CHAPTER 7: BIOENERGETICS: HOW THE BODY CONVERTS FOOD TO ENERGY

WHAT IS METABOLISM?
Living cells are in a dynamic state, which means that compounds are constantly being synthesized and
then broken down into smaller fragments. Thousands of different reactions take place at the same time.
✓ Metabolism is the sum total of all the chemical reactions involved in maintaining the dynamic state of the
cell.
In general, we can classify metabolic reactions into two broad groups: (1) those in which molecules are broken
down to provide the energy needed by cells and (2) those that synthesize the compounds needed by cells—both
simple and complex.
✓ Catabolism is the process of breaking down molecules to supply energy. The process of synthesizing
(building up) molecules is anabolism. The same compounds may be synthesized in one part of a cell and
broken down in a different part of the cell.
A biochemical pathway is a series of consecutive biochemical reactions. We will see the actual reactions that
enable the chemical energy stored in our food to be converted to the energy we use every minute of our lives—
to think, to breathe, and to use our muscles to walk, write, eat, and everything else. The food we eat consists of
many types of compounds, largely the ones we discussed in earlier chapters: carbohydrates, lipids, and proteins.
All of them can serve as fuel, and we derive our energy from them.
To convert those compounds to energy, the body uses a different pathway
for each type of compound. All of these diverse pathways converge to one
common catabolic pathway, which is illustrated in Figure 19.1. In the figure,
the diverse pathways are shown as different food streams. The small
molecules produced from the original large molecules in food drop into an
imaginary collecting funnel that represents the common catabolic pathway.
At the end of the funnel appears the energy carrier molecule, adenosine
triphosphate (ATP).
The purpose of catabolic pathways is to convert the chemical energy in foods to molecules of ATP. In the
process, foods also yield metabolic intermediates, which the body can use for synthesis. In this chapter,
we deal with the common catabolic pathway.

FIGURE 19.1 In this simplified schematic diagram of the common catabolic pathway, an imaginary funnel
represents what happens in the cell. (a) The diverse catabolic pathways drop their products into the funnel of
the common catabolic pathway, mostly in the form of C2 fragments (Section 19.4). (The source of the C4
fragments will be shown in Section 20.9.) (b) The spinning wheel of the citric acid cycle breaks these molecules
down further. (c) The carbon atoms are released in the form of CO2, and (d) the hydrogen atoms and electrons
are picked up by special compounds such as NAD1 and FAD. (e) Then the reduced NADH and FADH2 cascade
down into the stem of the funnel, where the electrons are transported inside the walls of the stem and the H1
ions are expelled to the outside. (f ) In their drive to get back, the H1 ions form the energy carrier ATP. Once
back inside, they combine with the oxygen that picked up the electrons and produce water.
The mitochondria, which possess two membranes, are the organelles in which the common catabolic pathway
takes place in higher organisms.
✓ The enzymes that catalyze the common pathway are all located in these organelles. Because these
enzymes are synthesized in the cytosol, they must be imported through the two membranes.
 ✓ Because the enzymes are located inside the inner
membrane of mitochondria, the starting materials of the reactions in
the common pathway must pass through the two membranes to
enter the mitochondria. Products must leave the same way.
✓ The inner membrane of a mitochondrion is quite resistant
to the penetration of any ions and of most uncharged molecules.
(Mitochondria is the plural form; mitochondrion is the singular form.)
However, ions and molecules can still get through the membrane—
they are transported across it by the numerous protein molecules
embedded in it
✓ The outer membrane, by contrast, is quite permeable to
small molecules and ions and does not have transporting
membrane proteins.
✓ The matrix is the inner nonmembranous portion of a
mitochondrion. The inner membrane is highly corrugated and folded.
✓ On the basis of electron microscopic studies, the Romanian-born American cell biologist George Palade
(1912–2008) proposed his baffle model of the mitochondrion in 1952.
✓ The baffles, which are called cristae, project into the matrix like the bellows of an accordion. The
enzymes of the oxidative phosphorylation cycle are localized on the cristae.
✓ The space between the inner and outer membranes is the intermembrane space. The enzymes of the
citric acid cycle are located in the matrix.

