi.
The Accessibility of Substrates Is Regulated
In eukaryotes, metabolic regulation and flexibility are enhanced by compartmentalization. For example, fatty acid oxidation takes place in mitochondria, whereas
fatty acid synthesis takes place in the cytoplasm. Compartmentalization segregates
opposed reactions.
Controlling the flux of substrates between compartments is another means of
regulating metabolism. For example, in many cells, glucose breakdown can take
place only if insulin is present to promote the entry of glucose into the cell. The
transfer of substrates from one compartment of a cell to another also can serve as
a control point, such as when fatty acids are moved from the cytoplasm to the
mitochondria for oxidation.
SUMMARY
14.1 Metabolism Is Composed of Many Interconnecting Reactions
The process of energy transduction takes place through metabolism, a
highly integrated network of chemical reactions. Metabolism can be subdivided into catabolism (reactions employed to extract energy from fuels)
and anabolism (reactions that use this energy for biosynthesis). The most
valuable thermodynamic concept for understanding bioenergetics is free
energy. A reaction can take place spontaneously only if the change in free
energy (⌬G) is negative. A thermodynamically unfavorable reaction can be
driven by a thermodynamically favorable one, which is the hydrolysis of
ATP in many cases.
14.2 ATP Is the Universal Currency of Free Energy
The energy derived from catabolism is transformed into adenosine triphosphate. ATP hydrolysis is exergonic and the energy released can be used to
power cellular processes, including motion, active transport, and biosynthesis. Under cellular conditions, the hydrolysis of ATP shifts the equilibrium of a coupled reaction by a factor of 108. ATP, the universal currency of
energy in biological systems, is an energy-rich molecule because it contains
two phosphoanhydride linkages.
14.3 The Oxidation of Carbon Fuels Is an Important
Source of Cellular Energy
ATP formation is coupled to the oxidation of carbon fuels. Electrons
are removed from carbon atoms and passed to O2 in a series of
oxidation–reduction reactions. Electrons flow down a stability gradient, a
process that releases energy. The energy of carbon oxidation can be trapped
as high-phosphoryl-transfer-potential compounds, which can then be used
to power the synthesis of ATP.
14.4 Metabolic Pathways Contain Many Recurring Motifs
Metabolism is characterized by common motifs. A small number of recurring activated carriers, such as ATP, NADH, and acetyl CoA, transfer activated groups in many metabolic pathways. NADPH, which carries two
electrons at a high potential, provides reducing power in the biosynthesis
of cell components from more-oxidized precursors. Many activated carriers are derived from vitamins, small organic molecules required in the diets
of many higher organisms.
221
Problems
14.5 Metabolic Processes Are Regulated in Three Principal Ways
Metabolism is regulated in a variety of ways. The amounts of some critical
enzymes are controlled by regulation of the rate of synthesis and degradation. In addition, the catalytic activities of many enzymes are regulated by
allosteric interactions (as in feedback inhibition) and by covalent modification. The movement of many substrates into cells and subcellular compartments also is controlled. The energy charge, which depends on the
relative amounts of ATP, ADP, and AMP, plays a role in metabolic regulation. A high energy charge inhibits ATP-generating (catabolic) pathways,
whereas it stimulates ATP-utilizing (anabolic) pathways.
Key Terms
phototroph (p. 203)
chemotroph (p. 203)
metabolism (p. 204)
intermediary metabolism (p. 204)
catabolism (p. 205)
anabolism (p. 205)
amphibolic pathway (p. 205)
adenosine triphosphate (ATP) (p. 206)
phosphoryl-transfer potential (p. 208)
activated carrier (p. 212)
vitamin (p. 216)
energy charge (p. 219)
phosphorylation potential (p. 220)
Answer to QUICK QUIZ
Charge repulsion is reduced when a phosphate is removed
from ATP. The products of ATP hydrolysis have more
resonance forms than does ATP. The products of ATP
hydrolysis are more effectively stabilized by association with
water than is ATP.
Problems
1. Energy flow. What is the direction of each of the following reactions when the reactants are initially present in
equimolar amounts? Use the data given in Table 14.1.
(a) ATP ⫹ creatine Δ creatine phosphate ⫹ ADP
(b) ATP ⫹ glycerol Δ glycerol 3-phosphate ⫹ ADP
(c) ATP ⫹ pyruvate Δ phosphoenolpyruvate ⫹ ADP
(d) ATP ⫹ glucose Δ glucose 6-phosphate ⫹ ADP
2. A proper inference. What information do the ⌬G°⬘ data
given in Table 14.1 provide about the relative rates of
hydrolysis of pyrophosphate and acetyl phosphate?
3. A potent donor. Consider the following reaction:
ATP + pyruvate Δ phosphoenolpyruvate + ADP
(a) Calculate ⌬G°⬘ and K⬘eq at 25°C for this reaction by
using the data given in Table 14.1.
(b) What is the equilibrium ratio of pyruvate to phosphoenolpyruvate if the ratio of ATP to ADP is 10?
