S E C T I O N

III Bioenergetics

C H A P T E R

Bioenergetics:
The Role of ATP
Kathleen M. Botham, PhD, DSc & Peter A. Mayes, PhD, DSc
11
OBJEC TIVES ■ State the first and second laws of thermodynamics and understand how they
apply to biologic systems.
After studying this chapter, ■ Explain what is meant by the terms free energy, entropy, enthalpy, exergonic,
you should be able to: and endergonic.
■ Appreciate how reactions that are endergonic may be driven by coupling to
those that are exergonic in biologic systems.
■ Understand the role of high-energy phosphates, ATP, and other nucleotide
triphosphates in the transfer of free energy from exergonic to endergonic
processes, enabling them to act as the “energy currency” of cells.

BIOMEDICAL IMPORTANCE FREE ENERGY IS THE USEFUL

Bioenergetics, or biochemical thermodynamics, is the study
of the energy changes accompanying biochemical reactions.
Biologic systems are essentially isothermic and use chemical
energy to power living processes. The way in which an ani-
mal obtains suitable fuel from its food to provide this energy
is basic to the understanding of normal nutrition and metab-
olism. Death from starvation occurs when available energy
reserves are depleted, and certain forms of malnutrition are
associated with energy imbalance (marasmus). Thyroid hor-
mones control the metabolic rate (rate of energy release), and
disease results if they malfunction. Excess storage of surplus
energy causes obesity, an increasingly common disease of
Western society which predisposes to many diseases, includ-
ing cardiovascular disease and diabetes mellitus type 2, and
lowers life expectancy.
ENERGY IN A SYSTEM
Gibbs change in free energy (ΔG) is that portion of the total
energy change in a system that is available for doing work—
that is, the useful energy, also known as the chemical potential.
Biologic Systems Conform to the General
Laws of Thermodynamics
The first law of thermodynamics states that the total energy
of a system, including its surroundings, remains constant.
It implies that within the total system, energy is neither lost
nor gained during any change. However, energy may be
transferred from one part of the system to another, or may be
transformed into another form of energy. In living systems,

