Metabolism of Carbohydrates and Formation of ATP pdf - Metabolism and Temperature Regulation

are necessary to maintain and propagate life.

impulses; (5) cell division and growth; and (6) many other physiologic functions that

branes, and many other essential molecules of the body; (4) conduction of nerve

mechanical work; (3) various synthetic reactions that create hormones, cell mem-

cules across cell membranes; (2) contraction of muscles and performance of

convert adenosine diphosphate (ADP) to ATP, which is then consumed by the

Energy derived from the oxidation of carbohydrates, proteins, and fats is used to

repeatedly.

has been called the energy currency of the body, and it can be gained and spent

and energy-producing functions of the body (Figure 67–1). For this reason, ATP

Adenosine triphosphate (ATP) is an essential link between energy-utilizing

Role of Adenosine Triphosphate in Metabolism

of 1 mole (180 grams) of glucose is 686,000 calories.

substance. For instance, the amount of free energy liberated by complete oxidation

G. Free energy is usually expressed in terms of calories per mole of

free energy of oxidation of the food,

The amount of energy liberated by complete oxidation of a food is

“Free Energy.”

of which are explained in this and subsequent chapters.

pling is accomplished by special cellular enzyme and energy transfer systems, some

“coupled” with the systems responsible for these physiologic functions. This cou-

and to effect other functions. To provide this energy, the chemical reactions must be

case of muscle function, to concentrate solutes in the case of glandular secretion,

released suddenly, all in the form of heat. The energy needed by the physiologic

fire, also releasing large amounts of energy; in this case, however, the energy is

These same foods can also be burned with pure oxygen outside the body in an actual

oxidized in the cells, and during this process, large amounts of energy are released.

All the energy foods—carbohydrates, fats, and proteins—can be

functions.

in the cells, absorption of foods from the gastrointestinal tract, and many other

of membrane potentials by the nerve and muscle fibers, synthesis of substances

instance, energy is required for muscle activity, secretion by the glands, maintenance

the energy in foods available to the various physiologic systems of the cell. For

fit into the overall concept of homeostasis.

logic implications, especially the manner in which they

the discipline of biochemistry. Instead, these chapters

of all the various cellular reactions, because this lies in

possible for the cells to continue living. It is not the

body, which means the chemical processes that make it

The next few chapters deal with metabolism in the

Triphosphate

and Formation of Adenosine

Metabolism of Carbohydrates,

829

purpose of this textbook to present the chemical details

are devoted to (1) a review of the principal chemical
processes of the cell and (2) an analysis of their physio-

Release of Energy from Foods, and the Concept of
“Free Energy”

A great proportion of the chemical reactions in the cells is concerned with making

Coupled Reactions.

processes of the cells is not heat but energy to cause mechanical movement in the

called the

and this is generally represented by

the symbol

various reactions of the body that are necessary for (1) active transport of mole-

fore, glucose-6-phosphate can be degraded to glucose

There-

glucose phosphatase.

entirely glucose. The reason for this is that the liver cells

rides back into the blood, the final product is almost

Figure 67–3. Furthermore, the dynamics of the reactions

rides—glucose, fructose, and galactose—as shown in

In liver cells, appropriate enzymes are available to

transport of almost all carbohydrates to the tissue cells.

Glucose thus becomes the final common pathway for the

verted into glucose in the liver. Therefore, little fructose

After absorption from the intestinal tract, much of the

representing, on average, about 80 per cent of these.

entirely glucose, fructose, and galactose—with glucose

As explained in Chapter 65, the final products of car-

purpose.

ATP in the cells. Normally, 90 per cent or more of all

The principal purpose of this chapter is to explain

transfers take place by means of coupled reactions.

maintaining a supply of this substance. All these energy

released energy is used to form new ATP, thus always

turn, the food in the cells is gradually oxidized, and the

energy compound—guanosine triphosphate [GTP]). In

obtain it directly from ATP (or another similar high-

nucleoplasm of all cells, and essentially all the physio-

ATP is present everywhere in the cytoplasm and

The interconversions among ATP, ADP, and AMP are

radical, it becomes

becomes ADP, and after loss of the second phosphate

one phosphate radical from ATP, the compound

liberates about 12,000 calories of energy. After loss of

body, removal of each of the last two phosphate radicals

trations of the reactants in the body. Therefore, in the

energy bonds per mole of ATP is about 7300 calories

The amount of free energy in each of these high-

bonds, which are indicated by the symbol

radicals. The last two phosphate radicals are connected

combination of adenine, ribose, and three phosphate

67–2. From this formula, it can be seen that ATP is a

all cells. It has the chemical structure shown in Figure

ATP is a labile chemical compound that is present in

Metabolism and Temperature Regulation

830

Unit XIII

with the remainder of the molecule by high-energy

under standard conditions and about 12,000 calories
under the usual conditions of temperature and concen-

adenosine monophosphate (AMP).

the following:

logic mechanisms that require energy for operation

how the energy from carbohydrates can be used to form

the carbohydrates utilized by the body are used for this

Central Role of Glucose in
Carbohydrate Metabolism

bohydrate digestion in the alimentary tract are almost

fructose and almost all the galactose are rapidly con-

and galactose are present in the circulating blood.

promote interconversions among the monosaccha-

are such that when the liver releases the monosaccha-

contain large amounts of

ATP

ADP

Oxidation

Energy production
•Proteins
•Carbohydrates
•Fats

Energy utilization
•Active ion transport
•Muscle contraction
•Synthesis of molecules
•Cell division and growth

producing and energy-utilizing systems of the body. ADP, adeno-

Adenosine triphosphate (ATP) as the central link between energy-

Figure 67–1

sine diphosphate; P

, inorganic phosphate.

Triphosphate

Adenine

Ribose

triphosphate (ATP).

