Human Physiology, 14th edition (2016)

Enzymes and Energy 95

Figure 4.7 The general pattern of a metabolic

pathway. In metabolic pathways, the product of one enzyme

becomes the substrate of the next.

Enz 2

B

Enz 3

C

Enz 4

DE

Intermediates

Initial

substrate

A

Final

product

F

Enz 1 Enz 5

Figure 4.8 A branched metabolic pathway. Two or

more different enzymes can work on the same substrate at the

branch point of the pathway, catalyzing two or more different

reactions.

Enz 2

BC

Intermediates

Initial

substrate

A

Final

products

Enz 5

Enz 1

Enz F'

5'

F

D'Enz4' E'

Enz 4

Enz^3 DE

Enz

3'

End-Product Inhibition

The activities of enzymes at the branch points of metabolic

pathways are often regulated by a process called end-product

inhibition, which is a form of negative feedback. In this pro-

cess, one of the final products of a divergent pathway inhibits

the activity of the branch-point enzyme that began the path

toward the production of this inhibitor. This inhibition pre-

vents that final product from accumulating excessively and

results in a shift toward the final product of the alternate path-

way ( fig. 4.9 ).

The mechanism by which a final product inhibits an earlier

enzymatic step in its pathway is known as allosteric inhibition.

The allosteric inhibitor combines with a part of the enzyme at

a location other than the active site. This causes the active site

to change shape so that it can no longer combine properly with

its substrate.

Inborn Errors of Metabolism

Because each different polypeptide in the body is coded by

a different gene (chapter 3), each enzyme protein that par-

ticipates in a metabolic pathway is coded by a different gene.

An inherited defect in one of these genes may result in a

disease known as an inborn error of metabolism. In this

type of disease, the quantity of intermediates formed prior

to the defective enzymatic step increases, and the quantity

of intermediates and final products formed after the defec-

tive step decreases. Diseases may result from deficiencies of

the normal end product or from excessive accumulation of

intermediates formed prior to the defective step. If the defec-

tive enzyme is active at a step that follows a branch point in a

Although some enzymatic reactions are not directly
reversible, the net effects of the reactions can be reversed by
the action of different enzymes. Some of the enzymes that con-
vert glucose to pyruvic acid, for example, are different from
those that reverse the pathway and produce glucose from pyru-
vic acid. Likewise, the formation and breakdown of glycogen
(a polymer of glucose; see fig. 2.15) are catalyzed by different
enzymes.

Metabolic Pathways

The many thousands of different types of enzymatic reactions
within a cell do not occur independently of each other. They
are, rather, all linked together by intricate webs of interrela-
tionships, the total pattern of which constitutes cellular metab-
olism. A sequence of enzymatic reactions that begins with an
initial substrate, progresses through a number of intermedi-
ates, and ends with a final product is known as a metabolic
pathway.
The enzymes in a metabolic pathway cooperate in a man-
ner analogous to workers on an assembly line, where each con-
tributes a small part to the final product. In this process, the
product of one enzyme in the line becomes the substrate of the
next enzyme, and so on ( fig. 4.7 ).
Few metabolic pathways are completely linear. Most are
branched so that one intermediate at the branch point can serve
as a substrate for two different enzymes. Two different prod-
ucts can thus be formed that serve as intermediates of two
pathways ( fig.  4.8 ). Generally, certain key enzymes in these
pathways are subject to regulation, so that the direction taken
by the metabolic pathways can be changed at different times
by the activation or inhibition of these enzymes.

CLINICAL APPLICATION

Gene therapy has made impressive strides over the past

several years. First, severe combined immunodeficiency

disease, a fatal disease that produces a deficiency in the

adenosine deaminase enzyme, was successfully treated.

Next, two other diseases, including adrenoleukodystrophy,

which is produced by an X-linked gene and causes demy-

elination of neurons, were treated by gene therapy. More

recently, gene therapy has been successful in treating two

other diseases, including metachromatic leukodystrophy.

This disease is caused by a lysosomal enzyme deficiency

that produces an excessive accumulation of a toxic mole-

cule, resulting in demyelination of neurons. These and other

gene therapies involve introducing the normal gene into

a particular virus, which then inserts its genome into host

cells of the patient. The newly transformed cells are now

able to produce the correct protein. Although these clini-

cal trials appear successful, there remains a concern that

the introduced viral carrier, or vector, of the gene might also

activate cancer-causing genes of the host.