113
114 SECTION III Bioenergetics
chemical energy may be transformed into heat or into electri-
cal, radiant, or mechanical energy.
The second law of thermodynamics states that the total
entropy of a system must increase if a process is to occur spon-
taneously. Entropy is the extent of disorder or randomness of the
system and becomes maximum as equilibrium is approached.
Under conditions of constant temperature and pressure, the rela-
tionship between the free-energy change (ΔG) of a reacting sys-
tem and the change in entropy (ΔS) is expressed by the following
equation, which combines the two laws of thermodynamics:
ΔG = ΔH −TΔS
where ΔH is the change in enthalpy (heat) and T is the absolute
temperature.
In biochemical reactions, since ΔH is approximately equal
to the total change in internal energy of the reaction or ΔE,
the above relationship may be expressed in the following way:
ΔG = ΔE −TΔS
If ΔG is negative, the reaction proceeds spontaneously with loss
of free energy; that is, it is exergonic. If, in addition, ΔG is of
great magnitude, the reaction goes virtually to completion and
is essentially irreversible. On the other hand, if ΔG is positive,
the reaction proceeds only if free energy can be gained; that is,
it is endergonic. If, in addition, the magnitude of ΔG is great,
the system is stable, with little or no tendency for a reaction
to occur. If ΔG is zero, the system is at equilibrium and no net
change takes place.
When the reactants are present in concentrations of
1.0 mol/L, ΔG0 is the standard free-energy change. For bio-
chemical reactions, a standard state is defined as having a pH
of 7.0. The standard free-energy change at this standard state
is denoted by ΔG0′.
The standard free-energy change can be calculated from
the equilibrium constant Keq.
ΔG 0′ = −RT ln K eq
′
where R is the gas constant and T is the absolute temperature
(see Chapter 8). It is important to note that the actual ΔG may be
larger or smaller than ΔG0′ depending on the concentrations of the
various reactants, including the solvent, various ions, and proteins.
In a biochemical system, an enzyme only speeds up the
attainment of equilibrium; it never alters the final concentra-
tions of the reactants at equilibrium.
ENDERGONIC PROCESSES
PROCEED BY COUPLING
TO EXERGONIC PROCESSES
The vital processes—for example, synthetic reactions, muscular
contraction, nerve impulse conduction, and active transport—
obtain energy by chemical linkage, or coupling, to oxida-
tive reactions. In its simplest form, this type of coupling may
be represented as shown in Figure 11–1. The conversion of
A
Heat
Ex
e
rg
on
D
ic
Free energy
Chemical
n ic energy
r go
de
En
C B
A+C B + D + Heat
FIGURE 111 Coupling of an exergonic to an endergonic
reaction.
metabolite A to metabolite B occurs with release of free energy
and is coupled to another reaction in which free energy is required
to convert metabolite C to metabolite D. The terms exergonic and
endergonic, rather than the normal chemical terms “exothermic”
and “endothermic,” are used to indicate that a process is accompa-
nied by loss or gain, respectively, of free energy in any form, not
necessarily as heat. In practice, an endergonic process cannot exist
independently, but must be a component of a coupled exergonic-
endergonic system where the overall net change is exergonic.
The exergonic reactions are termed catabolism (generally, the
breakdown or oxidation of fuel molecules), whereas the synthetic
reactions that build up substances are termed anabolism. The
combined catabolic and anabolic processes constitute metabolism.
If the reaction shown in Figure 11–1 is to go from left to
right, then the overall process must be accompanied by loss
of free energy as heat. One possible mechanism of coupling
could be envisaged if a common obligatory intermediate (I)
took part in both reactions, that is,
A+C→1→B+D
Some exergonic and endergonic reactions in biologic systems
are coupled in this way. This type of system has a built-in mech-
anism for biologic control of the rate of oxidative processes
since the common obligatory intermediate allows the rate of
utilization of the product of the synthetic path (D) to deter-
mine by mass action the rate at which A is oxidized. Indeed,
these relationships supply a basis for the concept of respiratory
control, the process that prevents an organism from burning
out of control. An extension of the coupling concept is pro-
vided by dehydrogenation reactions, which are coupled to
hydrogenations by an intermediate carrier (Figure 11–2).
AH2 Carrier BH2
A Carrier H2 B
FIGURE 112 Coupling of dehydrogenation and hydrogena-
tion reactions by an intermediate carrier.
 CHAPTER 11 Bioenergetics: The Role of ATP 115