Chemical structure of adenosine

Figure 67–2

ATP

-12,000 cal

+12,000 cal

-12,000 cal

+12,000 cal

ADP

2PO

diately for release of energy to the cell, or it can be

After absorption into a cell, glucose can be used imme-

Glycogen Is Stored in Liver

have phosphatase.

except from those special cells, especially liver cells, that

with phosphate, the glucose will not diffuse back out,

cell. That is, because of its almost instantaneous binding

it can reverse the reaction. In most tissues of the body,

, is also available, and when this is activated,

epithelial cells; in these cells, another enzyme,

the renal tubular epithelial cells, and the intestinal

almost completely irreversible except in the liver cells,

most other cells. The phosphorylation of glucose is

This phosphorylation is promoted mainly by the

Immediately on entry into the cells, glucose combines

Phosphorylation of Glucose

Chapter 78.

the pancreas. The functions of insulin and its control of

In effect, the rate of carbohydrate utilization by most

of liver and brain cells, are far too little to supply the

the body in the absence of insulin, with the exception

when no insulin is secreted. Conversely, the amounts of

the pancreas, the rate of glucose transport into most

insulin. When large amounts of insulin are secreted by

The rate of glucose transport as well as transport of

Insulin Increases Facilitated

The details of

active absorption of glucose. At other cell membranes,

This sodium

against a concentration difference.

these cases, the glucose is transported by the mechanism

through the epithelium of the renal tubules. In both

The transport of glucose through the membranes of

the other side, more glucose will be transported from

and then released. Therefore, if the concentration of

this bound form, the glucose can be transported by the

molecules that can bind with glucose. In

cally, they are the following. Penetrating through the

of this type of transport are discussed in Chapter 4. Basi-

The principles

molecular weight of 180. Yet glucose does pass to the

that can diffuse readily is about 100, and glucose has a

into the cellular cytoplasm. However, glucose

Before glucose can be used by the body’s tissue cells, it

Through the Cell Membrane

Transport of Glucose

glucose.

Once again, it should be emphasized that usually

and phosphate, and the glucose can then be transported

Metabolism of Carbohydrates, and Formation of Adenosine Triphosphate

Chapter 67

831

through the liver cell membrane back into the blood.

more than 95 per cent of all the monosaccharides that
circulate in the blood are the final conversion product,

must be transported through the tissue cell membrane

cannot

easily diffuse through the pores of the cell membrane
because the maximum molecular weight of particles

interior of the cells with a reasonable degree of freedom
by the mechanism of facilitated diffusion.

lipid matrix of the cell membrane are large numbers of
protein carrier

carrier from one side of the membrane to the other side

glucose is greater on one side of the membrane than on

the high-concentration area to the low-concentration
area than in the opposite direction.

most tissue cells is quite different from that which
occurs through the gastrointestinal membrane or

of active sodium-glucose co-transport, in which active
transport of sodium provides energy for absorbing
glucose
co-transport mechanism functions only in certain
special epithelial cells that are specifically adapted for

glucose is transported only from higher concentration
toward lower concentration by facilitated diffusion,
made possible by the special binding properties of mem-
brane glucose carrier protein.

facilitated

diffusion for cell membrane transport are presented in
Chapter 4.

Diffusion of Glucose

some other monosaccharides is greatly increased by

cells increases to 10 or more times the rate of transport

glucose that can diffuse to the insides of most cells of

amount of glucose normally required for energy metab-
olism.

cells is controlled by the rate of insulin secretion from

carbohydrate metabolism are discussed in detail in

with a phosphate radical in accordance with the follow-
ing reaction:

enzyme glucokinase in the liver and by hexokinase in

glucose

phosphatase

phosphorylation serves to capture the glucose in the

and Muscle

ææææææææ

Glucose

Glucose-6-phosphate

glucokinase or hexokinase

ATP

Galactose

Galactose-1-phosphate

ATP

Cell membrane

Uridine diphosphate galactose

Uridine diphosphate glucose

Glucose-1-phosphate

Glucose-6-phosphate

Fructose-6-phosphate

Glucose

Fructose

Glycogen

Glycolysis

Interconversions of the three major monosaccharides—glucose,

Figure 67–3

fructose, and galactose—in liver cells.

ATP.

The next sections describe the basic principles of

ATP for each mole of glucose metabolized by the cells.

cule of ATP at a time, forming a total of 38 moles of

a little at a time in many successive steps, so that its

cule. Fortunately, all cells of the body contain special

carbon dioxide while forming only a single ATP mole-

gram-molecule of ATP, energy would be wasted if

glucose releases 686,000 calories of energy and

Release of Energy from the

glucose concentration. The function of glucagon in

release into the blood, thereby elevating the blood

mainly in the liver cells, and this in turn promotes

falls too low. It stimulates formation of cyclic AMP

pathetic stimulation, to preparing the body for action,

thereby contributing, along with other effects of sym-

rine occurs markedly in both liver cells and muscle,

for rapid energy metabolism. This function of epineph-

Therefore, one of the functions of the sympathetic

the phosphorylase. This is discussed in detail in Chapter

in the cells, which then

phorylase and thereby cause rapid glycogenolysis. The

hormones,

Two

Activation of Phosphorylase by Epinephrine or by Glucagon.

two.

accomplished in several ways, including the following

rst be activated. This can be

it is necessary to re-form glucose from glycogen, the

inactive form, so that glycogen will remain stored. When

Under resting conditions, the phosphorylase is in an

phosphorylase.

reactions that form glycogen; instead, each succeeding

glucose can then be used to provide energy. Glycogenol-

stored glycogen to re-form glucose in the cells. The

deaminated amino acids,

lactic acid, glycerol, pyruvic acid,

pounds, including

can enter into the reactions. Certain smaller com-

enzymes are required to cause these conversions, and

nally converted into glycogen. Several speci

uridine diphosphate glucose,

gure, it can be seen that

4. From this

Figure 67

The chemical reactions for glycogenesis are shown in

of Glycogen Formation

uids.

low-molecular-weight soluble monosaccharides would

uids. High concentrations of

molecular-weight precipitated compound (glycogen)

This conversion of the monosaccharides into a high-

the form of solid granules.

million or greater; most of the glycogen precipitates in

weight, with the average molecular weight being 5

can store up to 1 to 3 per cent glycogen. The glycogen

muscle cells,

cent of their weight as glycogen, and

liver cells,

some glycogen, but certain cells can store large amounts,

of glucose.