The common catabolic pathway has two parts: the citric acid cycle (also called the tricarboxylic acid cycle
or the Krebs cycle) and the electron transport chain and phosphorylation, together called the oxidative
phosphorylation pathway. To understand what actually happens in these reactions, we must first introduce
the principal compounds participating in the common catabolic pathway.

The most important of these agents are three rather complex compounds: adenosine monophosphate
(AMP), adenosine diphosphate (ADP), and adenosine triphosphate (ATP) (Figures 19.4 and 19.5).

✓ All three of these molecules contain the heterocyclic amine adenine and the sugar D-ribose joined
together by a b-N-glycosidic bond, forming adenosine. AMP, ADP, and ATP all contain adenosine
connected to phosphate groups.
✓ The only difference between the three molecules is the number of phosphate groups.
✓ ATP releases the most energy and AMP releases the least energy when each gives up one phosphate
group.
✓ This property makes ATP a very useful compound for energy storage and release. The energy gained in
the oxidation of food is stored in the form of ATP, albeit only for a short while. ATP molecules in the cells
normally do not last longer than about 1 min. They are hydrolyzed to ADP and inorganic phosphate to
yield energy that drives other processes, such as muscle contraction, nerve signal conduction, and
biosynthesis. As a consequence, ATP is constantly being formed and decomposed. Its turnover rate is
very high.
 ✓ Estimates suggest that the human body manufactures and degrades as much as 40 kg (approximately
88 lb) of ATP every day. Even with these considerations, the body is able to extract only 40 to 60% of
the total caloric content of food.

These are the coenzymes NAD+ (nicotinamide adenine dinucleotide) and FAD (flavin adenine dinucleotide),
both of which contain an ADP core. (The + in NAD+ refers to the positive charge on the nitrogen.) In NAD+, the
operative part of the coenzyme is the nicotinamide part. In FAD, the operative part is the flavin portion. In both
molecules, ADP is the handle by which the apoenzyme holds on to the coenzyme; the other end of the molecule
carries out the actual chemical reaction. The reduced form of NAD+ is called NADH. The reduced form of FAD
is called FADH2. We view NAD+ and FAD coenzymes as the hydrogen ion and electron - transporting molecules.

The final principal compound in the common catabolic pathway is coenzyme A, which is the acetyl (CH3CO--)
transporting molecule. Coenzyme A also contains ADP, but here the next structural unit is pantothenic acid,
another B vitamin. Just as ATP can be viewed as an ADP molecule to which a -PO32- --- group is attached by a
high-energy bond, so acetyl coenzyme A can be considered a CoA molecule linked to an acetyl group by a high-
energy thioester bond, for which the energy of hydrolysis is 7.51 kcal/mol. The active part of coenzyme A is the
mercaptoethylamine. The acetyl group of acetyl coenzyme A is attached to the SH group:

The common catabolism of carbohydrates and lipids begins when they have been broken down into
pieces of two carbon atoms each. The two-carbon fragments are the acetyl portions of acetyl coenzyme A. The
acetyl is now fragmented further in the citric acid cycle.
Figure 19.8 gives the details of the citric acid cycle.
Step 1 Acetyl coenzyme A enters the cycle by combining with a C4 compound called oxaloacetate:

The first thing that happens is the addition of the iCH3 group of the acetyl CoA to the C w O of the
oxaloacetate, catalyzed by the enzyme citrate synthase. This event is followed by hydrolysis of the thioester to
produce the C6 compound citrate ion and CoA. Therefore, Step ➀ is a building-up rather than a breaking-down
process. In Step ➇ we will see where the oxaloacetate comes from.