A NH2
N
N

Mg2+ N
N
D
E O– O– O–
Free energy

–
O P O P O P O CH2 O
O O O C C
H H

E ATP H H
OH OH

B C
FIGURE 113 Transfer of free energy from an exergonic
to an endergonic reaction via a high-energy intermediate
compound (~ ).
An alternative method of coupling an exergonic to an end-
ergonic process is to synthesize a compound of high-energy
potential in the exergonic reaction and to incorporate this new
compound into the endergonic reaction, thus effecting a trans-
ference of free energy from the exergonic to the endergonic
pathway (Figure 11–3). The biologic advantage of this mecha-
nism is that the compound of high potential energy, ~ , unlike
I in the previous system, need not be structurally related to A,
B, C, or D, allowing to serve as a transducer of energy from
a wide range of exergonic reactions to an equally wide range of
endergonic reactions or processes, such as biosyntheses, mus-
cular contraction, nervous excitation, and active transport. In
the living cell, the principal high-energy intermediate or car-
rier compound (designated ~ in Figure 11–3) is adenosine
triphosphate (ATP) (Figure 11–4).
HIGHENERGY PHOSPHATES
PLAY A CENTRAL ROLE IN ENERGY
CAPTURE AND TRANSFER
In order to maintain living processes, all organisms must obtain
supplies of free energy from their environment. Autotrophic
organisms utilize simple exergonic processes; eg, the energy of
sunlight (green plants), the reaction Fe2+ → Fe3+ (some bacteria).
On the other hand, heterotrophic organisms obtain free energy
by coupling their metabolism to the breakdown of complex
organic molecules in their environment. In all these organisms,
ATP plays a central role in the transference of free energy
from the exergonic to the endergonic processes (Figure 11–3).
ATP is a nucleotide consisting of the nucleoside adenosine
(adenine linked to ribose), and three phosphate groups (see
Chapter 32). In its reactions in the cell, it functions as the Mg2+
complex (Figure 11–4).
The importance of phosphates in intermediary metabo-
lism became evident with the discovery of the role of ATP,
adenosine diphosphate (ADP) (Figure 11–4), and inorganic
phosphate (Pi) in glycolysis (see Chapter 17).
NH2
N
N
Mg2+ N
N
O– O– O–
–
O P O P O P O CH2 O
O O O C C
H H
ADP H H
OH OH
FIGURE 114 Adenosine triphosphate (ATP) and adenosine
diphosphate shown as the magnesium complexes.
The Intermediate Value for the Free
Energy of Hydrolysis of ATP Has
Important Bioenergetic Significance
The standard free energy of hydrolysis of a number of bio-
chemically important phosphates is shown in Table 11–1. An
estimate of the comparative tendency of each of the phosphate
groups to transfer to a suitable acceptor may be obtained from
the ΔG0′ of hydrolysis at 37°C. The value for the hydrolysis of
the terminal phosphate of ATP divides the list into two groups.
Low-energy phosphates, exemplified by the ester phosphates
found in the intermediates of glycolysis, have G0′ values
smaller than that of ATP, while in high-energy phosphates
the value is higher than that of ATP. The components of this
latter group, including ATP, are usually anhydrides (eg, the
1-phosphate of 1,3-bisphosphoglycerate), enolphosphates
(eg, phosphoenolpyruvate), and phosphoguanidines (eg, cre-
atine phosphate, arginine phosphate).
The symbol ~ indicates that the group attached to the
bond, on transfer to an appropriate acceptor, results in transfer
of the larger quantity of free energy. For this reason, the term
group transfer potential, rather than “high-energy bond,” is
preferred by some. Thus, ATP contains two high-energy phos-
phate groups and ADP contains one, whereas the phosphate
in AMP (adenosine monophosphate) is of the low-energy type
since it is a normal ester link (Figure 11–5).
116 SECTION III Bioenergetics

TABLE 111 Standard Free Energy of Hydrolysis of ADENOSINE

Some Organophosphates of Biochemical Importance
O– O– O–
ΔG 0′ –
O P O P O P O CH2 O
Compound kJ/mol kcal/mol O O O C C
H H
Phosphoenolpyruvate −61.9 −14.8 ATP4–
H H
Carbamoyl phosphate −51.4 −12.3
OH OH
3–
1,3-Bisphosphoglycerate −49.3 −11.8 Od –
(to 3-phosphoglycerate) Hydrolysis of ATP4– to
Od – P Od –
ADP3– relieves charge
Creatine phosphate −43.1 −10.3 Od – repulsion

ATP → AMP + PPi −32.2 −7.7 The phosphate released + H+

is stabilised by the formation of a
ATP → ADP + Pi −30.5 −7.3 resonance hybrid in which the ADP3–
3 negative charges are shared ADENOSINE
Glucose-1-phosphate −20.9 −5.0 between the four O atoms
O– O–
PPi −19.2 −4.6
–
O P O P O CH2 O
Fructose-6-phosphate −15.9 −3.8
O O C C
Glucose-6-phosphate −13.8 −3.3 H H

Glycerol-3-phosphate −9.2 −2.2 H H

OH OH
Abbreviations: PPi, pyrophosphate; Pi, inorganic orthophosphate.
Note: All values taken from Jencks (1976), except that for PPi which is from Frey and
Arabshahi (1995). Values differ between investigators, depending on the precise
FIGURE 116 The free-energy change on hydrolysis of ATP
conditions under which the measurements were made. to ADP.