Metabolism and Temperature Regulation

832

Unit XIII

stored in the form of glycogen, which is a large polymer

All cells of the body are capable of storing at least

especially

which can store up to 5 to 8 per

which

molecules can be polymerized to almost any molecular

makes it possible to store large quantities of carbohy-
drates without significantly altering the osmotic pres-
sure of the intracellular fl

play havoc with the osmotic relations between intracel-
lular and extracellular fl

Glycogenesis

—

The Process

–

glucose-

6-phosphate can become glucose-1-phosphate; this is
converted to

which is

fic

any monosaccharide that can be converted into glucose

and

some

can also be converted

into glucose or closely allied compounds and then con-
verted into glycogen.

Removal of Stored Glycogen—
Glycogenolysis

Glycogenolysis means the breakdown of the cell’s

ysis does not occur by reversal of the same chemical

glucose molecule on each branch of the glycogen
polymer is split away by phosphorylation, catalyzed by
the enzyme

phosphorylase must fi

epinephrine and glucagon, can activate phos-

initial effect of each of these hormones is to promote
the formation of cyclic AMP
initiates a cascade of chemical reactions that activates

78.

Epinephrine is released by the adrenal medullae

when the sympathetic nervous system is stimulated.

nervous system is to increase the availability of glucose

as discussed fully in Chapter 60.

Glucagon is a hormone secreted by the alpha cells

of the pancreas when the blood glucose concentration

conversion of liver glycogen into glucose and its

blood glucose regulation is discussed more fully in
Chapter 78.

Glucose Molecule by the
Glycolytic Pathway

Because complete oxidation of 1 gram-molecule of

only 12,000 calories of energy are required to form 1

glucose were decomposed all at once into water and

protein enzymes that cause the glucose molecule to split

energy is released in small packets to form one mole-

the processes by which the glucose molecule is pro-
gressively dissected and its energy released to form

Cell membrane

Uridine diphosphate glucose

Glycogen

Glycolysis

Glucose-1-phosphate

Glucose-6-phosphate

Glucose

Blood

glucose

(glucokinase)

(phosphatase)

(phosphorylase)

is present in liver cells but not in most other cells.)

(The phosphatase required for the release of glucose from the cell

also interconversions between blood glucose and liver glycogen.

Chemical reactions of glycogenesis and glycogenolysis, showing

Figure 67–4

more quantities of acetyl-CoA from pyruvic acid. The

coenzyme A portion of the acetyl-CoA is released and

The

oxaloacetic acid

In the initial stage of the citric acid cycle,

cycle can continue over and over.

is formed again. Thus, the

oxaloacetic acid

reactions,

oxaloacetic acid,

right. Note at the top of the column that the cycle begins

the left are added during the chemical reactions, and the

cal reactions in the citric acid cycle. The substances to

Figure 67

amounts of energy to form ATP.

oxidized (as discussed later), releasing tremendous

The released hydrogen atoms add to

mitochondrion.

atoms. These reactions all occur in the

). This is a sequence of

boxylic acid cycle

The next stage in the degradation of the glucose mole-

Citric Acid Cycle (Krebs Cycle)

dized, as discussed later.

formed, but up to six molecules of ATP are formed

molecules of acetyl-CoA. In this conversion, no ATP is

derivative of the vitamin pantothenic acid, to form two

pyruvic acid molecules combine with coenzyme A, a

released, while the remaining portions of the two

From this reaction, it can be seen that two carbon

(acetyl-CoA), in accordance with the following

Figure 67

The next stage in the degradation of glucose is a two-

to Acetyl Coenzyme A

Conversion of Pyruvic Acid

The remaining 57 per cent of the energy is lost in the

for ATP formation of only 43 per cent.

energy were lost from the original glucose, giving an

ATP, but during glycolysis, a total of 56,000 calories of

This amounts to

moles for each mole of glucose utilized.

ATP molecules by the entire glycolytic process is only 2

before glycolysis could begin. Therefore,

Yet 2 moles of ATP were required to phosphorylate

of 4 moles of ATP were formed for each mole of fruc-

coupled in such a way that ATP is formed. Thus, a total

amount required to form ATP, and the reactions are

released are greater than 12,000 calories per mole, the

and the pyruvic acid stages, the packets of energy

stages, and again between the phosphoenolpyruvic acid

released at most steps. However, between the 1,3-

ical reactions in the glycolytic series, only a small

Formation of ATP During Glycolysis.

3-phosphate, each of which is then converted through

into two three-carbon-atom molecules, glyceraldehyde-

c protein enzyme. Note that glucose is

5. Each step is catalyzed by at least

shown in Figure 67

Glycolysis occurs by 10 successive chemical reactions,

two molecules of pyruvic acid.

energy. Glycolysis means splitting of the glucose mole-

The

glycolysis.

of Pyruvic Acid

Glycolysis and the Formation

Metabolism of Carbohydrates, and Formation of Adenosine Triphosphate

Chapter 67

833

By far the most important means of releasing energy
from the glucose molecule is initiated by
end products of glycolysis are then oxidized to provide

cule to form

–

one specifi

first

converted into fructose-1,6-diphosphate and then split

five additional steps into pyruvic acid.