Step 2 The citrate ion is dehydrated to cis-aconitate, after which the cisaconitate is hydrated, but this time to
isocitrate instead of citrate

Step 3 The isocitrate is now oxidized and decarboxylated at the same time:

In oxidizing the secondary alcohol to a ketone, the oxidizing agent NAD+ removes two hydrogens. One of the
hydrogens is added to NAD+ to produce NADH. (Recall that NAD+ and NADH are the oxidized and reduced
forms, respectively, of nicotinamide adenine dinucleotide [Figure 19.6]). The other hydrogen replaces the COO-
that goes into making CO2. Note that the CO2 given off comes from the original oxaloacetate and not from the
two carbons of the acetyl CoA. Both of these carbons are still present in the a-ketoglutarate. Also note that we
are now down to a C5 compound, a-ketoglutarate.
Steps 4 and 5 Next, a complex system removes another CO2 once again from the original oxaloacetate
portion rather than from the acetyl CoA portion:

We are now down to a C4 compound, succinate. This oxidative decarboxylation is more complex than the first.
It occurs in many steps and requires a number of cofactors
✓ during this second oxidative decarboxylation, a high-energy compound called guanosine triphosphate
(GTP) is also formed. GTP is similar to ATP, except that guanine replaces adenine. Otherwise, the
linkages of the base to ribose and the phosphates are exactly the same as in ATP. The function of GTP
is also similar to that of ATP—namely, it stores energy in the form of high-energy phosphoric anhydride
bonds (chemical energy). The energy from the hydrolysis of GTP drives many important biochemical
reactions—for example, the signal transduction in neurotransmission. As a final note on the
decarboxylation steps, the CO2 molecules given off in Steps ③ and ④ are the ones we exhale
Step 6 In this step, succinate is oxidized by FAD, which removes two hydrogens to give fumarate.

This reaction cannot be carried out in the laboratory, but with the aid of an enzyme catalyst, the body does it
easily. (Recall that FAD and FADH2 are the oxidized and reduced forms, respectively, of flavin adenine
dinucleotide)
Step 7 The fumarate is now hydrated to give the malate ion:

Step 8 In the final step of the cycle, malate is oxidized to give oxaloacetate:

(Recall that NAD1 and NADH are the oxidized and reduced forms, respectively, of nicotinamide adenine
dinucleotide [Figure 19.6]). Thus the final product of the Krebs cycle is oxaloacetate, which is the compound with
which we started in Step ①.
In this process, the original two acetyl carbons of acetyl CoA were added to the C4 oxaloacetate to produce a
C6 unit, which then lost two carbons in the form of CO2 to produce, at the end of the process, the C4 unit
oxaloacetate. The net effect is that one two-carbon acetyl group enters the cycle and two carbon dioxides are
given off.
How does the citric acid cycle produce energy? We have already learned that one step in the process produces
a high-energy molecule of GTP. However, most of the energy is produced in the other steps that convert NAD+
to NADH and FAD to FADH2. These reduced coenzymes carry the H+ and electrons that eventually will provide
the energy for the synthesis of ATP (discussed in detail in Sections 19.5 and 19.6)
This stepwise degradation and oxidation of acetate in the citric acid cycle results in the most efficient extraction
of energy. Rather than being generated in one burst, the energy is released in small packets that are carried
away step by step in the form of NADH and FADH2. The cyclic nature of this acetate degradation has other
advantages besides maximizing energy yield:
1. The citric acid cycle components provide raw materials for amino acid synthesis as the need arises (Chapter
21). For example, a-ketoglutaric acid is used to synthesize glutamic acid.
2. The many-component cycle provides an excellent method for regulating the speed of catabolic reactions. The
regulation can occur at many different parts of the cycle, so that feedback information can be used at many
points to speed up or slow down the process as necessary.

The citric acid cycle is controlled by feedback mechanisms. When the essential product of this cycle, NADH +
H+, and the end product of the common catabolic pathway, ATP, accumulate, they inhibit some of the enzymes
in the cycle. Citrate synthase (Step ①), isocitrate dehydrogenase (Step ③), and a-ketoglutarate dehydrogenase
(part of the complex enzyme system in Step ④) are inhibited by ATP and/or by NADH + H+. This inhibition slows
down or shuts off the cycle. Conversely, when the feed material, acetyl CoA, is in abundance, the cycle
accelerates. The enzyme isocitrate dehydrogenase (Step ③) is stimulated by ADP and NAD+, which are the
essential reactants from which the end products of the cycle are derived.