are thiol esters involving coenzyme A (eg, acetyl-CoA), acyl

The intermediate position of ATP allows it to play an
carrier protein, amino acid esters involved in protein syn-
important role in energy transfer. The high free-energy change
thesis, S-adenosylmethionine (active methionine), UDPGlc
on hydrolysis of ATP is due to relief of charge repulsion of
(uridine diphosphate glucose), and PRPP (5-phosphoribosyl-
adjacent negatively charged oxygen atoms and to stabilization
1-pyrophosphate).
of the reaction products, especially phosphate, as resonance
hybrids (Figure 11–6). Other “high-energy compounds”
HIGHENERGY PHOSPHATES
O– O– O– ACT AS THE “ENERGY
Adenosine O P O P O P O– CURRENCY” OF THE CELL
O O O ATP is able to act as a donor of high-energy phosphate to form
or Adenosine P P P those compounds below it in Table 11–1. Likewise, with the
necessary enzymes, ADP can accept high-energy phosphate to
Adenosine triphosphate (ATP)
form ATP from those compounds above ATP in the table. In
O– O– effect, an ATP/ADP cycle connects those processes that gener-
Adenosine O P O P O–
ate ~ to those processes that utilize ~ (Figure 11–7), contin-
uously consuming and regenerating ATP. This occurs at a very
O O
rapid rate since the total ATP/ADP pool is extremely small and
or Adenosine P P sufficient to maintain an active tissue for only a few seconds.
There are three major sources of ~ taking part in energy
Adenosine diphosphate (ADP)
conservation or energy capture:
O–
1. Oxidative phosphorylation is the greatest quantitative
Adenosine O P O–
source of ~ in aerobic organisms. ATP is generated in
O the mitochondrial matrix as O2 is reduced to H2O by elec-
or Adenosine P
trons passing down the respiratory chain (see Chapter 13).
2. Glycolysis. A net formation of two ~ results from the
Adenosine monophosphate (AMP) formation of lactate from one molecule of glucose, gen-
FIGURE 115 Structure of ATP, ADP, and AMP showing the erated in two reactions catalyzed by phosphoglycerate
position and the number of high-energy phosphates (~ ). kinase and pyruvate kinase, respectively (see Figure 17–2).
 CHAPTER 11 Bioenergetics: The Role of ATP 117

Phosphoenolpyruvate 1,3-Bisphosphoglycerate to glucose-6-phosphate, the first reaction of glycolysis (see

Succinyl- Figure 17–2):
Oxidative
CoA phosphorylation
Creatine P
Glucose + Pi → Glucose-6-phosphate + H2 O (1)
0′
P ( ΔG ) = +13.8 kJ/mol)
(Store of P )

ATP Creatine is highly endergonic and cannot proceed under physiologic

conditions. Thus, in order to take place, the reaction must be
ATP/ADP coupled with another—more exergonic—reaction such as the
cycle
P
hydrolysis of the terminal phosphate of ATP.
Glucose-6-phosphate
ADP
Other phosphorylations, ATP → ADP + Pi (ΔG 0′ = −30.5 kJ/mol) (2)
activations,
Glucose-1,6- and endergonic
Glycerol-3-phosphate bisphosphate processes When (1) and (2) are coupled in a reaction catalyzed by hexo-
FIGURE 117 Role of ATP/ADP cycle in transfer of high-energy kinase, phosphorylation of glucose readily proceeds in a highly
phosphate. exergonic reaction that under physiologic conditions is irre-
versible. Many “activation” reactions follow this pattern.
3. The citric acid cycle. One ~ is generated directly in the
cycle at the succinate thiokinase step (see Figure 16–3).
Adenylate Kinase (Myokinase)
Phosphagens act as storage forms of high-energy phos-
phate and include creatine phosphate, which occurs in ver-
Interconverts Adenine Nucleotides
tebrate skeletal muscle, heart, spermatozoa, and brain, and This enzyme is present in most cells. It catalyzes the following
arginine phosphate, which occurs in invertebrate muscle. reaction:
When ATP is rapidly being utilized as a source of energy for
muscular contraction, phosphagens permit its concentrations ADENYLATE
KINASE
to be maintained, but when the ATP/ADP ratio is high, their
ATP + AMP 2ADP
concentration can increase to act as a store of high-energy
phosphate (Figure 11–8).
When ATP acts as a phosphate donor to form compounds Adenylate kinase is important for the maintenance of energy
of lower free energy of hydrolysis (Table 11–1), the phosphate homeostasis in cells because it allows:
group is invariably converted to one of low energy. For example, 1. High-energy phosphate in ADP to be used in the synthesis
the phosphorylation of glycerol to form glycerol-3-phosphate: of ATP.
GLYCEROL 2. The AMP formed as a consequence of activating reactions
KINASE involving ATP to rephosphorylated to ADP.
Glycerol + Adenosine P P P 3. AMP to increase in concentration when ATP becomes
Glycerol P + Adenosine P P depleted so that it is able to act as a metabolic (allosteric)
signal to increase the rate of catabolic reactions, which in
turn lead to the generation of more ATP (see Chapter 14).
ATP Allows the Coupling of
Thermodynamically Unfavorable When ATP Forms AMP, Inorganic
Reactions to Favorable Ones Pyrophosphate (PPi) Is Produced
Endergonic reactions cannot proceed without an input of
ATP can also be hydrolyzed directly to AMP, with the release
free energy. For example, the phosphorylation of glucose
of PPi (Table 11–1). This occurs, for example, in the activation
of long-chain fatty acids (see Chapter 22).
H Creatine
P N kinase H 2N ACYL-CoA
SYNTHETASE
C NH C NH
ATP +