Despite the many chem-

portion of the free energy in the glucose molecule is

diphosphoglyceric acid and the 3-phosphoglyceric acid

tose-1,6-diphosphate that is split into pyruvic acid.

the original glucose to form fructose-1,6-diphosphate

the net gain in

24,000 calories of energy that becomes transferred to

overall efficiency

form of heat.

step conversion of the two pyruvic acid molecules from

–5 into two molecules of acetyl coenzyme

A
reaction:

dioxide molecules and four hydrogen atoms are

when the four released hydrogen atoms are later oxi-

cule is called the citric acid cycle (also called the tricar-

or Krebs cycle

chemical reactions in which the acetyl portion of acetyl-
CoA is degraded to carbon dioxide and hydrogen

matrix of the

the number of these atoms that will subsequently be

–6 shows the different stages of the chemi-

products of the chemical reactions are shown to the

with

and at the bottom of the chain of

acetyl-CoA

combines with

to form citric acid.

can be used again and again for the formation of still

CoA

(Pyruvic acid)

(Coenzyme A)

COOH

2CoA

2CH

+ 2CO

+ 4H

(Acetyl-CoA)

2 Pyruvic acid + 2ATP + 4H

Glucose + 2ADP + 2PO

2ADP

2ATP

ATP

ADP

ATP

ADP

2ADP

Net reaction per molecule of glucose:

Glucose

Glucose-6-phosphate

Fructose-6-phosphate

Fructose-1,6-diphosphate

2 (1,3-Diphosphoglyceric acid)

2 (3-Phosphoglyceric acid)

2 (2-Phosphoglyceric acid)

Dihydroxyacetone phosphate

2 (Glyceraldehyde-3-phosphate)

2 (Phosphoenolpyruvic acid)

2 (Pyruvic acid)

Sequence of chemical reactions responsible for glycolysis.

Figure 67–5

citric acid cycle, as well as to those for the formation of

process.

. Instead, they pass

not subsequently released to NAD

citric acid cycle between the succinic and fumaric acid

The remaining four hydrogen atoms released during

later.

that form tremendous quantities of ATP, as discussed

gen ion and the hydrogen bound with NAD

to act as a hydrogen carrier. Both the free hydro-

NAD

This reaction will not occur without intermediation of

the vitamin niacin, in accordance with the following

), a derivative of

namide adenine dinucleotide (NAD

Twenty of the

dehydrogenase.

in each instance, the release is catalyzed by a speci

uid. Instead, they are released in packets of two, and

However, the hydrogen

original molecule of glucose.

this makes a total of 24 hydrogen atoms released for each

CoA from pyruvic acid, and 16 in the citric acid cycle;

atoms during glycolysis, 4 during formation of acetyl-

chemical reactions of the citric acid cycle

sion, hydrogen atoms are released during different

Function of Dehydrogenases and Nicotinamide Adenine Dinu-

a total of two molecules of ATP formed.

the citric acid cycle, each forming a molecule of ATP, or

metabolized, two acetyl-CoA molecules pass through

of ATP formed. Thus, for each molecule of glucose

of energy is released during the citric acid cycle itself; in

Formation of ATP in the Citric Acid Cycle.

molecules of ATP are formed, as follows.

hydrogen atoms, and 2 molecules of coenzyme A. Two

are then degraded into 4 carbon dioxide molecules, 16

citric acid cycle, along with 6 molecules of water. These

metabolized, 2 acetyl-CoA molecules enter into the

6, demon-

in the explanation at the bottom of Figure 67

The net results of the entire citric acid cycle are given

gure.

cycle, as shown on the right in the

carbon dioxide

gure, and

citric acid cycle, several molecules of water are added,

citric acid molecule. During the successive stages of the

acetyl portion, however, becomes an integral part of the

Metabolism and Temperature Regulation

834

Unit XIII

as shown on the left in the fi
and hydrogen atoms are released at other stages in the

–

strating that for each molecule of glucose originally

Not a great amount

only one of the chemical reactions—during the change
from

a-ketoglutaric acid to succinic acid—is a molecule

cleotide in Causing Release of Hydrogen Atoms in the Citric Acid
Cycle.

As already noted at several points in this discus-

—4 hydrogen

atoms are not simply turned loose in the intracellular
fl

fic

protein enzyme called a
24 hydrogen atoms immediately combine with nicoti-

reaction:

the specific dehydrogenase or without the availability of

subse-

quently enter into multiple oxidative chemical reactions

the breakdown of glucose—the four released during the

stages—combine with a specific dehydrogenase but are

directly from the dehydrogenase into the oxidative

Function of Decarboxylases in Causing Release of Carbon Dioxide.

Referring again to the chemical reactions of the

dehydrogenase

NADH

+ H

+ Substrate

+ NAD

Substrate

+ 16H + 2CoA + 2ATP

2 Acetyl-CoA + 6H

CoA

(Acetyl coenzyme A)

COOH

ATP

ADP

COOH

(Citric acid)

HOC

COOH

HOC

COOH

HOOC

COOH

(Oxaloacetic acid)

(cis-Aconitic acid)

(Isocitric acid)

(Oxalosuccinic acid)

COOH

(Malic acid)

(Oxaloacetic acid)

(

-Ketoglutaric acid)

(Succinic acid)

(Fumaric acid)

COOH

CoA

Net reaction per molecule of glucose:

O + 2ADP

4CO

carbon dioxide and a number of hydrogen atoms during the cycle.

Chemical reactions of the citric acid cycle, showing the release of

Figure 67–6

ATP synthetase.