4. Isomeric equilibrium. Calculate ⌬G°⬘ for the isomerization of glucose 6-phosphate to glucose 1-phosphate. What
is the equilibrium ratio of glucose 6-phosphate to glucose
1-phosphate at 25°C?
222
14 Metabolism: Basic Concepts and Design
5. Activated acetate. The formation of acetyl CoA from
acetate is an ATP-driven reaction:
Acetate + ATP + CoA Δ acetyl CoA + AMP + PPi
(a) Calculate ⌬G°⬘ for this reaction by using data given in
this chapter.
(b) The PPi formed in the preceding reaction is rapidly
hydrolyzed in vivo because of the ubiquity of inorganic
pyrophosphatase. The ⌬G°⬘ for the hydrolysis of PPi is
⫺19.2 kJ mol⫺1 (⫺4.6 kcal mol⫺1). Calculate the ⌬G°⬘ for
the overall reaction, including pyrophosphate hydrolysis.
What effect does the hydrolysis of PPi have on the formation of acetyl CoA?
6. Acid strength. The pKa of an acid is a measure of its
proton-group-transfer potential.
(a) Derive a relation between ⌬G°⬘ and pKa.
(b) What is the ⌬G°⬘ for the ionization of acetic acid, which
has a pKa of 4.8?
7. Raison d’être. The muscles of some invertebrates are
rich in arginine phosphate (phosphoarginine). Propose a
function for this amino acid derivative.
H
N
H
+H
3N
H
N
O
C
P
NH2+
O
The ⌬G°⬘ for the reaction is ⫹23.8 kJ mol⫺1 (⫹5.7 kcal
mol ⫺1 ), whereas the ⌬G in the cell is ⫺1.3 kJ mol ⫺1
(⫺0.3 kcal mol ⫺1 ). Calculate the ratio of reactants to
products under equilibrium and intracellular conditions.
Using your results, explain how the reaction can be endergonic under standard conditions and exergonic under
intracellular conditions.
11. Standard conditions versus real life 2. On page 207, a
reaction, A Δ B, with a ⌬G°⬘ ⫽ ⫹16.7 kJ mol⫺1 (⫹4.0
kcal mol⫺1) is shown to have a Keq of 1.15 ⫻ 10⫺3. The Keq
is increased to 2.67 ⫻ 102 if the reaction is coupled to ATP
hydrolysis under standard conditions. The ATP-generating
system of cells maintains the [ATP]/[ADP][Pi] ratio at a
high level, typically of the order of 500 M⫺1. Calculate the
ratio of B/A under cellular conditions.
12. Not all alike. The concentrations of ATP, ADP, and Pi
differ with cell type. Consequently, the release of free energy
with the hydrolysis of ATP will vary with cell type. Using the
following table, calculate the ⌬G for the hydrolysis of ATP
in liver, muscle, and brain cells. In which cell type is the free
energy of ATP hydrolysis most negative?
2–
O
Liver
Muscle
Brain
ATP (mM)
3.5
8.0
2.6
ADP (mM)
1.8
0.9
0.7
Pi (mM)
5.0
8.0
2.7
COO–
Arginine phosphate
8. Recurring motif. What is the structural feature common
to ATP, FAD, NAD⫹, and CoA?
9. Ergogenic help or hindrance? Creatine is a popular, but
untested, dietary supplement.
(a) What is the biochemical rationale for the use of creatine?
(b) What type of exercise would most benefit from creatine
supplementation?
10. Standard conditions versus real life 1. The enzyme
aldolase catalyzes the following reaction in the glycolytic
pathway:
Aldolase
Fructose 1,6-biphosphate ERRF
dihydroxyacetone phosphate + glyceraldehyde 3-phosphate
13. Running downhill. Glycolysis is a series of 10 linked
reactions that convert one molecule of glucose into two
molecules of pyruvate with the concomitant synthesis of
two molecules of ATP (Chapter 16). The ⌬G°⬘ for this set of
reactions is ⫺35.6 kJ mol⫺1 (⫺8.5 kcal mol⫺1), whereas the
⌬G is ⫺76.6 kJ mol⫺1 (⫺18.3 kcal mol⫺1). Explain why the
free-energy release is so much greater under intracellular
conditions than under standard conditions.
Chapter Integration Problem
14. Activated sulfate. Fibrinogen, a precursor to the bloodclot protein fibrin, contains tyrosine-O-sulfate. Propose an
activated form of sulfate that could react in vivo with the
aromatic hydroxyl group of a tyrosine residue in a protein
to form tyrosine-O-sulfate.
Problems
8.6
36
8.2
34
8.0
7.8
33
7.6
32
7.4
31
30
7.2
1
2
3
4
pMg
Selected readings for this chapter can be found online at www.whfreeman.com/Tymoczko
5
6
7
−ΔG (kcal mol −1)
8.4
35
−ΔG (kJ mol −1)
Data Interpretation Problem
15. Opposites attract. The graph at the right shows how the
⌬G for the hydrolysis of ATP varies as a function of the
Mg2⫹ concentration (pMg ⫽ ⫺log[Mg2⫹]).
(a) How does decreasing [Mg2⫹] affect the ⌬G of hydrolysis for ATP?
(b) Explain this effect.
223