 +




 AMP + PPi +






H3C N H3C N
ADP ATP
CH2 CH2
(ΔG 0′ = –12.6 kJ/mol) This reaction is accompanied by loss of free energy as heat,
COO– COO–
which ensures that the activation reaction will go to the right,
Creatine phosphate Creatine and is further aided by the hydrolytic splitting of PPi, cata-
FIGURE 118 Transfer of high-energy phosphate between lyzed by inorganic pyrophosphatase, a reaction that itself
ATP and creatine. has a large ΔG0′ of −19.2 kJ/mol. Note that activations via the
118 SECTION III Bioenergetics

Inorganic All of these triphosphates take part in phosphorylations in the

pyrophosphatase
cell. Similarly, specific nucleoside monophosphate (NMP)
2Pi
kinases catalyze the formation of nucleoside diphosphates
from the corresponding monophosphates.
Pi PPi Thus, adenylate kinase is a specialized NMP kinase.

SUMMARY
Acyl-CoA
synthetase, etc

■ Biologic systems use chemical energy to power living processes.

ATP
■ Exergonic reactions take place spontaneously with loss of free
energy (ΔG is negative). Endergonic reactions require the gain
of free energy (ΔG is positive) and occur only when coupled to
exergonic reactions.
X2
ADP AMP ■ ATP acts as the “energy currency” of the cell, transferring free
Adenylyl
kinase
energy derived from substances of higher energy potential to
those of lower energy potential.
FIGURE 119 Phosphate cycles and interchange of adenine
nucleotides.
REFERENCES
de Meis L: The concept of energy-rich phosphate compounds: water,
pyrophosphate pathway result in the loss of two ~ rather than transport ATPases, and entropy energy. Arch Biochem Biophys
one, as occurs when ADP and Pi are formed. 1993;306:287.
INORGANIC Frey PA, Arabshahi A: Standard free-energy change for the
PYROPHOSPHATASE hydrolysis of the alpha, beta-phosphoanhydride bridge in ATP.
PPi + H2O 2Pi Biochemistry 1995;34:11307.
Harris DA: Bioenergetics at a Glance: An Illustrated Introduction.
A combination of the above reactions makes it possible for Blackwell Publishing, 1995.
phosphate to be recycled and the adenine nucleotides to inter- Haynie D: Biological Thermodynamics. Cambridge University Press,
2008.
change (Figure 11–9).
Jencks WP: Free energies of hydrolysis and decarboxylation.
In: Handbook of Biochemistry and Molecular Biology, vol 1.
Other Nucleoside Triphosphates Physical and Chemical Data. Fasman GD (editor). CRC Press,
Participate in the Transfer 1976:296–304.
Nicholls DG, Ferguson SJ: Bioenergetics, 4th ed. Elsevier, 2013.
of High-Energy Phosphate
By means of the nucleoside diphosphate (NDP) kinases, UTP,
GTP, and CTP can be synthesized from their diphosphates,
for example, UDP reacts with ATP to form UTP.
NUCLEOSIDE
DIPHOSPHATE
KINASE
ATP + UDP ADP + UTP
(uridine triphosphate)