7. It is called

ical nature of which is shown in Figure 67

chondrial matrix. This molecule is an ATPase, the phys-

lation is to convert ADP into ATP. This occurs in con-

The next step in oxidative phosphory-

Formation of ATP.

chamber; it also creates a strong negative electrical

drial membranes (to the left). This creates a high con-

the mitochondrion (to the right in Figure 67

large amounts of energy are released. This energy is

chondrion, Caused by the Electron Transport Chain.

follows.

released that is used to cause the synthesis of ATP, as

trons through the electron transport chain, energy is

of water molecules. During the transport of these elec-

use by cytochrome oxidase to cause the formation

Thus, Figure 67

ions to form water.

form ionic oxygen, which then combines with hydrogen

cytochrome oxidase

nally reaches cytochrome A3, which is called

3. Each electron is shut-

, and

cytochromes B, C

iron sulfide proteins, ubiquinone,

accepting or giving up electrons. The important

shelf membrane) of the mitochondrion. The electron

electron transport chain of electron acceptors

The electrons that are removed from the hydrogen

; this process also reconstitutes NAD

gen ion, H

hydrogen atom from the NADH to form another hydro-

. The initial effect is to release the other

NADH and H

portion of Figure 67

to form NADH. The upper

other combines with NAD

; the

pairs: one immediately becomes a hydrogen ion, H

described earlier, these hydrogen atoms are removed in

have been removed from the food substrates. As

The

tion of Water.

Ionization of Hydrogen, the Electron Transport Chain, and Forma-

Mitochondria to Form ATP

Chemiosmotic Mechanism of the

mechanism.

chemiosmotic

This occurs entirely in the mitochondria by a

oxidative phospho-

tion of ATP in this manner is called

quantities of energy are released to form ATP. Forma-

this sequence of oxidative reactions, tremendous

combine with each other to form water. During

hydroxyl ions. Then the hydrogen and hydroxyl ions

These reactions (1) split

in the mitochondria.

7, by a series of enzymatically catalyzed

in Figure 67

Oxidation of hydrogen is accomplished, as illustrated

early stages of glucose degradation. Indeed, the princi-

almost 90 per cent of the total ATP created through

cycle for each molecule of glucose metabolized. Instead,

only two ATP molecules in

boxylation, pitifully small amounts of ATP are formed

citric acid cycle, (3) dehydrogenation, and (4) decar-

Despite all the complexities of (1) glycolysis, (2) the

(the Process of Oxidative

of ATP by Oxidation of Hydrogen

Formation of Large Quantities

lungs, where it is expired from the body (see Chapter

dioxide away from the substrate. The carbon dioxide is

decarboxylases,

protein enzymes, called

cause the release of carbon dioxide, other speci

three stages in which carbon dioxide is released. To

acetyl-CoA from pyruvic acid, we

Metabolism of Carbohydrates, and Formation of Adenosine Triphosphate

Chapter 67

835

find that there are

fic

split the carbon

then dissolved in the body fluids and transported to the

40).

Phosphorylation)

during all these processes—
the glycolysis scheme and another two in the citric acid

glucose metabolism is formed during subsequent oxi-
dation of the hydrogen atoms that were released at

pal function of all these earlier stages is to make the
hydrogen of the glucose molecule available in forms
that can be oxidized.

–

reactions
each hydrogen atom into a hydrogen ion and an elec-
tron and (2) use the electrons eventually to combine dis-
solved oxygen of the fluids with water molecules to form

rylation.
highly specialized process called the

first step in oxidative phosphorylation

in the mitochondria is to ionize the hydrogen atoms that

–7 shows the subsequent fate of the

that

will be reused again and again.

atoms to cause the hydrogen ionization immediately
enter an
that are an integral part of the inner membrane (the

acceptors can be reversibly reduced or oxidized by

members of this electron transport chain include flavo-
protein, several

and

1, C, A

tled from one of these acceptors to the next until it
fi

because it is capable of giving up

two electrons and thus reducing elemental oxygen to

–7 shows the transport of electrons

through the electron chain and then their ultimate

Pumping of Hydrogen Ions into the Outer Chamber of the Mito-

As the

electrons pass through the electron transport chain,

used to pump hydrogen ions from the inner matrix of

–7) into the

outer chamber between the inner and outer mitochon-

centration of positively charged hydrogen ions in this

potential in the inner matrix.

junction with a large protein molecule that protrudes all
the way through the inner mitochondrial membrane
and projects with a knoblike head into the inner mito-

–

ATPase

diffusion

Diffusion

3 ATP

ATP

3 ADP

Food substrate

Outer

membrane

Outer

membrane

Inner

membrane

Inner

membrane

Facilitated

FMN

FeS

NAD

NADH +

1/2 O

ADP

relationship of the oxidative and phosphorylation steps at the outer

lation for forming large quantities of ATP. This figure shows the

Mitochondrial chemiosmotic mechanism of oxidative phosphory-

Figure 67–7

and inner membranes of the mitochondrion.

glycolysis stage of carbohydrate degradation, because

take place. Yet even under these conditions, a small

cient, so that oxidative phosphorylation cannot

Occasionally, oxygen becomes either unavailable or

as very strenuous exercise.

maintained, except during extreme cellular activity, such

this way, essentially a full store of ATP is automatically

AMP are almost instantly returned to the ATP state. In

AMP turn on the energy processes again, and ADP and

siologic functions in the cell, the newly formed ADP and

ATP is used by the cell to energize the different phy-

to form ATP is stopped. Then, when

fats, and proteins

glucose,

ATP simply cannot be formed. As a result, the entire

cell has already been converted into ATP, additional

for energy release, we see that if all the ADP in the

lowing: Referring back to the various chemical reactions

ling energy release from fats and proteins, is the fol-

controls carbohydrate metabolism, as well as control-

A third way by which the ATP-ADP-AMP system

glycolysis.

acid cycle

inhibits phosphofructokinase,

the citric acid cycle. An excess of this ion also

store of ATP is replenished.

glycolytic process is set in motion, and the total cellular

activity as a result of the excess ADP formed. Thus, the

reactions, this reduces the ATP inhibition of the enzyme

ity. Whenever ATP is used by the tissues for energizing

site change in this enzyme, greatly increasing its activ-

Conversely, ADP (and AMP as well) causes the oppo-

excess cellular ATP is to slow or even stop glycolysis,

in the glycolytic series of reactions, the net effect of

tion of fructose-1,6-diphosphate, one of the initial steps

fructokinase.

energy metabolism is to inhibit the enzyme

One important way in which ATP helps control

reactions in the energy metabolism sequence.

both ADP and ATP in controlling the rates of chemical

within the chemical schemata. Among the more impor-

need for ATP. This control is

ful process. Instead, glycolysis and the subsequent oxi-

in Controlling the Rate of Glycolysis

of ATP and ADP Cell Concentrations

Needs Additional Energy: Effect

c functions.

and, therefore, cannot be used by the cells to perform

The remaining 34 per cent of the energy becomes heat

molecule of glucose. This represents an overall

in the form of ATP, whereas 686,000 calories are

and water. Thus, 456,000 calories of energy can be stored

38 ATP molecules

Now, adding all the ATP molecules formed, we

molecules.

four more ATP

oxidized, thus giving a total of

7. Two ATP molecules are

rst stage of Figure 67

4. The remaining four hydrogen atoms are released

30 ATP molecules.

atoms of hydrogen metabolized. This gives an

with the release of three ATP molecules per two

chemiosmotic mechanism shown in Figure 67

glycolysis and during the citric acid cycle. Twenty of

3. During the entire schema of glucose breakdown, a

ATP.

for each molecule of glucose metabolized, giving

molecules, there are two revolutions of the cycle

one molecule of ATP is formed. However, because

2. During each revolution of the citric acid cycle,

ATP.

going. This gives a net gain of

formed, and two are expended to cause the initial

1. During glycolysis, four molecules of ATP are

the energy from one molecule of glucose.

cules that, under optimal conditions, can be formed by

We can now determine the total number of ATP mole-

the Breakdown of Glucose

Summary of ATP Formation During

two hydrogen atoms), up to three ATP molecules are

For each two electrons that pass through the entire elec-

the other direction for continual conversion into ATP.

membrane. In turn, ADP is continually transferred in

plasm. This occurs by facilitated diffusion outward

the inside of the mitochondrion back to the cell cyto-

nal step in the process is transfer of ATP from

The

molecule.

ing ADP with a free ionic phosphate radical (Pi), thus

used by ATPase to convert ADP into ATP by combin-

doing so, energy derived from this hydrogen ion

through the substance of the ATPase molecule.

The high concentration of positively charged hydro-

Metabolism and Temperature Regulation

836

Unit XIII

gen ions in the outer chamber and the large electrical
potential difference across the inner membrane cause
the hydrogen ions to flow into the inner mitochondrial
matrix

flow is

adding another high-energy phosphate bond to the

through the inner membrane and then by simple dif-
fusion through the permeable outer mitochondrial

tron transport chain (representing the ionization of

synthesized.

phosphorylation of glucose to get the process

two molecules of

each glucose molecule splits into two pyruvic acid

a net production of two more molecules of

total of 24 hydrogen atoms are released during

these atoms are oxidized in conjunction with the

–7,

additional

by their dehydrogenase into the chemiosmotic
oxidative schema in the mitochondrion beyond the
fi

–

usually released for every two hydrogen atoms

find a maximum of

formed for each

molecule of glucose degraded to carbon dioxide

released during the complete oxidation of each gram-

maximum efficiency of energy transfer of 66 per cent.

specifi

Control of Energy Release from
Stored Glycogen When the Body

Continual release of energy from glucose when energy
is not needed by the cells would be an extremely waste-

dation of hydrogen atoms are continually controlled in
accordance with the cells’
accomplished by multiple feedback control mechanisms

tant of these are the effects of cell concentrations of

phospho-

Because this enzyme promotes the forma-

which in turn stops most carbohydrate metabolism.

a major fraction of almost all intracellular chemical

phosphofructokinase and at the same time increases its

Another control linkage is the citrate ion formed in

strongly

thus preventing the

glycolytic process from getting ahead of the citric

’s ability to use the pyruvic acid formed during

sequence involved in the use of foodstuffs—

—

Anaerobic Release of Energy—
“Anaerobic Glycolysis”

insuffi

amount of energy can still be released to the cells by the

the chemical reactions for the breakdown of glucose to
pyruvic acid do not require oxygen.

energy. By far the greatest portion of this reconversion

when oxygen is available again, the lactic acid can be

anaerobic glycolysis is not lost from the body because,

Thus, the large amount of lactic acid that forms during

glucose.

excess ATP then causes as much as three fourths of the

ately oxidized to form large quantities of ATP. This

. Large portions of these are immedi-

NADH plus H

When a person begins to breathe

Becomes Available Again.

quantities of ATP, even in the absence of respiratory

minutes, supplying the body with considerable extra

this conversion. Instead, it can proceed for several

longer than would otherwise be possible. Indeed, gly-

can disappear, thus allowing glycolysis to proceed far

less active cells. Therefore, lactic acid represents a type

of the pyruvic acid is converted into lactic acid, which

Thus, under anaerobic conditions, the major portion

other to form lactic acid, in accordance with the fol-

to be excessive, these two end products react with each

further formation of ATP. When their quantities begin

. The buildup of either or both of

form NADH and H

acid and (2) hydrogen atoms combined with NAD

5) are (1) pyruvic

the glycolytic reactions (see Figure 67

decreases, approaching zero. The two end products of

build up in a reacting medium, the rate of the reaction

The

Release of Extra Anaerobic Energy.

oxygen becomes unavailable.

anaerobic energy,

energy to the cells, which is called

glucose molecule. Nevertheless, this release of glycolytic

each molecule of glucose metabolized, which represents

only 24,000 calories of energy are used to form ATP for

This process is extremely wasteful of glucose, because

Metabolism of Carbohydrates, and Formation of Adenosine Triphosphate

Chapter 67

837

only a little over 3 per cent of the total energy in the

can

be a lifesaving measure for up to a few minutes when

Formation of Lactic Acid During Anaerobic Glycolysis Allows

law of mass action

states that as the end products of a chemical reaction

–

these would stop the glycolytic process and prevent

lowing equation:

diffuses readily out of the cells into the extracellular
fluids and even into the intracellular fluids of other

of “sinkhole” into which the glycolytic end products

colysis could proceed for only a few seconds without

oxygen.

Reconversion of Lactic Acid to Pyruvic Acid When Oxygen

oxygen again after a period of anaerobic metabolism,
the lactic acid is rapidly reconverted to pyruvic acid and

remaining excess pyruvic acid to be converted back into

either reconverted to glucose or used directly for

COOH

NAD

COOH

NADH

dehydrogenase

lactic

(Pyruvic acid)

(Lactic acid)

substances.

in the form of NADPH can be used for

with NADP

cant, because only hydrogen bound

for an extra phosphate radical, P. This difference is

), which is almost identical to NAD

(NADP

with NAD

during the pentose phosphate cycle does not combine

The hydrogen released

stances, as follows.

however, it is used for the synthesis of fat or other sub-

phosphorylation pathway to form ATP; more often,

and hydrogen, and the hydrogen can enter the oxidative

Thus, by repeating the cycle again and again, all the

glucose is metabolized for each revolution of the cycle.

pathway is a cyclical process in which one molecule of

That is, the pentose phosphate

into the reactions.

sized for every six molecules of glucose that initially enter

However,

nations of these sugars can resynthesize glucose.

seven-, and three-carbon sugars. Finally, various combi-

ve-, four-,

-ribulose. This substance can

ve-carbon sugar,

four atoms of hydrogen, with the resultant formation

version, can release one molecule of carbon dioxide and

demonstrates that glucose, during several stages of con-

chemical reactions in the pentose phosphate pathway. It

Figure 67

Phosphate Pathway.

viding energy to multiple cellular synthetic processes.

malities occur in cells. It has a special capacity for pro-

citric acid cycle and therefore is an alternative pathway

This pathway is especially important because it can

liver and even more than this in fat cells.

), which is responsible for as

phosphogluconate pathway

pentose phosphate pathway

can be degraded and used to provide energy. A second

acid by glycolysis and then oxidized. However, this gly-

s muscles, essentially all the car-

Release of Energy from

occurs to a great extent during heavy exercise, when

acid and then using the pyruvic acid for energy. This

Use of Lactic Acid by the Heart for Energy.

other tissues.

occurs in the liver, but a small amount can also occur in

Heart muscle

is especially capable of converting lactic acid to pyruvic

large amounts of lactic acid are released into the blood
from the skeletal muscles and consumed as an extra
energy source by the heart.

Glucose by the Pentose
Phosphate Pathway

In almost all the body’
bohydrates utilized for energy are degraded to pyruvic

colytic scheme is not the only means by which glucose

important mechanism for the breakdown and oxidation
of glucose is called the

(or

much as 30 per cent of the glucose breakdown in the

provide energy independently of all the enzymes of the

for energy metabolism when certain enzymatic abnor-

Release of Carbon Dioxide and Hydrogen by Means of the Pentose

–8 shows most of the basic

of a fi

change progressively into several other fi

only five molecules of glucose are resynthe-

glucose can eventually be converted into carbon dioxide

Use of Hydrogen to Synthesize Fat; the Function of Nicotinamide
Adenine Dinucleotide Phosphate.

as in the glycolytic pathway but combines

with nicotinamide adenine dinucleotide phosphate

except

extremely signifi

the synthesis of fats from carbohydrates (as discussed
in Chapter 68) and for the synthesis of some other

into glucose. Thus, one of the most important means

uids. A high

essentially all cells of the body, making these available

In turn, cortisol mobilizes proteins from

glucocorticoid hormones,

This stimulates the adrenal cortex to produce

for reasons not completely understood, begins to

are not available to the cells, the adenohypophysis,

When normal quantities of carbohydrates

Effect of Corticotropin and Glucocorticoids on Gluco-

follows.

is especially important in this regulation, as

glycerol into carbohydrates. In addition, the hormone

glycolytic and phosphogluconate reactions, thus allow-

stimuli that increase the rate of gluconeogenesis. Dimin-

become glucose. Similar interconversions can change

simple interconversions, many of the amino acids can

glucose. Thus, by means of deamination plus several

ve-, or seven-carbon atoms; they can then enter

four-,

into pyruvic acid simply by deamination; the pyruvic

process. For instance, alanine can be converted directly

cult or impossible. Each amino acid is

teins can be converted easily into carbohydrates; the

other precursors.

During prolonged fasting, the kidneys also synthesize

duction during fasting is from gluconeogenesis, helping

) and by synthesizing glucose,

in the blood for several hours between meals. The liver

cells, and adequate amounts of glucose must be present

tration during fasting. Glucose is the primary substrate

gluconeogenesis.

This process is called

below normal, moderate quantities of glucose can be

When the body

from Proteins and Fats—

Formation of Carbohydrates

cells and is stored as fat in the fat cells. Other steps

muscle cells) approach saturation with glycogen, the

When the glycogen-storing cells (primarily liver and

to 24 hours.

either stored as glycogen or converted into fat. Glucose

When glucose is not immediately required for energy,

for the formation and storage of fat in the body.

instance,

used other than for the formation of ATP

derived from glucose, into long fatty acid chains. This is

becomes abundant to help convert acetyl-CoA, also

tinues to be transported into the cells, and NADPH

becomes slowed because of cellular inactivity, the

When the glycolytic pathway for using glucose

Metabolism and Temperature Regulation

838

Unit XIII

pentose phosphate pathway remains operative (mainly
in the liver) to break down any excess glucose that con-

another way in which energy in the glucose molecule is

—in this

Glucose Conversion to Glycogen
or Fat

the extra glucose that continually enters the cells is

is preferentially stored as glycogen until the cells have
stored as much glycogen as they can—an amount suffi-
cient to supply the energy needs of the body for only 12

additional glucose is converted into fat in liver and fat

in the chemistry of this conversion are discussed in
Chapter 68.

“Gluconeogenesis”

’s stores of carbohydrates decrease

formed from amino acids and the glycerol portion of fat.

Gluconeogenesis is especially important in prevent-

ing an excessive reduction in the blood glucose concen-

for energy in tissues such as the brain and the red blood

plays a key role in maintaining blood glucose levels
during fasting by converting its stored glycogen to
glucose (glycogenolysis
mainly from lactate and amino acids (gluconeogenesis).
Approximately 25 per cent of the liver’s glucose pro-

to provide a steady supply of glucose to the brain.

considerable amounts of glucose from amino acids and

About 60 per cent of the amino acids in the body pro-

remaining 40 per cent have chemical configurations that
make this diffi
converted into glucose by a slightly different chemical

acid is then converted into glucose or stored glycogen.
Several of the more complicated amino acids can be
converted into different sugars that contain three-,

the phosphogluconate pathway and eventually form

glycerol into glucose or glycogen.

Regulation of Gluconeogenesis.

Diminished carbohydrates

in the cells and decreased blood sugar are the basic

ished carbohydrates can directly reverse many of the

ing the conversion of deaminated amino acids and

cortisol

neogenesis.

secrete increased quantities of the hormone corti-
cotropin.
large quantities of

especially

cortisol.

in the form of amino acids in the body fl
proportion of these immediately become deaminated
in the liver and provide ideal substrates for conversion

by which gluconeogenesis is promoted is through
the release of glucocorticoids from the adrenal
cortex.

Glucose-6-phosphate

6-Phosphoglucono-

-lactone

6-Phosphogluconic acid

3-Keto-6-phosphogluconic acid

D-Ribulose-5-phosphate

D-Xylulose-5-phosphate

D-Ribose-5-phosphate

D-Sedoheptulose-7-phosphate

D-Glyceraldehyde-3-phosphate

Fructose-6-phosphate

Erythrose-4-phosphate

Net reaction:
Glucose

12NADP

6CO

12H

12NADPH

Figure 67–8

Pentose phosphate pathway for glucose metabolism.

Endocr Metab Disord 4:95, 2003.

Wolfsdorf JI, Weinstein DA: Glycogen storage diseases. Rev

exercise. Acta Physiol Scand 178:443, 2003.

Spriet LL, Watt MJ: Regulatory mechanisms in the interac-

cal basis of certain disease states. J Intern Med 254:517,

Ronquist G, Waldenstrom A: Imbalance of plasma mem-

Clin Endocrinol Metab 17:365, 2003.

its role in health and disease. Best Pract Res

Roden M, Bernroider E: Hepatic glucose metabolism in

Physiol 54:885, 1992.

tion of hepatic gluconeogenesis and glycolysis. Annu Rev

Pilkis SJ, Granner DK: Molecular physiology of the regula-

Lett 545:47, 2003.

cytochrome c oxidase: lessons from other proteins. FEBS

Mills DA, Ferguson-Miller S: Understanding the mechanism

production. Am J Physiol Endocrinol Metab 284:E863,

Lam TK, Carpentier A, Lewis GF, et al: Mechanisms of

FEBS Lett 564:239, 2004.

Kunji ER: The role and structure of mitochondrial carriers.

Krebs HA: The tricarboxylic acid cycle. Harvey Lect 44:165,

humans. Physiol Rev 72:419, 1992.

Jungas RL, Halperin ML, Brosnan JT: Quantitative analysis

metabolism. Am J Physiol Endocrinol Metab 284:E671,

Jiang G, Zhang BB: Glucagon and regulation of glucose

FEBS Lett 545:18, 2003.

Jackson JB: Proton translocation by transhydrogenase.

chondria. FEBS Lett 567:96, 2004.

Gunter TE, Yule DI, Gunter KK, et al: Calcium and mito-

Physiol 58:565, 1996.

review of sites, pathways, and regulation. Annu Rev

Gleeson TT: Post-exercise lactate metabolism: a comparative

deposition. FEBS Lett 546:127, 2003.

Ferrer JC, Favre C, Gomis RR, et al: Control of glycogen

Diabetes 53(Suppl 1):S96, 2004.

Duchen MR: Roles of mitochondria in health and disease.

Physiol Rev 84:1, 2004.

phosphatase-1, a cellular economizer and reset button.

Ceulemans H, Bollen M: Functional diversity of protein

Metab 285:E685, 2003.

of hepatic gluconeogenesis. Am J Physiol Endocrinol

Barthel A, Schmoll D: Novel concepts in insulin regulation

indirect? J Clin Invest 111:434, 2003.

s effect on glucose production: direct or

Barrett EJ: Insulin

78 in relation to the functions of these hormones.

glucagon; this subject is discussed in detail in Chapter

The regulation of blood glucose concentration is inti-

dl unless the person has diabetes mellitus, which is dis-

of carbohydrates, this level seldom rises above 140 mg/

is about 90 mg/dl.After a meal containing large amounts

The normal blood glucose concentration in a person

Metabolism of Carbohydrates, and Formation of Adenosine Triphosphate

Chapter 67

839

Blood Glucose

who has not eaten a meal within the past 3 to 4 hours

cussed in Chapter 78.

mately related to the pancreatic hormones insulin and

References

’

2003.

of amino acid oxidation and related gluconeogenesis in

1948-1949.

the free fatty acid-induced increase in hepatic glucose

2003.

of proton movement linked to oxygen reduction in

humans—

brane ion leak and pump relationship as a new aetiologi-

2003.

tion between carbohydrate and lipid oxidation during